Non-Syndromic X-Linked Intellectual Disability

Genetic MONDO:0019181 Pathograph 28 Show in embeddings browser Non-Syndromic Intellectual Disability X-Linked Intellectual Disability

Non-syndromic X-linked intellectual disability (NS-XLID; historically MRX, and designated IDX in the contemporary family series) is the class of X-linked intellectual disability in which impaired intellectual functioning and adaptive behaviour are the only consistent shared feature. Critically, "non-syndromic" does not mean that every affected individual has isolated intellectual disability - variable speech delay, hypotonia, seizures, autistic traits, or minor dysmorphism may coexist - it means that no additional feature is reproducible across the families or disorders carrying the label. It is the third member of the non-syndromic intellectual-disability trio alongside the autosomal dominant and autosomal recessive classes, and is distinguished from both by its inheritance architecture: hemizygous males express a single mutant X allele in every cell, while heterozygous females express it only in the cells where the mutant X remains active, and are typically unaffected or mildly affected. That asymmetry, together with the reproducible male excess among people with intellectual disability (approximately 1.3-1.4 to 1), made X-linked defects the classical explanation for the sex-ratio imbalance and concentrated three decades of gene discovery on a single chromosome - one that carries about 5% of the human genome but about 15% of known intellectual-disability genes. Two structural facts define the class. First, it is extremely genetically heterogeneous while being clinically homogeneous: families were numbered by linkage interval (MRX1, MRX2, ...) rather than by phenotype, because there was no phenotype to distinguish them, and each individual gene accounts for only a small percentage of cases. Of 105 non-syndromal families assigned IDX numbers, 67 have a cloned gene, 33 are mapped without an identified gene, and 5 remain unpublished. Second, the boundary with the syndromic (MRXS) class is unstable and, on the authoritative view, blurred and sometimes arbitrary: 28 of the IDX genes are also associated with XLID syndromes, genes first reported as causing pure MRX acquire recognisable features once larger series are phenotyped, and allelic series place non-syndromic and severely syndromic phenotypes at opposite ends of one gene's mutation spectrum. ARX is the canonical example, spanning nonsyndromal XLID at one end and lissencephaly with abnormal genitalia at the other. Mechanistically the causal genes do not converge on a single pathway, but they fall repeatedly into a limited set of themes: Rho GTPase signalling to the actin cytoskeleton (PAK3), Rab-dependent synaptic vesicle recycling (GDI1), proposed roles in excitatory synapse formation and neurite outgrowth (IL1RAPL1, TSPAN7), tRNA anticodon-loop modification and translational fidelity (FTSJ1), lipid metabolism (ACSL4), Golgi pH regulation and glycosylation (SLC9A7), and telencephalic transcriptional control (ARX). The unifying pathology is a functional lesion of synaptic plasticity in an anatomically normal brain - a mis-tuned rather than a mis-built or damaged circuit - which is why neuroimaging is characteristically unremarkable. The class is conventionally described as static rather than progressive, though no source cited in this entry quantifies its temporal course. A critical caveat governs curation of this class. Because genes were nominated from small families before large population control sets existed, a systematic reassessment against 10,563 control X chromosomes challenged 25 of the 106 genes then accepted; as of the 2017 update, 17 of those 25 remain unresolved. Gene lists for this class published before roughly 2013 should not be treated as settled.

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Inheritance

X-linked HP:0001417

Causal variants lie on the X chromosome. Hemizygous males carry a single copy of the mutant allele with no second copy to compensate and are fully affected; heterozygous females are usually unaffected or only mildly affected, because random X-chromosome inactivation makes them mosaic for expression of the mutant allele. In several subtypes carrier females show completely skewed X-inactivation that silences the mutant X and confers additional protection. There is no male-to-male transmission. Large multiplex pedigrees showing this segregation pattern were the substrate for the linkage studies that defined the numbered MRX/IDX series, and the relative ease of ascertaining such families is why X-linked intellectual disability was delineated far ahead of its autosomal counterparts.

X-linked inheritance Expressivity: VARIABLE

Show evidence (3 references)

PMID:38424476 SUPPORT Human Clinical

"This is because most genes on the X chromosome are subject to random X chromosome inactivation (XCI) during early embryonic development, which results in a mosaic pattern of gene expression for a given X-linked mutant allele."

Establishes the mosaic-expression mechanism that makes heterozygous females variably and usually mildly affected relative to hemizygous males.

PMID:11889465 SUPPORT Human Clinical

"All carrier females with either point mutations or genomic deletions in FACL4 showed a completely skewed X-inactivation, suggesting that the gene influences survival advantage."

Documents the completely skewed X-inactivation that spares carrier females, using the ACSL4/FACL4 subtype as the worked example.

PMID:22482801 SUPPORT Human Clinical

"Progress in delineating XLID has far outpaced the efforts to understand the genetic basis for autosomal intellectual disability. In large measure, this has been because of the relative ease of identifying families with XLID and finding the responsible mutations"

Explains why this class was characterised ahead of its autosomal counterparts: X-linked segregation makes multiplex families straightforward to ascertain.

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Subtypes

Intellectual disability, X-linked 21 (IL1RAPL1) MONDO:0010256

IL1RAPL1 hgnc:5996

Deletions and loss-of-function point variants in IL1RAPL1 at Xp22.1-21.3, encoding an interleukin-1 receptor accessory protein family member highly expressed in postnatal hippocampus. The founding report explicitly describes patients with cognitive impairment only, one of the clearest original descriptions in the class - though see the caveat below on later families. IL1RAPL1 is understood to act in excitatory synapse formation, though the cited primary report establishes only its hippocampal expression and infers a role in memory and learning. Later series identified behavioural problems and mild dysmorphism in some families, illustrating the instability of the non-syndromic label.

Show evidence (3 references)

PMID:10471494 SUPPORT Human Clinical

"Non-overlapping deletions and a nonsense mutation in this gene were identified in patients with cognitive impairment only."

Establishes the IL1RAPL1 subtype and, critically, its purely non-syndromic presentation - cognitive impairment as the sole feature.

PMID:10471494 SUPPORT Model Organism

"Its high level of expression in post-natal brain structures involved in the hippocampal memory system suggests a specialized role for this new gene in the physiological processes underlying memory and learning abilities."

Links the subtype to hippocampal learning circuitry, the anatomical substrate shared across the class. Tagged MODEL_ORGANISM: the expression analysis is animal tissue work (the paper's MeSH terms include Mice), and the role in memory and learning is the authors' inference from that expression pattern rather than a demonstrated function.

PMID:21484992 SUPPORT Human Clinical

"We have identified an additional two families with deletions of a portion of the gene that give rise to cognitive impairment, as well as some behavioral problems and mild dysmorphism."

Documents phenotypic expansion beyond pure cognitive impairment, supporting the subtype while qualifying the strictness of its non-syndromic classification.

Intellectual disability, X-linked 30 (PAK3) MONDO:0010361

PAK3 hgnc:8592

Truncating variants in PAK3 (p21-activated kinase) at Xq22, identified in the multiplex MRX30 pedigree. PAK3 couples Rho family GTPases to actin cytoskeletal reorganisation in postmitotic cortical and hippocampal neurons, and this subtype anchors the Rho GTPase theme that recurs across the class. MRI was normal in affected individuals - the imaging correlate of a functional rather than structural lesion.

Show evidence (2 references)

PMID:9731525 SUPPORT Human Clinical

"Affected individuals in a multiplex pedigree with MRX (MRX30), previously mapped to Xq22, show a point mutation in the PAK3 (p21-activated kinase) gene, which encodes a serine-threonine kinase."

Establishes the PAK3 lesion defining the MRX30 subtype.

PMID:9731525 SUPPORT Human Clinical

"MRI analysis showed no gross defects in brain development."

Documents the absence of structural brain malformation that distinguishes non-syndromic from malformative X-linked intellectual disability.

Intellectual disability, X-linked 41 (GDI1) MONDO:0010451

GDI1 hgnc:4226

Missense and null variants in GDI1, encoding alpha-GDI (Rab GDP dissociation inhibitor), which recycles Rab GTPases for synaptic vesicle traffic; the L92P allele reduces RAB3A binding and recycling. One of the purest non-syndromic exemplars in the class - a large German multiplex family had neither abnormal body measurements nor any other significant clinical problem, and the authors concluded that a clinical diagnosis of GDI1-associated disease is impossible.

Show evidence (3 references)

PMID:9620768 SUPPORT Human Clinical

"We have found mutations in the GDI1 gene (which encodes uGDI) in two families affected with X-linked non-specific mental retardation. One of the mutations caused a non-conservative substitution (L92P) which reduced binding and recycling of RAB3A, the second was a null mutation."

Establishes the GDI1 subtype and its Rab-recycling mechanism.

PMID:22002931 SUPPORT Human Clinical

"the affected male family members had nonsyndromic intellectual disability, that is, they had neither abnormal body measurements nor any other significant clinical problems"

Confirms the strictly non-syndromic presentation of this subtype in an independent multiplex family.

PMID:22002931 SUPPORT Human Clinical

"The present family supports the lack of additional phenotypic features in patients with GDI1 mutations, rendering a clinical diagnosis of GDI1-associated XLID impossible."

States the diagnostic consequence that defines the whole class - with no distinguishing features, molecular testing rather than clinical recognition is the only route to diagnosis.

Intellectual disability, X-linked 58 (TSPAN7/TM4SF2) MONDO:0010266

TSPAN7 hgnc:11854

TSPAN7 (formerly TM4SF2) at Xp11.4, first implicated through an X;2 balanced translocation that disrupted the gene, then confirmed by point variants in MRX families. Encodes a tetraspanin that complexes with beta-1 integrins and is implicated in the control of neurite outgrowth, contributing to the synapse-formation theme.

Show evidence (2 references)

PMID:10655063 SUPPORT Human Clinical

"Here we show that the gene TM4SF2 at Xp11.4 is inactivated by the X breakpoint of an X;2 balanced translocation in a patient with MR. Further investigation led to identification of TM4SF2 mutations in 2 of 33 other MRX families."

Establishes the TSPAN7/TM4SF2 subtype through two independent lines of genetic evidence.

PMID:10655063 SUPPORT In Vitro

"TM4SF2 encodes a member of the tetraspanin family of proteins, which are known to contribute in molecular complexes including beta-1 integrins. We speculate that through this interaction, TM4SF2 might have a role in the control of neurite outgrowth."

Assigns the subtype to the neurite-outgrowth/synapse-formation theme; marked PARTIAL because the source explicitly frames the mechanism as speculation.

Intellectual disability, X-linked 9 (FTSJ1) MONDO:0010660

FTSJ1 hgnc:13254

Loss-of-function variants in FTSJ1, the human TRM7 homolog, which 2'-O-methylates positions C32 and G34 of the tRNA anticodon loop. Patient cell lines almost completely lack Cm32 and Gm34 on tRNA-Phe. Places translational fidelity - rather than synaptic structure - in the mechanistic theme set for this class, and provides a directly measurable molecular readout, unusual for non-syndromic intellectual disability.

Show evidence (2 references)

PMID:26310293 SUPPORT In Vitro

"Mutations in human FTSJ1, the likely TRM7 homolog, cause nonsyndromic X-linked intellectual disability (NSXLID), but the role of FTSJ1 in tRNA modification is unknown."

Establishes FTSJ1 as a non-syndromic X-linked intellectual disability gene.

PMID:26310293 SUPPORT In Vitro

"we report that tRNA(Phe) from two genetically independent cell lines of NSXLID patients with loss-of-function FTSJ1 mutations nearly completely lacks Cm32 and Gm34 , and has reduced peroxywybutosine (o2yW37 )"

Provides the direct biochemical consequence of FTSJ1 loss in patient cells, grounding the tRNA-modification mechanism.

Intellectual disability, X-linked 63 (ACSL4/FACL4) MONDO:0010313

ACSL4 hgnc:3571

Null variants in ACSL4 (FACL4), encoding fatty acid-CoA ligase 4, mapped to Xq22.3 by comparing deletion extents between contiguous-gene ATS-MR patients and Alport-only patients. The first gene to link non-syndromic intellectual disability to fatty-acid metabolism, and the subtype in which complete X-inactivation skewing in carrier females is best documented.

Show evidence (2 references)

PMID:11889465 SUPPORT Human Clinical

"Here we report the identification of two point mutations, one missense and one splice-site change, in the gene FACL4 in two families with nonspecific mental retardation."

Establishes the ACSL4/FACL4 subtype in non-specific (non-syndromic) X-linked intellectual disability.

PMID:11889465 SUPPORT Human Clinical

"FACL4 is the first gene shown to be involved in nonspecific mental retardation and fatty-acid metabolism."

Places lipid metabolism in the mechanistic theme set for this class.

FRAXE intellectual disability (AFF2/FMR2) MONDO:0010659

AFF2 hgnc:3776

CCG repeat expansion and consequent methylation-mediated silencing of AFF2 (FMR2) at the FRAXE folate-sensitive fragile site in Xq28. Mechanistically the repeat-expansion member of the class and the closest non-syndromic counterpart to fragile X syndrome, from which it is distinguished by a milder cognitive phenotype without the fragile X somatic features. AFF2 is among the genes found in non-syndromal families that were never assigned an IDX number.

Show evidence (4 references)

PMID:8673086 SUPPORT Human Clinical

"Mild mental retardation without consistent physical findings has been found associated with expanded CCG repeats at FRAXE."

Establishes both defining properties of this subtype in one statement: the repeat-expansion mechanism, and the non-syndromic phenotype (mild impairment WITHOUT consistent physical findings), which is what qualifies it for this entry.

PMID:8673086 SUPPORT Human Clinical

"We have identified a large gene (FMR2) transcribed distally from the CpG island at FRAXE, and down-regulated by repeat expansion and methylation."

Provides the methylation-mediated silencing mechanism asserted in this subtype's description, which the sequence-variant evidence cited elsewhere does not cover.

PMID:8673086 SUPPORT Human Clinical

"FRAXA expansion results in fragile X syndrome due to down regulation of expression of the FMR1 gene"

Grounds the contrast with fragile X syndrome drawn in this subtype's description - the two are parallel folate-sensitive fragile-site expansions with different genes and different phenotypic severity.

+ 1 more reference

Intellectual disability, X-linked, with or without seizures (ARX) MONDO:0010317

ARX hgnc:18060

The non-syndromic end of the ARX allelic series. ARX encodes an Aristaless-related homeobox transcription factor expressed specifically in telencephalon and ventral thalamus. Polyalanine-tract expansions and certain missense alleles produce intellectual disability with or without seizures and no detectable brain malformation, and account for nine separately numbered nonsyndromal IDX families. Other alleles in the same gene cause distinct syndromic entities (X-linked lissencephaly with abnormal genitalia, Partington syndrome, West and Ohtahara syndromes, Proud syndrome) that are deliberately NOT modelled here. This subtype is therefore the worked example of why the syndromic/non-syndromic boundary in this class is a property of the allele rather than of the gene.

Show evidence (4 references)

PMID:11971879 SUPPORT Human Clinical

"Inherited and de novo ARX mutations, including missense mutations and in frame duplications/insertions leading to expansions of polyalanine tracts in ARX, were found in nine familial and one sporadic case of MR."

Establishes the ARX allelic spectrum, including the polyalanine expansions associated with the milder non-syndromic end of the series.

PMID:11971879 SUPPORT Human Clinical

"The absence of detectable brain malformations in patients suggests that ARX may have an essential role, in mature neurons, required for the development of cognitive abilities."

Confirms the non-syndromic, non-malformative presentation of these ARX alleles, distinguishing them from the lissencephaly-causing alleles in the same gene.

PMID:29696803 SUPPORT Human Clinical

"This is not the case for ARX variants, which have been found in the disparate phenotypes of Partington syndrome, West syndrome, X-linked lissencephaly with abnormal genitalia, hydranencephaly with abnormal genitalia, Proud syndrome, Ohtahara syndrome as well as nonsyndromal XLID (IDX 29, 32, 33,..."

Documents that ARX spans both syndromic entities and nine separately numbered nonsyndromal IDX families, which is the basis for modelling only the nonsyndromal arm here.

+ 1 more reference

Intellectual disability, X-linked 1 (IQSEC2) MONDO:0010656

IQSEC2 hgnc:29059

The founding entity of the whole numbered series: MRX1 is the family mapped in 1988 that gave the series its first number, and its causal gene was not identified until X-chromosome exome resequencing reached it in 2010. IQSEC2 encodes a guanine nucleotide exchange factor for the ADP-ribosylation factor family of small GTPases, placing this subtype in the same small-GTPase-signalling theme as PAK3 and RAB39B rather than in a pathway of its own. Three further X-linked intellectual disability families carried IQSEC2 variants in the same study. Two cautions apply to this row. First, MONDO merges the former MRX78 into this term and carries "IQSEC2-related syndromic intellectual disability" among its exact synonyms, so the label under which a given patient is reported varies. Second, the allelic spectrum reaches well beyond pure intellectual disability - the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel curates IQSEC2 against "X-linked complex neurodevelopmental disorder" rather than against this class. This row records the non-syndromic arm that OMIM and MONDO still number as XLID1, exactly as the ARX row records one arm of a wider allelic series.

Show evidence (2 references)

PMID:20473311 SUPPORT Human Clinical

"The first family identified as having a nonsyndromic intellectual disability was mapped in 1988. Here we show that a mutation of IQSEC2, encoding a guanine nucleotide exchange factor for the ADP-ribosylation factor family of small GTPases, caused this disorder."

Establishes IQSEC2 as the causal gene of the index MRX1 family and states the non-syndromic presentation and the GEF function on which this row rests.

PMID:20473311 SUPPORT Human Clinical

"In addition to MRX1, IQSEC2 mutations were identified in three other families with X-linked intellectual disability."

Provides the independent families beyond the index pedigree, which is what distinguishes a gene assignment from a single-family observation in this class.

Intellectual disability, X-linked 19 (RPS6KA3) MONDO:0010447

RPS6KA3 hgnc:10432

The attenuated, non-syndromic arm of the RPS6KA3 (RSK2) allelic series, whose severe arm is Coffin-Lowry syndrome - curated separately in dismech as Coffin-Lowry_Syndrome (MONDO:0010561). RSK2 is a serine-threonine kinase, and the variants reported in this arm are single-amino-acid deletions and a missense change in the protein's proximal domain, similar in kind to Coffin-Lowry alleles; two of the three reported families had been given a non-syndromic clinical diagnosis, and in the third Coffin-Lowry had been suspected but the features were atypical and the intellectual disability much milder than expected. The clinically important consequence, and the reason the row is worth modelling separately, is diagnostic: the reporting authors conclude that strict reliance on classical clinical criteria for mutation testing may result in a missed diagnosis. ClinGen's Intellectual Disability and Autism Gene Curation Expert Panel curates RPS6KA3 only against Coffin-Lowry syndrome, so this arm has no separate expert-panel classification.

Show evidence (2 references)

PMID:17100996 SUPPORT Human Clinical

"We describe three families with X-linked mental retardation, two with a deletion of a single amino acid and one with a missense mutation in the proximal domain of the RSK2(RPS6KA3) (ribosomal protein S6 kinase, 90 kDa, polypeptide 3) protein similar to mutations found in Coffin-Lowry syndrome (CLS)."

Establishes the allele class of this arm and its relation to the Coffin-Lowry allele spectrum in the same gene.

PMID:17100996 SUPPORT Human Clinical

"In two families, the clinical diagnosis had been nonsyndromic X-linked mental retardation."

States the non-syndromic clinical assignment that places this arm in this class rather than under Coffin-Lowry syndrome.

Intellectual disability, X-linked 50 (SYN1) MONDO:0010251

SYN1 hgnc:11494

A missense variant in SYN1, encoding the presynaptic phosphoprotein synapsin I, segregating in the MRX50 family, in which intellectual disability is the sole clinical manifestation in every affected member - which makes this one of the strictest non-syndromic rows in the entry. SYN1 regulates neurotransmitter release and neuronal development, so the subtype belongs to the synaptic-vesicle theme alongside GDI1 and TSPAN7. It is a distinct allelic entity from the SYN1 epilepsy/autism disorder (MONDO:0010339), which dismech curates separately as SYN1-Related_Disorder: the authors of this report make exactly that point, noting that distinct SYN1 mutations may lead to distinct brain pathologies. ClinGen's Intellectual Disability and Autism Gene Curation Expert Panel lumps SYN1 under "X-linked complex neurodevelopmental disorder" and does not curate this arm separately.

Show evidence (2 references)

PMID:28973667 SUPPORT Human Clinical

"We identified a missense mutation (c.236 C > G; p.S79W) in the SYN1 gene coding for synapsin I in the MRX50 family, affected by non-syndromic X-linked intellectual disability."

Ties the causal gene and allele directly to the numbered MRX50 family and to the non-syndromic designation this row carries.

PMID:28973667 SUPPORT Human Clinical

"The S79W mutation segregates with the disease in the MRX50 family and all affected members display intellectual disability as sole clinical manifestation."

The explicit statement of sole-feature presentation, which is the defining criterion for membership of this class.

Intellectual disability, X-linked 72 (RAB39B) MONDO:0010289

RAB39B hgnc:16499

Null alleles of RAB39B, a neuronal-specific small GTPase of the Golgi compartment, identified in two male patients - one of them in the MRX72 family, where a 5' splice-site change abolished normal splicing. Its downregulation alters neurite growth cone number and morphology and reduces presynaptic boutons, placing the subtype in the vesicular trafficking theme. Intellectual disability was accompanied by autism spectrum disorder, epileptic seizures and macrocephaly in some, not all, affected family members, which is the variable-comorbidity pattern this class tolerates rather than a reproducible syndromic signature. The row carries a live caveat: the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel curates RAB39B as Definitive against an early-onset parkinsonism-intellectual disability syndrome (MONDO:0010709), a separate MONDO term with no dismech entry, rather than against this one. Parkinsonism is not reported in the founding MRX72 publication, so the two entities are separated here by phenotype and age of onset rather than by allele, and this row should not be read as covering the parkinsonism entity.

Show evidence (3 references)

PMID:20159109 SUPPORT Human Clinical

"A second mutation, in the MRX72 family, altered the 5' splice site (c.215+1G > A) and normal splicing."

Ties RAB39B to the numbered MRX72 family that this subtype term denotes, and states the allele class.

PMID:20159109 SUPPORT Human Clinical

"Mutations segregate with the disease in the families, and in some family members intellectual disabilities were associated with autism spectrum disorder, epileptic seizures, and macrocephaly."

Documents the associated features and, critically for the scope call, that they occur in only some family members rather than reproducibly.

PMID:20159109 SUPPORT In Vitro

"Its downregulation leads to an alteration in the number and morphology of neurite growth cones and a significant reduction in presynaptic buttons, suggesting that RAB39B is required for synapse formation and maintenance."

Supplies the cellular mechanism linking this gene to the entry's shared synaptic endpoint.

Intellectual disability, X-linked 90 (DLG3) MONDO:0010452

DLG3 hgnc:2902

Truncating variants in DLG3, which encodes synapse-associated protein 102 (SAP102), found in 4 of 329 families screened for moderate to severe X-linked intellectual disability - among the higher per-gene yields in the class. SAP102 is a membrane-associated guanylate kinase localised to the postsynaptic density of excitatory synapses, whose PDZ domains bind the NR2 subunits of the NMDA receptor. Every reported allele truncates within or before the third PDZ domain, so the proposed mechanism is loss of NMDA receptor targeting and downstream signalling, which is the most direct molecular route to the impaired synaptic plasticity this entry models as the shared endpoint. Together with SYP this is one of only two genes in the whole checklist that the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel curates against this entry's own MONDO term rather than against a broader neurodevelopmental anchor, and it holds the Definitive classification.

Show evidence (2 references)

PMID:15185169 SUPPORT Human Clinical

"We have identified truncating mutations in the human DLG3 (neuroendocrine dlg) gene in 4 of 329 families with moderate to severe X-linked mental retardation."

Establishes the gene assignment and gives the per-cohort yield quoted in this row's description.

PMID:15185169 SUPPORT Human Clinical

"The mutations identified in this study all introduce premature stop codons within or before the third PDZ domain, and it is likely that this impairs the ability of SAP102 to interact with the NMDA receptor and/or other proteins involved in downstream NMDA receptor signaling pathways."

Supplies the allele class and the proposed loss-of-function mechanism at the NMDA receptor, stated by the authors as a likelihood rather than a demonstration.

Intellectual disability, X-linked 96 (SYP) MONDO:0010429

SYP hgnc:11506

SYP, encoding synaptophysin, was one of nine genes implicated in X-linked intellectual disability by the systematic resequencing of X-chromosome coding exons in 208 families. Synaptophysin is an integral synaptic vesicle protein accounting for roughly a tenth of total synaptic vesicle protein cargo; four separate SYP variants were found in affected families. Functional follow-up in synaptophysin-knockout mouse neurons showed that the patient variants fail to support efficient retrieval of synaptobrevin II, giving this subtype a defined lesion in the synaptic vesicle cycle. The ClinGen Intellectual Disability and Autism Gene Curation Expert Panel curates SYP against this entry's own MONDO term and classifies the relationship as Moderate, so the gene assignment is supported but not yet definitive.

Show evidence (3 references)

PMID:19377476 SUPPORT Human Clinical

"The screen has discovered nine genes implicated in XLMR, including SYP, ZNF711 and CASK reported here, confirming the power of this strategy."

The primary gene-discovery statement for both this row and the ZNF711 row, from the screen that reported them.

PMID:23966691 SUPPORT BACKGROUND Human Clinical

"Synaptophysin has been implicated in X-linked intellectual disability, with a recent study identifying four separate synaptophysin gene mutations in families affected by the disorder."

Independent restatement of the human genetic finding, giving the number of variant families. Graded HUMAN_CLINICAL for the evidence the sentence describes with quote_role BACKGROUND because the citing paper is a mouse-neuron functional study restating somebody else's human genetics in its introduction.

PMID:23966691 SUPPORT In Vitro

"Two distinct truncating mutants were mislocalized throughout the axon and phenocopied the arrest of sybII retrieval in synaptophysin knock-out cultures."

Functional consequence of the patient alleles in cultured neurons, supplying the mechanism this row attributes to the subtype.

Intellectual disability, X-linked 97 (ZNF711) MONDO:0010430

ZNF711 hgnc:13128

ZNF711 was implicated by the same 208-family X-chromosome resequencing screen that reported SYP, and was subsequently confirmed in two large four-generation pedigrees with eleven affected males, bringing the total to four families. The consistent picture is mild to moderate intellectual disability with poor speech; autistic features and mild facial dysmorphisms occur in some patients but not reproducibly, which is why the reporting authors themselves conclude the phenotype is non-syndromic. Note that this subtype is distinct from contiguous-gene deletions at Xq21 that remove ZNF711 along with neighbouring genes, which dismech models elsewhere as Choroideremia-Deafness-Obesity_Syndrome.

Show evidence (2 references)

PMID:27993705 SUPPORT Human Clinical

"Here, we present two large four-generation families with a total of 11 males affected with ID caused by mutations in ZNF711, thereby expanding the total number of families with ID and a ZNF711 mutation to four."

Gives the replication that carries this gene assignment beyond its single discovery screen, and the family count quoted in the description.

PMID:27993705 SUPPORT Human Clinical

"Patients with mutations in ZNF711 all present with mild to moderate ID and poor speech accompanied by additional features in some patients, including autistic features and mild facial dysmorphisms, suggesting that ZNF711 mutations cause non-syndromic ID."

The authors' own non-syndromic assignment, together with the qualifier that additional features appear only in some patients - the exact distinction this class turns on.

Intellectual disability, X-linked 101 (MID2) MONDO:0010489

MID2 hgnc:7096

A missense variant in MID2, encoding an E3 ubiquitin ligase, reported as the likely cause of X-linked intellectual disability in one large Indian kindred, where it was present in all affected males and obligate carriers and absent from unaffected males and from 200 population controls. The variant abolishes the function of the protein's COS domain, and the mutant protein accumulates in the cytoplasm instead of binding the cytoskeleton. This row rests on a single large pedigree plus one further variant found by screening 480 unrelated individuals, and MID2 has no ClinGen gene-disease validity curation, so the assignment is thinner than most in this entry and is recorded with that caveat. It is the ubiquitin-pathway theme's entry point in the class, and the authors emphasise that the MID2 phenotype differs from that reported for its paralogue MID1.

Show evidence (2 references)

PMID:24115387 SUPPORT Human Clinical

"We report a novel missense mutation (c.1040G>A, p.Arg347Gln) in MID2, which encodes ubiquitin ligase E3, as the likely cause of X-linked mental retardation in a large kindred."

The gene assignment, stated by the authors themselves as a likelihood rather than a certainty - the hedge this row preserves.

PMID:24115387 SUPPORT Human Clinical

"The mutation was observed in all affected and obligate carriers but not in any unaffected males of the family or in population controls (n = 200)."

The segregation and control data that constitute the evidence base for this subtype, and the control count quoted in the description.

Intellectual disability, X-linked 103 (KLHL15) MONDO:0010508

KLHL15 hgnc:29347

KLHL15 was one of seven novel and validated X-linked intellectual disability genes identified by X-exome sequencing of 405 unresolved families - the study that also delivered FRMPD4 and USP27X in this entry. A protein-truncating variant was found in a large family, with further support from an unrelated family carrying a partial KLHL15 deletion. KLHL15 is a kelch-like protein that acts as a substrate adaptor for Cul3-based E3 ubiquitin ligases, targeting a brain-specific regulatory subunit of protein phosphatase 2A for proteasomal degradation, so like MID2 and USP27X it belongs to the ubiquitin-proteasome theme. The phenotype is not uniformly pure: the same report notes a KLHL15 partial deletion described in a proband with severe intellectual disability, epilepsy and cortical developmental anomalies, and KLHL15 has no ClinGen gene-disease validity curation.

Show evidence (2 references)

PMID:25644381 SUPPORT Human Clinical

"In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X)"

The gene-discovery statement underlying this row and the USP27X row, and one of the two independent lines behind the FRMPD4 row.

PMID:25644381 SUPPORT Human Clinical

"Further support for KLHL15 being implicated in XLID comes from an unrelated XLID family, which carries a small deletion that removes part of KLHL15"

The second, independent family that carries this gene assignment past a single observation.

Intellectual disability, X-linked 104 (FRMPD4) MONDO:0010509

FRMPD4 hgnc:29007

Deleterious FRMPD4 variants - an exon deletion, a nonsense change, a frameshift and a conserved-residue missense - in ten affected males from four unrelated families. FRMPD4 is a neural scaffolding protein that binds PSD-95 to promote dendritic spine morphogenesis and regulates mGluR1/5 signalling through Homer, so this subtype sits at the postsynaptic scaffold alongside DLG3. The frameshift allele disrupts binding to both PSD-95 and HOMER1 and fails to increase spine density in transfected hippocampal neurons, and knockout mice show hippocampus-dependent spatial learning deficits. Two qualifications belong on this row: the reporting authors describe the entity as a new X-linked intellectual disability syndrome, with language delay, seizures and behavioural or psychiatric disturbance alongside moderate-to-severe intellectual disability, and the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel curates FRMPD4 as Definitive against "X-linked complex neurodevelopmental disorder" rather than against this class. OMIM and MONDO nonetheless number the entity within the non-syndromic series, and it is recorded here on that basis with the comorbidity stated rather than suppressed. A third point matters for the evidence audit this entry runs on itself: of the fourteen genes admitted in this enumeration pass, FRMPD4 is the only one named in either list that the 2013 reassessment against 10,563 control X chromosomes singles out, and it falls in the fifteen for which replication studies were warranted rather than in the ten whose involvement was questioned. Both reports cited on this row postdate that flag and supply the independent families it asked for.

Show evidence (4 references)

PMID:29267967 SUPPORT Human Clinical

"These mutations were found to be associated with ID in ten affected male patients from four unrelated families, following an apparent X-linked mode of inheritance."

The cohort and inheritance pattern on which the gene assignment rests.

PMID:29267967 SUPPORT Human Clinical

"Clinical features of these patients consisted of moderate to severe ID, language delay and seizures alongside with behavioral and/or psychiatric disturbances."

The phenotype statement behind this row's caveat that the presentation is not confined to isolated intellectual disability.

PMID:29267967 SUPPORT In Vitro

"In-depth functional studies showed that a frame-shift mutation, FRMPD4p.Cys618ValfsX8, results in a disruption of FRMPD4 binding with PSD-95 and HOMER1, and a failure to increase spine density in transfected hippocampal neurons."

The molecular lesion at the postsynaptic scaffold that this row attributes to the subtype.

+ 1 more reference

Intellectual disability, X-linked 105 (USP27X) MONDO:0010510

USP27X hgnc:13486

USP27X, encoding ubiquitin-specific peptidase 27, was identified in the same X-exome screen of 405 unresolved families as KLHL15 and FRMPD4, with a second unrelated family carrying a missense variant substituting a highly conserved tryptophan. The gene's function in neurons is largely uncharacterised - its only known interaction partner is USP22, required for glial and neuronal development in flies - so this subtype currently has a gene assignment without a worked-out mechanism, and the entry wires it to the class's shared convergent node rather than to a specific pathway. The ClinGen Intellectual Disability and Autism Gene Curation Expert Panel classifies USP27X as Moderate against "X-linked complex neurodevelopmental disorder".

Show evidence (2 references)

PMID:25644381 SUPPORT Human Clinical

"In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X)"

The gene-discovery statement that assigns USP27X to this class.

PMID:25644381 SUPPORT Human Clinical

"The unrelated family L75 with four affected males (Figure 2f) carries a potentially deleterious missense variant in USP27X, which substitutes a highly conserved tryptophane by a histidine residue"

The second family behind this assignment, quoted with the authors' own "potentially deleterious" hedge preserved.

Intellectual developmental disorder, X-linked 108 (SLC9A7) MONDO:0026723

SLC9A7 hgnc:17123

A recurrent missense variant (p.Leu515Phe) in the alkali cation/proton exchanger SLC9A7, segregating with multigenerational non-syndromic intellectual disability in two unrelated families. SLC9A7 resides in the trans-Golgi network and post-Golgi vesicles; the mutant protein is correctly targeted but alkalinises those compartments and impairs N-linked oligosaccharide maturation of exported cargo, which the authors read as a gain of function. Unusually for a class defined by the absence of biochemical features, it comes with a laboratory readout: patient sera show an abnormal transferrin N-glycosylation profile, the standard diagnostic marker for congenital disorders of glycosylation. SLC9A7 has no ClinGen gene-disease validity curation.

Show evidence (2 references)

PMID:30335141 SUPPORT Human Clinical

"We report two unrelated families with multigenerational nonsyndromic intellectual disability (ID) segregating with a recurrent de novo missense variant (c.1543C>T:p.Leu515Phe) in the alkali cation/proton exchanger gene SLC9A7 (also commonly referred to as NHE7)."

Establishes the gene, the recurrent allele, the two-family segregation and the explicitly non-syndromic presentation.

PMID:30335141 SUPPORT In Vitro

"This correlated with alkalinization of the TGN/post-Golgi compartments, suggestive of a gain-of-function."

The functional consequence, quoted with the authors' own "suggestive" hedge on the gain-of-function reading.

Intellectual developmental disorder, X-linked 110 (FGF13) MONDO:0859086

FGF13 hgnc:3670

A single-nucleotide variant in the 5' untranslated region of FGF13, shared by three male children with severe intellectual disability in a screen of Chinese Han children. The mechanism is translational rather than coding: the variant reduces FGF13 translation by weakening the interaction between the 5' UTR and polypyrimidine-tract-binding protein 2, and FGF13 protein stabilises microtubules in developing neurons. Mice carrying the homologous point mutation show delayed neuronal migration during cortical development and weakened learning and memory. This row rests on one report of three male children plus its mouse model, with no ClinGen gene-disease validity curation and no independent replicating family found by a PubMed title search on FGF13 combined with intellectual disability, mental retardation or neurodevelopmental (run 2026-09-23), which returns this report alone. It is therefore the thinnest gene assignment admitted to the entry and should be revisited when a second cohort is published.

Show evidence (2 references)

PMID:34184986 SUPPORT Human Clinical

"We screened gene mutations in Chinese Han children suffering from severe ID and found a single-nucleotide polymorphism (SNP) in the 5'-untranslated region (5'-UTR) of fibroblast growth factor 13 (FGF13) mRNA (NM_001139500.1:c.-32c>G) shared by three male children."

The whole human evidence base for this subtype, stated with its cohort size, which is why the description carries an explicit thinness caveat.

PMID:34184986 SUPPORT Model Organism

"Mice carrying the homologous point mutation in 5'-UTR of Fgf13 showed delayed neuronal migration during cortical development, and weakened learning and memory."

The in vivo support for causality of the same allele, graded MODEL_ORGANISM because the experiment is a mouse knock-in.

Intellectual developmental disorder, X-linked 112 (ZMYM3) MONDO:0957496

ZMYM3 hgnc:13054

Protein-altering variants in ZMYM3, a transcriptional coregulator and component of the KDM1A-RCOR1 chromatin-modifying complex, in a MatchMaker Exchange cohort of 27 individuals - the largest cohort behind any row in this entry. Almost all variants are missense, several recurring at the same two residues, and a ChIP-seq experiment on one of them shows dramatically reduced genomic occupancy consistent with a hypomorphic effect. This places the subtype in the transcriptional-control theme alongside ARX and ZNF711 rather than at the synapse. The reported phenotype includes developmental delay, intellectual disability and behavioural abnormalities, with a specific facial gestalt in a subset of males only; the authors state that they cannot perform statistical evaluations to definitively support causation and rest the case on the totality of the evidence, and ZMYM3 has no ClinGen gene-disease validity curation.

Show evidence (3 references)

PMID:36586412 SUPPORT Human Clinical

"Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome."

Establishes the gene, its molecular class and the cohort size quoted in the description.

PMID:36586412 SUPPORT Human Clinical

"Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males."

The phenotype, including the qualifier that the facial gestalt appears in only a subset - the basis for admitting this term to the non-syndromic class as MONDO and OMIM do.

PMID:36586412 SUPPORT Computational

"ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex."

The constraint and expression argument supporting pathogenicity, graded COMPUTATIONAL because population-constraint intolerance is derived from in-silico analysis of variation databases.

Discussions and Knowledge Gaps

Which of the genes historically assigned to non-syndromic X-linked intellectual disability are genuinely causal, given that many were nominated from small families before large population control sets were available?

KNOWLEDGE GAP questioned_xlid_gene_assignments

Attached to

pathophysiology#X-Linked Gene Disruption

Gene lists for this class carry an unusual historical liability. Genes were nominated by linkage in individual families at a time when systematic sequencing of control X chromosomes was not possible, so rare non-disease-causing variants could not be excluded. When 106 proposed XLID genes were reassessed against 10,563 control X chromosomes from the NHLBI Exome Sequencing Project, ten were specifically questioned because truncating or previously published variants occurred at appreciable frequency in controls, and a further fifteen were flagged as requiring replication. The 2017 authoritative update revisited those 25 challenged genes: none of the five highly questionable assignments has been confirmed, only ATP6AP2 of the five questionable ones has been confirmed, and additional cases have been published for seven of the fifteen needing replication - leaving 17 of the 25 still unresolved. This directly affects curation of this entry: AGTR2 in particular is frequently cited in older reviews as a non-syndromic XLID gene and is among the questioned set, so it is deliberately not modelled as a subtype here. Any gene list for this class drawn from literature predating the reassessment should be treated as provisional.

Proposed experiments

Re-evaluation of questioned XLID genes against contemporary population databases

reassess_questioned_xlid_genes_gnomad

Repeat the control-frequency reassessment against gnomAD-scale population data, which offers far more X chromosomes than the NHLBI cohort, and combine with independent replication cohorts and functional assays for the genes still flagged as requiring replication.

Show evidence (4 references)

PMID:23871722 SUPPORT Human Clinical

"We used this NHLBI cohort to systematically reassess the implication of 106 genes proposed to be involved in monogenic forms of XLID. We particularly question the implication in XLID of ten of them (AGTR2, MAGT1, ZNF674, SRPX2, ATP6AP2, ARHGEF6, NXF5, ZCCHC12, ZNF41, and ZNF81), in which..."

Names the specific genes whose causal role in this class is in doubt, including AGTR2, ZNF41, and ARHGEF6, which appear in older MRX gene lists.

PMID:23871722 SUPPORT Human Clinical

"Nonetheless, the boundary between true mutations and rare non-disease-causing variants often remains elusive. The sequencing of a large number of control X chromosomes, required for avoiding false-positive results, was not systematically possible in the past."

Explains the methodological reason this class accumulated false-positive gene assignments.

PMID:29696803 SUPPORT Human Clinical

"Of the 15 assignments in need of replication, additional cases with MAOA, HCFC1, CCDC22, CNKSR2, KIAA2022, NAA10 and SHROOM4 sequence variants have now been published, leaving 17 of the 25 challenged genes unresolved."

Gives the current resolution status of the challenged genes - the direct measure of how much of this gap remains open.

+ 1 more reference

Is "non-syndromic" a stable property of a gene, or an artefact of limited phenotyping and allele sampling?

KNOWLEDGE GAP syndromic_nonsyndromic_boundary_stability

Attached to

pathophysiology#Static Cognitive Impairment Without Structural Brain Malformation

The class boundary moves in both directions and is explicitly described in the authoritative update as blurred, sometimes arbitrary, and difficult to defend biologically - retained mainly for historical continuity. IL1RAPL1 was reported as causing cognitive impairment only, but later families showed behavioural problems and mild dysmorphism. ARX shows the converse within a single gene: polyalanine expansions give a non-syndromic phenotype across nine numbered IDX families while other alleles cause lissencephaly with abnormal genitalia, Partington, West, and Ohtahara syndromes. Twenty-eight IDX genes are also associated with XLID syndromes. Whether a given gene stays in this class therefore depends on how many patients have been phenotyped, how deeply, and which alleles they carry - not on a fixed biological property. This matters for the KB because membership of this entry is provisional for several subtypes, and it is the reason FGD1, ZDHHC9, and OPHN1, which are named in older non-syndromic gene lists but map to explicitly syndromic MONDO entities, are excluded here.

Show evidence (4 references)

PMID:29696803 SUPPORT Human Clinical

"Even though the line dividing the two classes is blurred, sometimes arbitrary and difficult to defend from a biological standpoint, it has by now acquired quasi-historical value and deserves to be retained."

The authoritative statement that the syndromic/non-syndromic distinction is retained for historical rather than biological reasons - the core of this knowledge gap.

PMID:31898314 SUPPORT Human Clinical

"Nevertheless, new advances on the study of these entities have showed that this classification is not always clear-cut because distinct variants in several of these XLID genes can result in S-XLID as well as in NS-XLID."

States the allele-level mechanism behind the unstable boundary directly: it is the variant, not the gene, that determines which class a case falls into. This is the evidential basis for admitting only the non-syndromic arm of the ARX allelic series.

PMID:21484992 SUPPORT Human Clinical

"Our clinical findings better delineate the phenotypic spectrum associated with IL1RAPL1 mutations."

Demonstrates phenotypic expansion of a subtype originally described as purely non-syndromic.

+ 1 more reference

What is the population prevalence of non-syndromic X-linked intellectual disability as distinct from X-linked intellectual disability as a whole?

KNOWLEDGE GAP nonsyndromic_xlid_group_level_prevalence

Attached to

pathophysiology#X-Linked Gene Disruption

The prevalence figures recorded on this entry - approximately 1 in 600 males, and 5-10% of intellectual disability in males - are for X-linked intellectual disability overall, syndromic and non-syndromic combined. No robust population prevalence or incidence exists for the non-syndromic class alone, because it aggregates many individually rare gene-defined disorders whose ascertainment has historically depended on the availability of large multiplex pedigrees. This is a genuine measurement gap rather than a curation omission, and the recorded rates should not be presented as if MONDO:0019181 were a uniform entity with its own prevalence.

Proposed experiments

Population-scale sequencing estimate of non-syndromic XLID prevalence

population_scale_nsxlid_prevalence

Estimate class prevalence from unselected population-scale exome or genome cohorts with linked phenotype data, ascertaining on validated causal variants in confirmed non-syndromic XLID genes rather than on pedigree structure, which avoids the multiplex-family ascertainment bias that inflates familial forms.

Show evidence (2 references)

PMID:10655063 SUPPORT Human Clinical

"X-linked forms of mental retardation (MR) affect approximately 1 in 600 males and are likely to be highly heterogeneous."

The available rate is explicitly for X-linked forms as a whole, not the non-syndromic class, which is the substance of this gap.

PMID:29696803 SUPPORT Human Clinical

"As to the families with nonsyndromal XLID which have received IDX numbers, their total is currently 105 (Figure 3). For 67 of these families, the genes have been cloned, 33 have been mapped but the genes have not been identified and 5 have reserved IDX numbers (IDX8, 50, 69, 83 and 86) but have..."

Shows the class is enumerated by ascertained families rather than by population sampling, which is why no population prevalence exists for it.

⚙

Pathophysiology

X-Linked Gene Disruption

Rare germline loss-of-function, hypomorphic, repeat-expansion, or copy-number variants in any one of a large set of genes on the X chromosome remove or reduce the activity of the encoded product in the developing and mature brain. The class is clinically homogeneous but genetically heterogeneous: variants at many different loci converge on the same single clinical outcome, and each individual gene accounts for only a small fraction of cases. The X chromosome is disproportionately represented among intellectual-disability genes relative to its size.

Downstream

Hemizygous Male Expression of the Mutant Allele A variant on the single male X chromosome is expressed without a compensating allele. Note this edge encodes a dosage/conditioning relationship (hemizygosity is a property of male karyotype, not an event caused by the variant) rather than a downstream biochemical step; `DIRECT` is used because CausalLinkTypeEnum offers no conditioning value.

Show evidence (3 references)

PMID:9731525 SUPPORT Human Clinical

"Nonsyndromic X-linked mental retardation (MRX) syndromes are clinically homogeneous but genetically heterogeneous disorders, whose genetic bases are largely unknown."

States the defining architecture of the class - one phenotype, many loci - which is why the numbered MRX series was defined by linkage rather than by clinical features.

PMID:10655063 SUPPORT Human Clinical

"At least five MRX genes have been identified by positional cloning, but each accounts for only 0.5%-1.0% of MRX cases."

Quantifies the per-gene contribution, establishing that no single gene dominates this class.

PMID:29696803 SUPPORT Human Clinical

"The X-chromosome comprises only about 5% of the human genome but accounts for about 15% of the genes currently known to be associated with intellectual disability."

Quantifies the disproportionate contribution of the X chromosome to intellectual-disability genetics, the observation that motivated the field.

Hemizygous Male Expression of the Mutant Allele

Males carry one X chromosome, so a loss-of-function allele is expressed in every cell with no second copy to buffer it. Heterozygous females are mosaic, because random X-chromosome inactivation silences one X per cell, so the mutant allele is expressed in only a subset of cells; such carriers are typically unaffected or mildly affected, and in several subtypes completely skewed X-inactivation silences the mutant X entirely. This dosage asymmetry is the mechanistic basis of the male excess observed among people with intellectual disability, and the mosaicism is the principal obstacle to studying the circuit pathophysiology in females.

Downstream

Convergent Disruption of Neuronal Function Loss of the gene product in neurons impairs the synaptic processes it supports.

Show evidence (3 references)

PMID:23871722 SUPPORT Human Clinical

"Because of the unbalanced sex ratio (1.3-1.4 to 1) observed in intellectual disability (ID) and the identification of large ID-affected families showing X-linked segregation, much attention has been focused on the genetics of X-linked ID (XLID)."

Quantifies the male excess that hemizygous expression explains and that motivated the field's focus on the X chromosome.

PMID:38424476 SUPPORT Other

"This mosaic expression produces substantial complexity, especially when attempting to study the already complicated neural circuits that underly behavior, thus impeding the understanding of disease-related pathophysiology and the development of therapeutics."

Establishes the consequence of female mosaicism for mechanistic study and therapeutic development in this class. Tagged OTHER: the quoted sentence is a methodological statement about the difficulty of studying mosaic neural circuits, not a human clinical observation.

PMID:11889465 SUPPORT Human Clinical

"All carrier females with either point mutations or genomic deletions in FACL4 showed a completely skewed X-inactivation, suggesting that the gene influences survival advantage."

Demonstrates the complete X-inactivation skewing that spares carrier females in this class.

Convergent Disruption of Neuronal Function

Although the causal genes do not share a single pathway, their products fall repeatedly into a limited set of themes that converge on the same functional endpoint: Rho GTPase signalling to the actin cytoskeleton (PAK3), Rab-dependent synaptic vesicle recycling (GDI1), proposed roles in excitatory synapse formation and neurite outgrowth (IL1RAPL1, TSPAN7 - both inferred rather than directly demonstrated in the cited reports), tRNA anticodon-loop modification and translational fidelity (FTSJ1), fatty-acid metabolism (ACSL4), Golgi/trans-Golgi-network pH regulation and glycosylation (SLC9A7), transcriptional activation (AFF2, silenced by the FRAXE repeat expansion), and telencephalic transcriptional control (ARX). Most of these arms act on synapse formation, maintenance, and plasticity, and synaptic convergence is the field's dominant framing of the class. It is not, however, established for all of them: the tRNA-modification (FTSJ1), fatty-acid (ACSL4), Golgi-pH (SLC9A7), and transcriptional (AFF2) arms have documented molecular and cellular consequences but no cited evidence of a synaptic endpoint, so the node is deliberately named for neuronal rather than synaptic function. What is shared across every arm is that convergence happens at the level of neuronal cell biology rather than through a common molecular pathway - which is why no single pathway-directed therapy addresses the class. Enumerating the rest of the numbered series adds further themes without disturbing that conclusion: postsynaptic scaffolding at the NMDA receptor and the dendritic spine (DLG3, FRMPD4), synaptic vesicle clustering, mobility and cargo retrieval (SYN1, SYP), presynaptic terminal formation and maintenance from the Golgi (RAB39B), ubiquitin-proteasome substrate handling (MID2, KLHL15, USP27X), chromatin and transcriptional coregulation (ZNF711, ZMYM3), Arf-family guanine-nucleotide exchange (IQSEC2), serine-threonine kinase signalling (RPS6KA3) and microtubule stabilisation in developing neurons (FGF13). The ubiquitin arm is the clearest illustration that convergence here is thematic rather than directional: MID2 and KLHL15 are ubiquitin-ligase pathway components whose loss impairs degradation of specific substrates, whereas USP27X is a deubiquitinase, so the arm has no single direction and its process annotation deliberately carries no modifier. USP27X is also the one gene admitted here with essentially no characterised neuronal function, so for that arm this node records convergence without a mechanism.

neuron CL:0000540

PAK3 hgnc:8592 GDI1 hgnc:4226 IL1RAPL1 hgnc:5996 TSPAN7 hgnc:11854 FTSJ1 hgnc:13254 ACSL4 hgnc:3571 AFF2 hgnc:3776 ARX hgnc:18060 SLC9A7 hgnc:17123 IQSEC2 hgnc:29059 RPS6KA3 hgnc:10432 SYN1 hgnc:11494 RAB39B hgnc:16499 DLG3 hgnc:2902 SYP hgnc:11506 ZNF711 hgnc:13128 MID2 hgnc:7096 KLHL15 hgnc:29347 FRMPD4 hgnc:29007 USP27X hgnc:13486 FGF13 hgnc:3670 ZMYM3 hgnc:13054

chemical synaptic transmission GO:0007268 ↓ DECREASED regulation of synapse structure or activity GO:0050803 ↓ DECREASED Rho protein signal transduction GO:0007266 ↓ DECREASED vesicle-mediated transport GO:0016192 ↓ DECREASED tRNA modification GO:0006400 ↓ DECREASED Golgi and post-Golgi pH regulation GO:0051453 ↓ DECREASED glycosylation of exported cargo GO:0009101 ↓ DECREASED FMR2/AFF2-dependent transcriptional activation GO:0045893 ↓ DECREASED postsynaptic density organization GO:0097106 ↓ DECREASED synaptic vesicle endocytosis and cargo retrieval GO:0048488 ↓ DECREASED ubiquitin-proteasome substrate handling GO:0006511 chromatin and transcriptional coregulation GO:0006325 ↓ DECREASED microtubule stabilisation in developing neurons GO:0000226 ↓ DECREASED

Downstream

Impaired Synaptic Plasticity in Learning and Memory Circuits Disrupted synapse formation, transmission, and recycling degrade activity-dependent plasticity.

Show evidence (7 references)

PMID:9731525 SUPPORT Other

"PAK proteins are crucial effectors linking Rho GTPases to cytoskeletal reorganization and to nuclear signalling."

Establishes the Rho GTPase-to-cytoskeleton arm of the convergence. Tagged OTHER: this is a background statement of established protein function, not a result generated by the cited study.

PMID:9731525 SUPPORT Human Clinical

"Signal transduction through Rho GTPases and PAK3 may be critical for human cognitive function."

Connects the Rho GTPase theme directly to the cognitive endpoint.

PMID:9620768 SUPPORT Other

"Rab GDP-dissociation inhibitors (GDI) are evolutionarily conserved proteins that play an essential role in the recycling of Rab GTPases required for vesicular transport through the secretory pathway."

Establishes the vesicle-trafficking arm of the convergence. Tagged OTHER: a background statement of established protein function rather than a result of the cited study.

+ 4 more references

Impaired Synaptic Plasticity in Learning and Memory Circuits

The convergent synaptic lesion degrades activity-dependent plasticity in the hippocampal and cortical circuits that support learning and memory. Several causal genes are selectively or highly expressed in exactly these structures - IL1RAPL1 in the postnatal hippocampal memory system, PAK3 in postmitotic neurons of developing and postnatal cerebral cortex and hippocampus, TSPAN7 in cerebral cortex and hippocampus - which is the anatomical reason a diffuse molecular lesion produces a circumscribed cognitive phenotype.

neuron CL:0000540

regulation of synaptic plasticity GO:0048167 ↓ DECREASED dendritic spine morphogenesis GO:0060997 ↓ DECREASED

cerebral cortex UBERON:0000956 hippocampus UBERON:0002421

Downstream

Static Cognitive Impairment Without Structural Brain Malformation Degraded plasticity in an anatomically normal brain manifests as non-progressive intellectual disability.

Show evidence (3 references)

PMID:9731525 SUPPORT Model Organism

"Immunofluorescence analysis showed that PAK3 protein is highly expressed in postmitotic neurons of the developing and postnatal cerebral cortex and hippocampus."

Localises a causal gene product to the cortical and hippocampal circuits that carry the cognitive phenotype. Tagged MODEL_ORGANISM: the immunofluorescence was performed in animal tissue (the paper's MeSH terms include Mice and Rats), not in patients.

PMID:10655063 SUPPORT In Vitro

"RNA in situ hybridization showed that TM4SF2 is highly expressed in the central nervous system, including the cerebral cortex and hippocampus."

Independent confirmation that causal genes in this class are enriched in the same learning-and-memory circuits. Tagged IN_VITRO: an in situ hybridisation tissue-expression assay rather than a clinical observation.

PMID:9620768 SUPPORT Human Clinical

"Our results show that both functional and developmental alterations in the neuron may account for the severe impairment of learning abilities as a consequence of mutations in GDI1, emphasizing its critical role in development of human intellectual and learning abilities."

Links the vesicle-recycling lesion to impaired learning through both functional and developmental neuronal alterations.

Static Cognitive Impairment Without Structural Brain Malformation

The endpoint of the class: non-progressive impairment of intellectual functioning and adaptive behaviour in a brain that is structurally normal on imaging and free of any consistently reproducible dysmorphic, metabolic, or systemic sign. This is a mis-tuned rather than a mis-built or damaged circuit, which is why brain MRI is characteristically unremarkable and why - in the absence of any distinguishing feature - molecular testing rather than clinical recognition is the only route to a specific diagnosis. The class is conventionally described as static and non-progressive, with developmental regression arguing against the diagnosis; note that none of the evidence cited on this node speaks to temporal course, so the staticity claim rests on clinical convention rather than on a source quoted here.

brain UBERON:0000955

Downstream

Intellectual disability The clinical expression of this endpoint node. Impaired intellectual functioning is what the class is defined by, and in the strictest members of the series it is the only feature present, so the terminal mechanism node and this phenotype stand in a direct relation with no intervening step. The remaining phenotypes in this entry - global developmental delay, speech and language delay, behavioural and autistic features, and seizures - are deliberately left unwired: they appear in some subtypes and not others, and assigning each to a mechanism node requires per-subtype evidence this pass did not gather.

Show evidence (3 references)

PMID:9731525 SUPPORT Human Clinical

"MRI analysis showed no gross defects in brain development."

Documents the structurally normal brain that defines the non-syndromic endpoint.

PMID:11971879 SUPPORT Human Clinical

"The absence of detectable brain malformations in patients suggests that ARX may have an essential role, in mature neurons, required for the development of cognitive abilities."

Independent confirmation, in a second subtype, that the lesion is functional rather than malformative.

PMID:22002931 SUPPORT Human Clinical

"The present family supports the lack of additional phenotypic features in patients with GDI1 mutations, rendering a clinical diagnosis of GDI1-associated XLID impossible."

States the diagnostic consequence of a phenotype with no distinguishing features.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Nervous System 6

Intellectual disability VERY_FREQUENT HP:0001249

Show evidence (2 references)

PMID:10471494 SUPPORT Human Clinical

"Non-overlapping deletions and a nonsense mutation in this gene were identified in patients with cognitive impairment only."

Documents cognitive impairment as the sole clinical feature, which is the definition of the non-syndromic class. The VERY_FREQUENT band follows from the phenotype being definitional rather than variable.

PMID:22002931 SUPPORT Human Clinical

"the affected male family members had nonsyndromic intellectual disability, that is, they had neither abnormal body measurements nor any other significant clinical problems"

Independent confirmation that intellectual disability is the isolated finding in a second subtype.

Global developmental delay HP:0001263

Delayed speech and language development HP:0000750

Atypical behavior HP:0000708

Show evidence (1 reference)

PMID:21484992 SUPPORT Human Clinical

"We have identified an additional two families with deletions of a portion of the gene that give rise to cognitive impairment, as well as some behavioral problems and mild dysmorphism."

Documents behavioural problems in a subset of IL1RAPL1 families. No frequency is asserted: this is a subset finding within two reported families, not a quantified class-wide feature.

Autistic behavior OCCASIONAL HP:0000729

Show evidence (1 reference)

PMID:31906484 SUPPORT Human Clinical

"Most of the selected patients did not have relevant dysmorphic features, confirming that they show an unspecific phenotype. However, autism spectrum disorders were present in nearly 30% of them."

Quantifies autistic features in a cohort selected for suggestive non-syndromic XLID, in the same sentence in which the authors characterise that cohort as phenotypically unspecific - so the figure is drawn from the non-syndromic population this entry is about, though the authors write "most", not all, of the patients lacked relevant dysmorphic features. OCCASIONAL (5-29%) is the conservative reading of "nearly 30%", which sits exactly on the OCCASIONAL/FREQUENT boundary; the band would be FREQUENT if the true value were at or above 30%.

Seizure OCCASIONAL HP:0001250

Show evidence (1 reference)

PMID:31906484 SUPPORT Human Clinical

"Almost 15% of the patients in the X-linked group also reported having epilepsy."

Quantifies epilepsy in the X-linked-family arm of a cohort selected for suggestive non-syndromic XLID, supporting the OCCASIONAL band (5-29%).

Context-specific annotations (1)

ARX-related

Seizures are a designated variable feature of this subtype, whose MONDO label is "intellectual disability, X-linked, with or without seizures, ARX-related" (MONDO:0010317). No frequency is recorded for the context: the label establishes that seizures vary within the subtype without quantifying them, and the only ARX-specific seizure quote available enumerates the syndromic ARX entities this entry excludes. The context exists so the subtype association survives structurally now that the phenotype itself is recorded at class level on cohort evidence.

Other 1

Absence of distinctive clinical or biochemical features

Show evidence (2 references)

PMID:10655063 SUPPORT Human Clinical

"They can be categorized into syndromic (MRXS) and nonspecific (MRX) forms. In MRX forms, affected patients have no distinctive clinical or biochemical features."

States the defining negative criterion separating this class from the syndromic (MRXS) forms.

PMID:31898314 SUPPORT Human Clinical

"Classically, XLID has been subdivided in syndromic intellectual disability (S-XLID)-where intellectual disability (ID) is always associated with other recognizable physical and/or neurological features-and non-specific or non-syndromic intellectual disability (NS-XLID) where the only common..."

The dedicated NS-XLID review's definition of the class, stating precisely that the defining property is ID being the only COMMON feature - a statement about consistency across cases rather than about isolation in each patient.

🧬

Genetic Associations

IL1RAPL1

Gene: IL1RAPL1 hgnc:5996 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:10471494 SUPPORT Human Clinical

"Thorough investigation of an MRX critical region in Xp22.1-21.3 enabled us to identify a new gene expressed in brain that is responsible for a non-specific form of X-linked mental retardation."

Establishes IL1RAPL1 as causal for the non-specific (non-syndromic) form.

PAK3

Gene: PAK3 hgnc:8592 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:9731525 SUPPORT Human Clinical

"The mutation produces premature termination, disrupting kinase function."

Establishes the loss-of-function mechanism of the causal PAK3 allele.

GDI1

Gene: GDI1 hgnc:4226 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:9620768 SUPPORT Human Clinical

"One of the mutations caused a non-conservative substitution (L92P) which reduced binding and recycling of RAB3A, the second was a null mutation."

Characterises both the missense and null mechanisms at this locus.

TSPAN7

Gene: TSPAN7 hgnc:11854 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:10655063 SUPPORT Human Clinical

"Further investigation led to identification of TM4SF2 mutations in 2 of 33 other MRX families."

Provides the independent point-variant evidence beyond the index translocation.

FTSJ1

Gene: FTSJ1 hgnc:13254 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:26310293 SUPPORT In Vitro

"Additionally, tRNA(Phe) from an NSXLID patient with a novel FTSJ1-p.A26P missense allele specifically lacks Gm34 , but has normal levels of Cm32 and o2yW37 ."

Demonstrates allele-specific biochemical consequences at this locus.

ACSL4

Gene: ACSL4 hgnc:3571 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:11889465 SUPPORT In Vitro

"Analysis of enzymatic activity in lymphoblastoid cell lines from affected individuals of both families revealed low levels compared with normal cells, indicating that both mutations are null mutations."

Provides the functional confirmation that both alleles are null.

ARX

Gene: ARX hgnc:18060 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:11971879 SUPPORT Human Clinical

"In contrast to other genes involved in XLMR, ARX expression is specific to the telencephalon and ventral thalamus."

Characterises the restricted expression domain that distinguishes ARX from the broadly expressed genes in this class.

AFF2

Gene: AFF2 hgnc:3776 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:29696803 SUPPORT Human Clinical

"Sequence variants in 11 genes (KLF8, AFF2, SLC6A8, NDUFA1, ALG13, SRPX2, ATRX, NLGN3, FGDY, CDKL5, and NLGN4) have been found in families with IDX but in whom IDX numbers were never assigned."

Places AFF2 among the genes causing non-syndromal X-linked intellectual disability.

SLC9A7

Gene: SLC9A7 hgnc:17123 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:30335141 SUPPORT Human Clinical

Establishes SLC9A7 as causal for a non-syndromic form in two independent families.

PMID:30335141 SUPPORT Human Clinical

"Mass spectrometry analysis of patient sera also revealed an abnormal N-glycosylation profile for transferrin, a clinical diagnostic marker for congenital disorders of glycosylation."

Provides a measurable biochemical readout for this form, unusual in a class defined by the absence of biochemical features.

IQSEC2

Gene: IQSEC2 hgnc:29059 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:20473311 SUPPORT Human Clinical

Establishes IQSEC2 as causal for the non-syndromic form and gives the protein function recorded in these notes.

RPS6KA3

Gene: RPS6KA3 hgnc:10432 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:17100996 SUPPORT Human Clinical

"In two families, the clinical diagnosis had been nonsyndromic X-linked mental retardation."

Establishes that RPS6KA3 variants are found in families diagnosed as non-syndromic, which is what admits this gene to this entry.

PMID:17100996 SUPPORT BACKGROUND Human Clinical

"The disorder is now recognized to be due to mutations in a serine threonine kinase RSK2(RPS6KA3) located at Xp22.2"

Source for the kinase function and the Xp22.2 location recorded in these notes. Marked BACKGROUND because the sentence is the paper's introductory framing of previously established Coffin-Lowry genetics, not its own result.

SYN1

Gene: SYN1 hgnc:11494 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:28973667 SUPPORT Human Clinical

"We identified a missense mutation (c.236 C > G; p.S79W) in the SYN1 gene coding for synapsin I in the MRX50 family, affected by non-syndromic X-linked intellectual disability."

Establishes SYN1 as causal in the numbered MRX50 family with a non-syndromic presentation.

PMID:28973667 SUPPORT In Vitro

"In addition, the presence of S79W Synapsin I strongly reduces the mobility of synaptic vesicles, with possible implications for the regulation of neurotransmitter release and synaptic plasticity."

The functional consequence of the causal allele recorded in these notes, demonstrated in cultured knockout hippocampal neurons.

RAB39B

Gene: RAB39B hgnc:16499 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:20159109 SUPPORT Human Clinical

"One mutation in family X (D-23) introduced a stop codon seven amino acids after the start codon (c.21C > A; p.Y7X). A second mutation, in the MRX72 family, altered the 5' splice site (c.215+1G > A) and normal splicing. Neither instance produced a protein."

Establishes both causal alleles and the loss-of-function mechanism recorded in these notes.

PMID:20159109 SUPPORT In Vitro

"We show that RAB39B, a novel RAB GTPase of unknown function, is a neuronal-specific protein that is localized to the Golgi compartment."

Source for the protein family, neuronal specificity and Golgi localisation recorded in these notes and in the MRX72 subtype row.

DLG3

Gene: DLG3 hgnc:2902 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:15185169 SUPPORT Human Clinical

"We have identified truncating mutations in the human DLG3 (neuroendocrine dlg) gene in 4 of 329 families with moderate to severe X-linked mental retardation."

Establishes DLG3 as causal, with the cohort yield that supports the gene assignment.

PMID:15185169 SUPPORT Human Clinical

"DLG3 encodes synapse-associated protein 102 (SAP102), a member of the membrane-associated guanylate kinase protein family."

Source for the protein identity and family recorded in these notes.

SYP

Gene: SYP hgnc:11506 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:19377476 SUPPORT Human Clinical

"The screen has discovered nine genes implicated in XLMR, including SYP, ZNF711 and CASK reported here, confirming the power of this strategy."

The gene-discovery statement assigning SYP to X-linked intellectual disability.

PMID:23966691 SUPPORT In Vitro

"Synaptophysin is an integral synaptic vesicle (SV) protein that accounts for ∼10% of total SV protein cargo."

Source for the protein identity and abundance recorded in these notes.

ZNF711

Gene: ZNF711 hgnc:13128 gene page relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:27993705 SUPPORT Human Clinical

Establishes the phenotype and the authors' non-syndromic assignment recorded in these notes.

PMID:20346720 SUPPORT In Vitro

"Furthermore, PHF8 interacts with another XMLR protein, ZNF711, which binds to a subset of PHF8 target genes, including the XLMR gene JARID1C."

Source for describing ZNF711 as a chromatin-associated transcription factor and for its functional link to two other X-linked intellectual disability genes. Quoted verbatim, including the source's "XMLR" typographical error.

PMID:19377476 SUPPORT Human Clinical

"The screen has discovered nine genes implicated in XLMR, including SYP, ZNF711 and CASK reported here, confirming the power of this strategy."

The 208-family resequencing screen that first implicated ZNF711, cited here so the claim in these notes does not depend on an evidence item attached to a different row.

MID2

Gene: MID2 hgnc:7096 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:24115387 SUPPORT Human Clinical

"We report a novel missense mutation (c.1040G>A, p.Arg347Gln) in MID2, which encodes ubiquitin ligase E3, as the likely cause of X-linked mental retardation in a large kindred."

The gene assignment, preserving the authors' "likely cause" hedge.

PMID:24115387 SUPPORT In Vitro

"When transiently expressed in HEK293T cell line, the mutation was found to abolish the function of the COS domain in the protein."

Source for the molecular consequence recorded in these notes.

KLHL15

Gene: KLHL15 hgnc:29347 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:25644381 SUPPORT Human Clinical

"In the poorly characterized KLHL15 gene, encoding a member of the kelch-like protein family, we identified a protein-truncating variant"

The causal allele class identified in this gene by the discovery study.

PMID:25644381 SUPPORT In Vitro

"KLHL15-Cul3 specifically targets a brain-specific regulatory subunit of the protein phosphatase 2A (PP2A/B'ß) and thereby promotes its proteasomal degradation, resulting in the formation of alternative PP2A holoenzymes."

Source for the molecular function recorded in these notes.

FRMPD4

Gene: FRMPD4 hgnc:29007 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:29267967 SUPPORT Human Clinical

"Mutations include deletion of an entire coding exon, a nonsense mutation, a frame-shift mutation resulting in premature termination of translation, and a missense mutation involving a highly conserved amino acid residue neighboring FRMPD4-FERM domain."

The allele spectrum recorded in these notes.

PMID:29267967 SUPPORT In Vitro

"FRMPD4 (FERM and PDZ Domain Containing 4) is a neural scaffolding protein that interacts with PSD-95 to positively regulate dendritic spine morphogenesis, and with mGluR1/5 and Homer to regulate mGluR1/5 signaling."

Source for the protein function recorded in these notes.

USP27X

Gene: USP27X hgnc:13486 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:25644381 SUPPORT Human Clinical

"In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X)"

The gene-discovery statement assigning USP27X to X-linked intellectual disability.

PMID:25644381 SUPPORT Other

"Little is currently known about the functional role of the ubiquitin specific peptidase USP27X."

Source for the statement in these notes that the gene's function is uncharacterised. Graded OTHER because the sentence reports the state of the literature rather than any experimental result.

FGF13

Gene: FGF13 hgnc:3670 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:34184986 SUPPORT In Vitro

"In both HEK293 cells and patient-derived induced pluripotent stem cells, this SNP reduced the translation of FGF13, which stabilizes microtubules in developing neurons."

The translational mechanism and the protein's function recorded in these notes, demonstrated in cell lines including patient-derived iPSCs.

PMID:34184986 SUPPORT In Vitro

"Furthermore, this SNP reduced the interaction between FGF13 5'-UTR and polypyrimidine-tract-binding protein 2 (PTBP2), which was required for FGF13 translation in cortical neurons."

Source for the PTBP2 interaction recorded in these notes.

ZMYM3

Gene: ZMYM3 hgnc:13054 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:36586412 SUPPORT In Vitro

"ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect."

The functional consequence recorded in these notes, from a chromatin immunoprecipitation experiment.

PMID:36586412 SUPPORT Human Clinical

"Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues."

Source for the allele spectrum and recurrence recorded in these notes.

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Medical Actions

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Other

Establishing a molecular diagnosis enables carrier detection in female relatives and informs recurrence-risk counselling and reproductive options, including prenatal diagnosis and preimplantation genetic testing where a familial pathogenic variant is known. Because the mode of inheritance is X-linked, carrier females have a 50% chance of transmitting the allele to each child, and the counselling yield is high in the large multiplex pedigrees characteristic of this class.

Show evidence (1 reference)

PMID:22482801 SUPPORT Human Clinical

"At the same time, it has improved the clinical diagnosis of XLID and allowed for carrier detection and prevention strategies through gamete donation, prenatal diagnosis, and genetic counseling."

Documents genetic counselling and carrier detection as the established clinical payoff of molecular diagnosis in this class.

Supportive Care

Action: Supportive Care NCIT:C15747

Platform: Other

No disease-modifying therapy is established for this class. Management is supportive and individualised: developmental, educational, speech-language, occupational, physical, and behavioural interventions, with psychiatric and antiseizure treatment where indicated. This entry carries the umbrella claim and the evidence that care is supportive only; the two most consistently named allied-health modalities are additionally recorded as their own NCIT-coded entries below, for queryability. Because management is phenotype- and gene-specific, the evidence base is largely extrapolated from broader neurodevelopmental care rather than generated for this class. Gene therapy, selective X-reactivation, and synapse- or circuit-directed interventions remain experimental and are mostly not specific to this class.

Show evidence (2 references)

PMID:38424476 SUPPORT Other

"Here, we review a few selected X-linked forms of ID that predominantly affect heterozygous females and the current obstacles for developing effective therapies for such disorders."

Documents that effective disease-modifying therapies for X-linked intellectual disability remain obstructed and under development, which is why care is supportive. Tagged OTHER for the same reason as the hemizygous-expression node: the sentence states the scope of a review rather than reporting a clinical observation.

PMID:29696803 SUPPORT Human Clinical

"The progress in identifying genetic and genomic alterations associated with XLID has not been matched with insights that improve the clinician's ability to form differential diagnoses, that bring into view the possibility of curative therapies for patients"

States explicitly that gene discovery in this class has not yet translated into curative therapy, grounding the supportive-care-only position.

Speech and Language Therapy

Action: speech and language therapy Ontology label: Speech Language Therapy NCIT:C159273

Platform: Behavioral / lifestyle

Speech-language intervention, including augmentative and alternative communication where speech is absent or limited, is a standard component of multidisciplinary care and is tied to the group rather than to any single causal gene. No evidence block is attached, and this is deliberate: none of the references cached for this entry mentions speech-language therapy at all - including the two the deep-research report attributed the modality list to, one of which is cached as full text - so there is no quotable source, and the DR report over-attributed the enumeration. Recorded as a queryable NCIT-coded entry under the supportive-care umbrella above, not as an evidenced claim.

Occupational Therapy

Action: occupational therapy Ontology label: Occupational Therapy NCIT:C121351

Platform: Behavioral / lifestyle

Occupational therapy addressing adaptive, motor, and daily-living skills, likewise tied to the group rather than to a specific gene. As with speech and language therapy, no evidence block is attached because no cached reference for this entry mentions the modality; the entry exists to make it queryable rather than to assert a class-specific evidence base.

🔬

Diagnosis

Fragile X (FMR1) repeat testing

Sizing of the FMR1 CGG trinucleotide repeat, performed before or alongside sequencing. It is separated from the sequencing entry below because it is a mechanically distinct assay: a repeat expansion is not reliably called by exome or panel sequencing, so a normal sequencing result does not exclude fragile X syndrome. Fragile X is the most common single XLID entity, and excluding it is the conventional first step in a male with intellectual disability and a suggestive X-linked family history - in the Basque targeted-panel cohort, every one of the 61 patients had already been referred for FMR1 testing and shown a normal repeat number before enrolment.

Molecular Analysis NCIT:C19770

Show evidence (3 references)

PMID:22482801 SUPPORT Other

"Over 150 syndromes, the most common of which is the fragile X syndrome, have been described."

Establishes fragile X syndrome as the most common of the XLID syndromes, which is why its exclusion is the conventional first diagnostic step in this population. Tagged OTHER: the source is a historical review and the sentence summarises the field rather than reporting a clinical series.

PMID:31906484 SUPPORT Human Clinical

"These patients were initially referred to the molecular genetics laboratory to exclude Fragile X Syndrome."

Documents FMR1 testing as the referral-level first step preceding sequencing in a suggestive non-syndromic XLID cohort.

PMID:31906484 SUPPORT Human Clinical

"All 61 patients had normal G-banded karyotype and showed normal FMR1 trinucleotide repeat numbers."

Documents that a normal FMR1 repeat number was, in this cohort, already established before enrolment - so fragile X exclusion preceded the non-syndromic XLID workup rather than running alongside it. The generalisation to practice is the entry's own inference from the referral pattern, not a claim of the quoted sentence.

Molecular genetic testing (exome or genome sequencing)

Because affected individuals have no distinguishing clinical features, a specific diagnosis cannot be reached by examination and requires parallel molecular testing of all known intellectual-disability genes. The contemporary workup is clinical evaluation with a family pedigree, fragile X (FMR1) testing (recorded as its own entry above), chromosomal microarray, and exome or genome sequencing with segregation analysis; of these, only fragile X exclusion and panel sequencing with segregation are covered by the evidence cited here, the remainder - chromosomal microarray in particular - reflecting standard practice. Targeted XLID panels retain a role in pedigrees with suggestive X-linked family history: in one cohort of 61 unrelated males with suggestive non-syndromic XLID and negative fragile X testing, an 82-gene panel identified 17 candidate variants in 16 patients.

Genetic Testing NCIT:C15709

Show evidence (3 references)

PMID:22002931 SUPPORT Human Clinical

"Thus, this family not only broadens the spectrum of GDI1 mutations but also emphasizes the need for parallel testing of all known genes associated with ID in patients with an unspecific phenotype."

States the diagnostic strategy the class requires and the reason for it.

PMID:31906484 SUPPORT Human Clinical

"We have performed targeted next-generation sequencing of 82 XLID genes on 61 non-related male patients with suggestive non-syndromic XLID. These patients were initially referred to the molecular genetics laboratory to exclude Fragile X Syndrome."

Documents the cohort design and the position of targeted panels after fragile X exclusion in this population.

PMID:31906484 SUPPORT Human Clinical

"Sequencing data analysis identified 17 candidate variants in 16 patients."

Quantifies the diagnostic yield of a targeted panel in a suggestive non-syndromic XLID cohort.

Brain MRI

Characteristically unremarkable. Its role here is exclusionary - normal imaging supports a non-syndromic, non-malformative diagnosis and argues against the malformative X-linked entities (for example ARX-related lissencephaly) that enter the differential.

Magnetic Resonance Imaging NCIT:C16809

Show evidence (1 reference)

PMID:9731525 SUPPORT Human Clinical

"MRI analysis showed no gross defects in brain development."

Documents the normal imaging expected in this class.

X-chromosome inactivation studies in female relatives

Assessment of X-inactivation skewing in mothers and female relatives. Extreme skewing supports an X-linked cause and, in cohorts of females with idiopathic intellectual disability, enriches for pathogenic findings on subsequent sequencing - 11 of 136 informative women showed at least 90% skewing, and exome sequencing found pathogenic variants in 8 of those 11. Note that those variants were dominant and included autosomal genes, so skewing is an ascertainment aid toward a genetic diagnosis generally, not a diagnostic criterion for this class.

Molecular Analysis NCIT:C19770

Show evidence (3 references)

PMID:31906484 SUPPORT Human Clinical

"and 14 male patients with ID and affected brothers whose mothers show skewed X-inactivation"

Documents maternal X-inactivation skewing used as an ascertainment criterion for suspected X-linked intellectual disability.

PMID:36943625 SUPPORT Human Clinical

"Among the 136 patients who were informative, 11 (8%) presented with extreme or total XCI skewing (>= 90%), which was significantly higher than expected by chance."

Quantifies the enrichment of extreme X-inactivation skewing in women with idiopathic intellectual disability.

PMID:36943625 SUPPORT Human Clinical

"All variants were mapped to ID-related genes with dominant phenotypes: four variants in the X-linked genes DDX3X (an XCI escape gene; two cases), WDR45, and PDHA1, and four variants in the autosomal genes KCNB1, CTNNB1, YY1, and ANKRD11."

Important qualification, and the reason this is PARTIAL for this entry: half the variants recovered by the skewing-guided strategy were autosomal, so the yield is not specific to X-linked - let alone non-syndromic X-linked - intellectual disability.

📊

Prevalence

Males, worldwide

Point Prevalence 166.7 per 100,000 >1 in 1,000

Estimate for X-linked intellectual disability as a whole (syndromic plus non-syndromic), given in the source as approximately 1 in 600 males. The non-syndromic class is a subset of this figure; no robust population prevalence exists for the non-syndromic class alone, because it aggregates many individually rare gene-defined disorders.

Show evidence (1 reference)

PMID:10655063 SUPPORT Human Clinical

"X-linked forms of mental retardation (MR) affect approximately 1 in 600 males and are likely to be highly heterogeneous."

Provides the population rate for X-linked intellectual disability as a whole. Marked PARTIAL because the figure covers syndromic and non-syndromic forms together, not the non-syndromic class this entry describes.

Males with intellectual disability

Unknown Common

X-linked intellectual disability (syndromic and non-syndromic combined) accounts for 5-10% of intellectual disability in males, and is the classical explanation for the male excess observed among people with intellectual disability. `measure_type: UNKNOWN` is deliberate: this is a case fraction within an already-affected population rather than a population rate, and no source defines a time interval, so none of the prevalence/incidence measure types applies.

Show evidence (2 references)

PMID:22482801 SUPPORT Human Clinical

"X-Linked intellectual disability (XLID) accounts for 5%-10% of intellectual disability in males."

Quantifies the fraction of male intellectual disability attributable to X-linked causes.

PMID:31906484 SUPPORT Human Clinical

"X-linked intellectual disability (XLID) is known to contribute up to 10% of intellectual disability (ID) in males and could explain the increased ratio of affected males observed in patients with ID."

Independent confirmation of the 10% upper bound and explicit statement that it explains the male excess.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Non-Syndromic X-Linked Intellectual Disability:

Syndromic X-linked intellectual disability (MRXS)

Overlapping Features The primary differential. MRXS entities share X-linked inheritance and intellectual disability but add distinguishing physical, neurological, or biochemical features. The boundary is explicitly regarded as blurred and sometimes arbitrary: 28 of the numbered non-syndromal (IDX) genes are also associated with XLID syndromes. Separately curated dismech entries in this family (Claes-Jensen, Siderius, Shashi, Turner type) are deliberately not modelled as subtypes here.

Show evidence (2 references)

PMID:10655063 SUPPORT Human Clinical

"They can be categorized into syndromic (MRXS) and nonspecific (MRX) forms. In MRX forms, affected patients have no distinctive clinical or biochemical features."

States the criterion that separates the two classes.

PMID:29696803 SUPPORT Human Clinical

"Twenty-eight of the “IDX genes” in Figure 3 have also been associated with XLID syndromes."

Quantifies the overlap between the two classes at the gene level, showing the differential is often not resolvable by gene identity alone.

Fragile X syndrome

Overlapping Features The most common syndromic XLID entity and the standard exclusion before this diagnosis is entertained - patients in non-syndromic XLID cohorts are typically referred after negative FMR1 testing. Distinguished by the characteristic somatic features and the FMR1 CGG expansion.

Show evidence (1 reference)

PMID:31906484 SUPPORT Human Clinical

"These patients were initially referred to the molecular genetics laboratory to exclude Fragile X Syndrome."

Documents fragile X exclusion as the standard first step before non-syndromic XLID is pursued.

Autosomal recessive non-syndromic intellectual disability

Overlapping Features Clinically indistinguishable in an isolated male. Distinguished by pedigree structure (affected siblings of both sexes, parental consanguinity, no X-linked segregation) and ultimately by molecular testing.

Autosomal dominant non-syndromic intellectual disability

Overlapping Features The dominant class, in which sporadic de novo heterozygous variants in constraint-intolerant autosomal genes predominate. In a sporadic male with no family history this is now a more likely explanation than a novel X-linked cause, a reversal of the pre-exome-era prior.

📊

Related Datasets

The ribose methylation enzyme FTSJ1 has a conserved role in neuron morphology and learning performance geo:GSE179384

human BULK RNA SEQ n=9

PMID:36720500

Human lymphoblastoid material from patients with FTSJ1 loss of function, supporting the MRX9 subtype and the tRNA-modification arm of the convergence node. Selected by relevance triage from the dataset-discovery candidates as the only DIRECT (disease-named, human, primary-material) hit; the remaining candidates were GENE_ONLY matches whose biology is unrelated to this disease (for example TSPAN7 in pancreatic beta-cell exocytosis, GDI1 in yeast Ypt1 trafficking) and were rejected. No evidence block is attached, per the dataset-curation SOP.

{ }

Source YAML

click to show

name: Non-Syndromic X-Linked Intellectual Disability
creation_date: "2026-08-12T00:00:00Z"
description: >-
  Non-syndromic X-linked intellectual disability (NS-XLID; historically MRX,
  and designated IDX in the contemporary family series) is the class of
  X-linked intellectual disability in which impaired intellectual functioning
  and adaptive behaviour are the only consistent shared feature. Critically,
  "non-syndromic" does not mean that every affected individual has isolated
  intellectual disability - variable speech delay, hypotonia, seizures,
  autistic traits, or minor dysmorphism may coexist - it means that no
  additional feature is reproducible across the families or disorders carrying
  the label. It is the third member of the non-syndromic
  intellectual-disability trio alongside the autosomal dominant and autosomal
  recessive classes, and is distinguished from both by its inheritance
  architecture: hemizygous males express a single mutant X allele in every
  cell, while heterozygous females express it only in the cells where the
  mutant X remains active, and are typically unaffected or mildly affected.
  That asymmetry, together with the reproducible male excess among people with
  intellectual disability (approximately 1.3-1.4 to 1), made X-linked defects
  the classical explanation for the sex-ratio imbalance and concentrated three
  decades of gene discovery on a single chromosome - one that carries about 5%
  of the human genome but about 15% of known intellectual-disability genes.

  Two structural facts define the class. First, it is extremely genetically
  heterogeneous while being clinically homogeneous: families were numbered by
  linkage interval (MRX1, MRX2, ...) rather than by phenotype, because there
  was no phenotype to distinguish them, and each individual gene accounts for
  only a small percentage of cases. Of 105 non-syndromal families assigned IDX
  numbers, 67 have a cloned gene, 33 are mapped without an identified gene,
  and 5 remain unpublished. Second, the boundary with the syndromic (MRXS)
  class is unstable and, on the authoritative view, blurred and sometimes
  arbitrary: 28 of the IDX genes are also associated with XLID syndromes,
  genes first reported as causing pure MRX acquire recognisable features once
  larger series are phenotyped, and allelic series place non-syndromic and
  severely syndromic phenotypes at opposite ends of one gene's mutation
  spectrum. ARX is the canonical example, spanning nonsyndromal XLID at one
  end and lissencephaly with abnormal genitalia at the other.

  Mechanistically the causal genes do not converge on a single pathway, but
  they fall repeatedly into a limited set of themes: Rho GTPase signalling to
  the actin cytoskeleton (PAK3), Rab-dependent synaptic vesicle recycling
  (GDI1), proposed roles in excitatory synapse formation and neurite
  outgrowth (IL1RAPL1, TSPAN7), tRNA anticodon-loop modification and translational fidelity
  (FTSJ1), lipid metabolism (ACSL4), Golgi pH regulation and glycosylation
  (SLC9A7), and telencephalic transcriptional control (ARX). The unifying
  pathology is a functional lesion of synaptic plasticity in an anatomically
  normal brain - a mis-tuned rather than a mis-built or damaged circuit -
  which is why neuroimaging is characteristically unremarkable. The class is
  conventionally described as static rather than progressive, though no source
  cited in this entry quantifies its temporal course.

  A critical caveat governs curation of this class. Because genes were
  nominated from small families before large population control sets existed,
  a systematic reassessment against 10,563 control X chromosomes challenged 25
  of the 106 genes then accepted; as of the 2017 update, 17 of those 25 remain
  unresolved. Gene lists for this class published before roughly 2013 should
  not be treated as settled.
category: Genetic
disease_term:
  preferred_term: non-syndromic X-linked intellectual disability
  term:
    id: MONDO:0019181
    label: non-syndromic X-linked intellectual disability
parents:
- Non-Syndromic Intellectual Disability
- X-Linked Intellectual Disability
synonyms:
- X-linked non-specific intellectual disability
- X-linked non-syndromic intellectual disability
- intellectual disability, X-linked, nonsyndromic
- non-specific X-linked intellectual disability
- isolated X-linked intellectual disability
- nonsyndromic X-linked mental retardation
- NS-XLID
- MRX
- IDX

references:
- reference: PMID:31898314
  title: "Non-syndromic X linked intellectual disability: Current knowledge in light of the recent advances in molecular and functional studies."
- reference: PMID:29696803
  title: "X-linked intellectual disability update 2017."
- reference: PMID:22482801
  title: "Fragile X and X-linked intellectual disability: four decades of discovery."
- reference: PMID:23871722
  title: "XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing."
- reference: PMID:19377476
  title: "A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation."
- reference: PMID:15630421
  title: "X-linked mental retardation."
- reference: PMID:31906484
  title: "Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability."
- reference: PMID:38424476
  title: "Overcoming genetic and cellular complexity to study the pathophysiology of X-linked intellectual disabilities."

inheritance:
- name: X-linked
  description: >-
    Causal variants lie on the X chromosome. Hemizygous males carry a single
    copy of the mutant allele with no second copy to compensate and are fully
    affected; heterozygous females are usually unaffected or only mildly
    affected, because random X-chromosome inactivation makes them mosaic for
    expression of the mutant allele. In several subtypes carrier females show
    completely skewed X-inactivation that silences the mutant X and confers
    additional protection. There is no male-to-male transmission. Large
    multiplex pedigrees showing this segregation pattern were the substrate
    for the linkage studies that defined the numbered MRX/IDX series, and the
    relative ease of ascertaining such families is why X-linked intellectual
    disability was delineated far ahead of its autosomal counterparts.
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  expressivity: VARIABLE
  evidence:
  - reference: PMID:38424476
    reference_title: "Overcoming genetic and cellular complexity to study the pathophysiology of X-linked intellectual disabilities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is because most genes on the X chromosome are subject to random X
      chromosome inactivation (XCI) during early embryonic development, which
      results in a mosaic pattern of gene expression for a given X-linked
      mutant allele.
    explanation: >-
      Establishes the mosaic-expression mechanism that makes heterozygous
      females variably and usually mildly affected relative to hemizygous
      males.
  - reference: PMID:11889465
    reference_title: "FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All carrier females with either point mutations or genomic deletions in
      FACL4 showed a completely skewed X-inactivation, suggesting that the
      gene influences survival advantage.
    explanation: >-
      Documents the completely skewed X-inactivation that spares carrier
      females, using the ACSL4/FACL4 subtype as the worked example.
  - reference: PMID:22482801
    reference_title: "Fragile X and X-linked intellectual disability: four decades of discovery."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Progress in delineating XLID has far outpaced the efforts to understand
      the genetic basis for autosomal intellectual disability. In large
      measure, this has been because of the relative ease of identifying
      families with XLID and finding the responsible mutations
    explanation: >-
      Explains why this class was characterised ahead of its autosomal
      counterparts: X-linked segregation makes multiplex families
      straightforward to ascertain.

prevalence:
- population: Males, worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 166.7
  notes: >-
    Estimate for X-linked intellectual disability as a whole (syndromic plus
    non-syndromic), given in the source as approximately 1 in 600 males. The
    non-syndromic class is a subset of this figure; no robust population
    prevalence exists for the non-syndromic class alone, because it aggregates
    many individually rare gene-defined disorders.
  evidence:
  - reference: PMID:10655063
    reference_title: "A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      X-linked forms of mental retardation (MR) affect approximately 1 in 600
      males and are likely to be highly heterogeneous.
    explanation: >-
      Provides the population rate for X-linked intellectual disability as a
      whole. Marked PARTIAL because the figure covers syndromic and
      non-syndromic forms together, not the non-syndromic class this entry
      describes.
- population: Males with intellectual disability
  measure_type: UNKNOWN
  prevalence_class: COMMON
  notes: >-
    X-linked intellectual disability (syndromic and non-syndromic combined)
    accounts for 5-10% of intellectual disability in males, and is the
    classical explanation for the male excess observed among people with
    intellectual disability. `measure_type: UNKNOWN` is deliberate: this is a
    case fraction within an already-affected population rather than a
    population rate, and no source defines a time interval, so none of the
    prevalence/incidence measure types applies.
  evidence:
  - reference: PMID:22482801
    reference_title: "Fragile X and X-linked intellectual disability: four decades of discovery."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      X-Linked intellectual disability (XLID) accounts for 5%-10% of
      intellectual disability in males.
    explanation: >-
      Quantifies the fraction of male intellectual disability attributable to
      X-linked causes.
  - reference: PMID:31906484
    reference_title: "Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      X-linked intellectual disability (XLID) is known to contribute up to 10%
      of intellectual disability (ID) in males and could explain the increased
      ratio of affected males observed in patients with ID.
    explanation: >-
      Independent confirmation of the 10% upper bound and explicit statement
      that it explains the male excess.

has_subtypes:
- name: MRX21
  display_name: Intellectual disability, X-linked 21 (IL1RAPL1)
  classification: molecular
  subtype_term:
    preferred_term: intellectual disability, X-linked 21
    term:
      id: MONDO:0010256
      label: intellectual disability, X-linked 21
  genes:
  - preferred_term: IL1RAPL1
    term:
      id: hgnc:5996
      label: IL1RAPL1
  description: >-
    Deletions and loss-of-function point variants in IL1RAPL1 at Xp22.1-21.3,
    encoding an interleukin-1 receptor accessory protein family member highly
    expressed in postnatal hippocampus. The founding report explicitly describes
    patients with cognitive impairment only, one of the clearest original
    descriptions in the class - though see the caveat below on later
    families. IL1RAPL1 is understood to act in excitatory synapse
    formation, though the cited primary report establishes only its
    hippocampal expression and infers a role in memory and learning. Later series identified
    behavioural problems and mild dysmorphism in some families, illustrating
    the instability of the non-syndromic label.
  evidence:
  - reference: PMID:10471494
    reference_title: "A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Non-overlapping deletions and a nonsense mutation in this gene were
      identified in patients with cognitive impairment only.
    explanation: >-
      Establishes the IL1RAPL1 subtype and, critically, its purely
      non-syndromic presentation - cognitive impairment as the sole feature.
  - reference: PMID:10471494
    reference_title: "A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Its high level of expression in post-natal brain structures involved in
      the hippocampal memory system suggests a specialized role for this new
      gene in the physiological processes underlying memory and learning
      abilities.
    explanation: >-
      Links the subtype to hippocampal learning circuitry, the anatomical
      substrate shared across the class. Tagged MODEL_ORGANISM: the expression
      analysis is animal tissue work (the paper's MeSH terms include Mice),
      and the role in memory and learning is the authors' inference from that
      expression pattern rather than a demonstrated function.
  - reference: PMID:21484992
    reference_title: "Deletion of the immunoglobulin domain of IL1RAPL1 results in nonsyndromic X-linked intellectual disability associated with behavioral problems and mild dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified an additional two families with deletions of a
      portion of the gene that give rise to cognitive impairment, as well as
      some behavioral problems and mild dysmorphism.
    explanation: >-
      Documents phenotypic expansion beyond pure cognitive impairment,
      supporting the subtype while qualifying the strictness of its
      non-syndromic classification.
- name: MRX30
  display_name: Intellectual disability, X-linked 30 (PAK3)
  classification: molecular
  subtype_term:
    preferred_term: intellectual disability, X-linked 30
    term:
      id: MONDO:0010361
      label: intellectual disability, X-linked 30
  genes:
  - preferred_term: PAK3
    term:
      id: hgnc:8592
      label: PAK3
  description: >-
    Truncating variants in PAK3 (p21-activated kinase) at Xq22, identified in
    the multiplex MRX30 pedigree. PAK3 couples Rho family GTPases to actin
    cytoskeletal reorganisation in postmitotic cortical and hippocampal
    neurons, and this subtype anchors the Rho GTPase theme that recurs across
    the class. MRI was normal in affected individuals - the imaging correlate
    of a functional rather than structural lesion.
  evidence:
  - reference: PMID:9731525
    reference_title: "PAK3 mutation in nonsyndromic X-linked mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals in a multiplex pedigree with MRX (MRX30),
      previously mapped to Xq22, show a point mutation in the PAK3
      (p21-activated kinase) gene, which encodes a serine-threonine kinase.
    explanation: >-
      Establishes the PAK3 lesion defining the MRX30 subtype.
  - reference: PMID:9731525
    reference_title: "PAK3 mutation in nonsyndromic X-linked mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRI analysis showed no gross defects in brain development.
    explanation: >-
      Documents the absence of structural brain malformation that
      distinguishes non-syndromic from malformative X-linked intellectual
      disability.
- name: MRX41
  display_name: Intellectual disability, X-linked 41 (GDI1)
  classification: molecular
  subtype_term:
    preferred_term: intellectual disability, X-linked 41
    term:
      id: MONDO:0010451
      label: intellectual disability, X-linked 41
  genes:
  - preferred_term: GDI1
    term:
      id: hgnc:4226
      label: GDI1
  description: >-
    Missense and null variants in GDI1, encoding alpha-GDI (Rab GDP
    dissociation inhibitor), which recycles Rab GTPases for synaptic vesicle
    traffic; the L92P allele reduces RAB3A binding and recycling. One of the
    purest non-syndromic exemplars in the class - a large German multiplex
    family had neither abnormal body measurements nor any other significant
    clinical problem, and the authors concluded that a clinical diagnosis of
    GDI1-associated disease is impossible.
  evidence:
  - reference: PMID:9620768
    reference_title: "Mutations in GDI1 are responsible for X-linked non-specific mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have found mutations in the GDI1 gene (which encodes uGDI) in two
      families affected with X-linked non-specific mental retardation. One of
      the mutations caused a non-conservative substitution (L92P) which
      reduced binding and recycling of RAB3A, the second was a null mutation.
    explanation: >-
      Establishes the GDI1 subtype and its Rab-recycling mechanism.
  - reference: PMID:22002931
    reference_title: "Novel GDI1 mutation in a large family with nonsyndromic X-linked intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the affected male family members had nonsyndromic intellectual
      disability, that is, they had neither abnormal body measurements nor any
      other significant clinical problems
    explanation: >-
      Confirms the strictly non-syndromic presentation of this subtype in an
      independent multiplex family.
  - reference: PMID:22002931
    reference_title: "Novel GDI1 mutation in a large family with nonsyndromic X-linked intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present family supports the lack of additional phenotypic features
      in patients with GDI1 mutations, rendering a clinical diagnosis of
      GDI1-associated XLID impossible.
    explanation: >-
      States the diagnostic consequence that defines the whole class - with no
      distinguishing features, molecular testing rather than clinical
      recognition is the only route to diagnosis.
- name: MRX58
  display_name: Intellectual disability, X-linked 58 (TSPAN7/TM4SF2)
  classification: molecular
  subtype_term:
    preferred_term: intellectual disability, X-linked 58
    term:
      id: MONDO:0010266
      label: intellectual disability, X-linked 58
  genes:
  - preferred_term: TSPAN7
    term:
      id: hgnc:11854
      label: TSPAN7
  description: >-
    TSPAN7 (formerly TM4SF2) at Xp11.4, first implicated through an X;2
    balanced translocation that disrupted the gene, then confirmed by point
    variants in MRX families. Encodes a tetraspanin that complexes with
    beta-1 integrins and is implicated in the control of neurite outgrowth,
    contributing to the synapse-formation theme.
  evidence:
  - reference: PMID:10655063
    reference_title: "A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we show that the gene TM4SF2 at Xp11.4 is inactivated by the X
      breakpoint of an X;2 balanced translocation in a patient with MR.
      Further investigation led to identification of TM4SF2 mutations in 2 of
      33 other MRX families.
    explanation: >-
      Establishes the TSPAN7/TM4SF2 subtype through two independent lines of
      genetic evidence.
  - reference: PMID:10655063
    reference_title: "A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      TM4SF2 encodes a member of the tetraspanin family of proteins, which are
      known to contribute in molecular complexes including beta-1 integrins.
      We speculate that through this interaction, TM4SF2 might have a role in
      the control of neurite outgrowth.
    explanation: >-
      Assigns the subtype to the neurite-outgrowth/synapse-formation theme;
      marked PARTIAL because the source explicitly frames the mechanism as
      speculation.
- name: MRX9
  display_name: Intellectual disability, X-linked 9 (FTSJ1)
  classification: molecular
  subtype_term:
    preferred_term: intellectual disability, X-linked 9
    term:
      id: MONDO:0010660
      label: intellectual disability, X-linked 9
  genes:
  - preferred_term: FTSJ1
    term:
      id: hgnc:13254
      label: FTSJ1
  description: >-
    Loss-of-function variants in FTSJ1, the human TRM7 homolog, which
    2'-O-methylates positions C32 and G34 of the tRNA anticodon loop. Patient
    cell lines almost completely lack Cm32 and Gm34 on tRNA-Phe. Places
    translational fidelity - rather than synaptic structure - in the
    mechanistic theme set for this class, and provides a directly measurable
    molecular readout, unusual for non-syndromic intellectual disability.
  evidence:
  - reference: PMID:26310293
    reference_title: "Defects in tRNA Anticodon Loop 2'-O-Methylation Are Implicated in Nonsyndromic X-Linked Intellectual Disability due to Mutations in FTSJ1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mutations in human FTSJ1, the likely TRM7 homolog, cause nonsyndromic
      X-linked intellectual disability (NSXLID), but the role of FTSJ1 in tRNA
      modification is unknown.
    explanation: >-
      Establishes FTSJ1 as a non-syndromic X-linked intellectual disability
      gene.
  - reference: PMID:26310293
    reference_title: "Defects in tRNA Anticodon Loop 2'-O-Methylation Are Implicated in Nonsyndromic X-Linked Intellectual Disability due to Mutations in FTSJ1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we report that tRNA(Phe) from two genetically independent cell lines of
      NSXLID patients with loss-of-function FTSJ1 mutations nearly completely
      lacks Cm32 and Gm34 , and has reduced peroxywybutosine (o2yW37 )
    explanation: >-
      Provides the direct biochemical consequence of FTSJ1 loss in patient
      cells, grounding the tRNA-modification mechanism.
- name: MRX63
  display_name: Intellectual disability, X-linked 63 (ACSL4/FACL4)
  classification: molecular
  subtype_term:
    preferred_term: intellectual disability, X-linked 63
    term:
      id: MONDO:0010313
      label: intellectual disability, X-linked 63
  genes:
  - preferred_term: ACSL4
    term:
      id: hgnc:3571
      label: ACSL4
  description: >-
    Null variants in ACSL4 (FACL4), encoding fatty acid-CoA ligase 4, mapped
    to Xq22.3 by comparing deletion extents between contiguous-gene ATS-MR
    patients and Alport-only patients. The first gene to link non-syndromic
    intellectual disability to fatty-acid metabolism, and the subtype in which
    complete X-inactivation skewing in carrier females is best documented.
  evidence:
  - reference: PMID:11889465
    reference_title: "FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report the identification of two point mutations, one missense
      and one splice-site change, in the gene FACL4 in two families with
      nonspecific mental retardation.
    explanation: >-
      Establishes the ACSL4/FACL4 subtype in non-specific (non-syndromic)
      X-linked intellectual disability.
  - reference: PMID:11889465
    reference_title: "FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FACL4 is the first gene shown to be involved in nonspecific mental
      retardation and fatty-acid metabolism.
    explanation: >-
      Places lipid metabolism in the mechanistic theme set for this class.
- name: FRAXE
  display_name: FRAXE intellectual disability (AFF2/FMR2)
  classification: molecular
  subtype_term:
    preferred_term: FRAXE intellectual disability
    term:
      id: MONDO:0010659
      label: FRAXE intellectual disability
  genes:
  - preferred_term: AFF2
    term:
      id: hgnc:3776
      label: AFF2
  description: >-
    CCG repeat expansion and consequent methylation-mediated silencing of AFF2
    (FMR2) at the FRAXE folate-sensitive fragile site in Xq28. Mechanistically
    the repeat-expansion member of the class and the closest non-syndromic
    counterpart to fragile X syndrome, from which it is distinguished by a
    milder cognitive phenotype without the fragile X somatic features. AFF2 is
    among the genes found in non-syndromal families that were never assigned
    an IDX number.
  evidence:
  - reference: PMID:8673086
    reference_title: "Identification of FMR2, a novel gene associated with the FRAXE CCG repeat and CpG island."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mild mental retardation without consistent physical findings has been
      found associated with expanded CCG repeats at FRAXE.
    explanation: >-
      Establishes both defining properties of this subtype in one statement:
      the repeat-expansion mechanism, and the non-syndromic phenotype
      (mild impairment WITHOUT consistent physical findings), which is what
      qualifies it for this entry.
  - reference: PMID:8673086
    reference_title: "Identification of FMR2, a novel gene associated with the FRAXE CCG repeat and CpG island."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified a large gene (FMR2) transcribed distally from the CpG
      island at FRAXE, and down-regulated by repeat expansion and methylation.
    explanation: >-
      Provides the methylation-mediated silencing mechanism asserted in this
      subtype's description, which the sequence-variant evidence cited
      elsewhere does not cover.
  - reference: PMID:8673086
    reference_title: "Identification of FMR2, a novel gene associated with the FRAXE CCG repeat and CpG island."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FRAXA expansion results in fragile X syndrome due to down regulation of
      expression of the FMR1 gene
    explanation: >-
      Grounds the contrast with fragile X syndrome drawn in this subtype's
      description - the two are parallel folate-sensitive fragile-site
      expansions with different genes and different phenotypic severity.
  - reference: PMID:29696803
    reference_title: "X-linked intellectual disability update 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence variants in 11 genes (KLF8, AFF2, SLC6A8, NDUFA1, ALG13, SRPX2,
      ATRX, NLGN3, FGDY, CDKL5, and NLGN4) have been found in families with
      IDX but in whom IDX numbers were never assigned.
    explanation: >-
      Places AFF2 among the genes causing non-syndromal (IDX) X-linked
      intellectual disability; marked PARTIAL because this passage concerns
      sequence variants, a different mutational class from the repeat
      expansion that defines the FRAXE subtype.
- name: ARX-related
  display_name: Intellectual disability, X-linked, with or without seizures (ARX)
  classification: molecular
  subtype_term:
    preferred_term: intellectual disability, X-linked, with or without seizures, ARX-related
    term:
      id: MONDO:0010317
      label: intellectual disability, X-linked, with or without seizures, ARX-related
  genes:
  - preferred_term: ARX
    term:
      id: hgnc:18060
      label: ARX
  description: >-
    The non-syndromic end of the ARX allelic series. ARX encodes an
    Aristaless-related homeobox transcription factor expressed specifically in
    telencephalon and ventral thalamus. Polyalanine-tract expansions and
    certain missense alleles produce intellectual disability with or without
    seizures and no detectable brain malformation, and account for nine
    separately numbered nonsyndromal IDX families. Other alleles in the same
    gene cause distinct syndromic entities (X-linked lissencephaly with
    abnormal genitalia, Partington syndrome, West and Ohtahara syndromes,
    Proud syndrome) that are deliberately NOT modelled here. This subtype is
    therefore the worked example of why the syndromic/non-syndromic boundary
    in this class is a property of the allele rather than of the gene.
  evidence:
  - reference: PMID:11971879
    reference_title: "ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Inherited and de novo ARX mutations, including missense mutations and in
      frame duplications/insertions leading to expansions of polyalanine
      tracts in ARX, were found in nine familial and one sporadic case of MR.
    explanation: >-
      Establishes the ARX allelic spectrum, including the polyalanine
      expansions associated with the milder non-syndromic end of the series.
  - reference: PMID:11971879
    reference_title: "ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The absence of detectable brain malformations in patients suggests that
      ARX may have an essential role, in mature neurons, required for the
      development of cognitive abilities.
    explanation: >-
      Confirms the non-syndromic, non-malformative presentation of these ARX
      alleles, distinguishing them from the lissencephaly-causing alleles in
      the same gene.
  - reference: PMID:29696803
    reference_title: "X-linked intellectual disability update 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is not the case for ARX variants, which have been found in the
      disparate phenotypes of Partington syndrome, West syndrome, X-linked
      lissencephaly with abnormal genitalia, hydranencephaly with abnormal
      genitalia, Proud syndrome, Ohtahara syndrome as well as nonsyndromal
      XLID (IDX 29, 32, 33, 36, 38, 43, 54, 76, 87).
    explanation: >-
      Documents that ARX spans both syndromic entities and nine separately
      numbered nonsyndromal IDX families, which is the basis for modelling
      only the nonsyndromal arm here.
  - reference: PMID:31898314
    reference_title: "Non-syndromic X linked intellectual disability: Current knowledge in light of the recent advances in molecular and functional studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      this classification is not always clear-cut because distinct variants in
      several of these XLID genes can result in S-XLID as well as in NS-XLID
    explanation: >-
      Provides the general principle that licenses admitting one allelic arm
      of a gene to this class while leaving its syndromic alleles to separate
      entities - the reasoning applied to ARX here.

- name: MRX1
  display_name: Intellectual disability, X-linked 1 (IQSEC2)
  classification: molecular
  subtype_term:
    preferred_term: intellectual disability, X-linked 1
    term:
      id: MONDO:0010656
      label: intellectual disability, X-linked 1
  genes:
  - preferred_term: IQSEC2
    term:
      id: hgnc:29059
      label: IQSEC2
  description: >-
    The founding entity of the whole numbered series: MRX1 is the family
    mapped in 1988 that gave the series its first number, and its causal gene
    was not identified until X-chromosome exome resequencing reached it in
    2010. IQSEC2 encodes a guanine nucleotide exchange factor for the
    ADP-ribosylation factor family of small GTPases, placing this subtype in
    the same small-GTPase-signalling theme as PAK3 and RAB39B rather than in a
    pathway of its own. Three further X-linked intellectual disability
    families carried IQSEC2 variants in the same study. Two cautions apply to
    this row. First, MONDO merges the former MRX78 into this term and carries
    "IQSEC2-related syndromic intellectual disability" among its exact
    synonyms, so the label under which a given patient is reported varies.
    Second, the allelic spectrum reaches well beyond pure intellectual
    disability - the ClinGen Intellectual Disability and Autism Gene Curation
    Expert Panel curates IQSEC2 against "X-linked complex neurodevelopmental
    disorder" rather than against this class. This row records the
    non-syndromic arm that OMIM and MONDO still number as XLID1, exactly as
    the ARX row records one arm of a wider allelic series.
  evidence:
  - reference: PMID:20473311
    reference_title: Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first family identified as having a nonsyndromic intellectual
      disability was mapped in 1988. Here we show that a mutation of IQSEC2,
      encoding a guanine nucleotide exchange factor for the ADP-ribosylation
      factor family of small GTPases, caused this disorder.
    explanation: >-
      Establishes IQSEC2 as the causal gene of the index MRX1 family and
      states the non-syndromic presentation and the GEF function on which this
      row rests.
  - reference: PMID:20473311
    reference_title: Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to MRX1, IQSEC2 mutations were identified in three other
      families with X-linked intellectual disability.
    explanation: >-
      Provides the independent families beyond the index pedigree, which is
      what distinguishes a gene assignment from a single-family observation in
      this class.
- name: MRX19
  display_name: Intellectual disability, X-linked 19 (RPS6KA3)
  classification: molecular
  subtype_term:
    preferred_term: intellectual disability, X-linked 19
    term:
      id: MONDO:0010447
      label: intellectual disability, X-linked 19
  genes:
  - preferred_term: RPS6KA3
    term:
      id: hgnc:10432
      label: RPS6KA3
  description: >-
    The attenuated, non-syndromic arm of the RPS6KA3 (RSK2) allelic series,
    whose severe arm is Coffin-Lowry syndrome - curated separately in dismech
    as Coffin-Lowry_Syndrome (MONDO:0010561). RSK2 is a serine-threonine
    kinase, and the variants reported in this arm are single-amino-acid
    deletions and a missense change in the protein's proximal domain, similar
    in kind to Coffin-Lowry alleles; two of the three reported families had
    been given a non-syndromic clinical diagnosis, and in the third
    Coffin-Lowry had been suspected but the features were atypical and the
    intellectual disability much milder than expected. The clinically
    important consequence, and the reason the row is worth modelling
    separately, is diagnostic: the reporting authors conclude that strict
    reliance on classical clinical criteria for mutation testing may result in
    a missed diagnosis. ClinGen's Intellectual Disability and Autism Gene
    Curation Expert Panel curates RPS6KA3 only against Coffin-Lowry syndrome,
    so this arm has no separate expert-panel classification.
  evidence:
  - reference: PMID:17100996
    reference_title: Mutations in the RSK2(RPS6KA3) gene cause Coffin-Lowry syndrome and nonsyndromic X-linked mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe three families with X-linked mental retardation, two with a
      deletion of a single amino acid and one with a missense mutation in the
      proximal domain of the RSK2(RPS6KA3) (ribosomal protein S6 kinase, 90
      kDa, polypeptide 3) protein similar to mutations found in Coffin-Lowry
      syndrome (CLS).
    explanation: >-
      Establishes the allele class of this arm and its relation to the
      Coffin-Lowry allele spectrum in the same gene.
  - reference: PMID:17100996
    reference_title: Mutations in the RSK2(RPS6KA3) gene cause Coffin-Lowry syndrome and nonsyndromic X-linked mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In two families, the clinical diagnosis had been nonsyndromic X-linked
      mental retardation.
    explanation: >-
      States the non-syndromic clinical assignment that places this arm in
      this class rather than under Coffin-Lowry syndrome.
- name: MRX50
  display_name: Intellectual disability, X-linked 50 (SYN1)
  classification: molecular
  subtype_term:
    preferred_term: intellectual disability, X-linked 50
    term:
      id: MONDO:0010251
      label: intellectual disability, X-linked 50
  genes:
  - preferred_term: SYN1
    term:
      id: hgnc:11494
      label: SYN1
  description: >-
    A missense variant in SYN1, encoding the presynaptic phosphoprotein
    synapsin I, segregating in the MRX50 family, in which intellectual
    disability is the sole clinical manifestation in every affected member -
    which makes this one of the strictest non-syndromic rows in the entry.
    SYN1 regulates neurotransmitter release and neuronal development, so the
    subtype belongs to the synaptic-vesicle theme alongside GDI1 and TSPAN7.
    It is a distinct allelic entity from the SYN1 epilepsy/autism disorder
    (MONDO:0010339), which dismech curates separately as SYN1-Related_Disorder:
    the authors of this report make exactly that point, noting that distinct
    SYN1 mutations may lead to distinct brain pathologies. ClinGen's
    Intellectual Disability and Autism Gene Curation Expert Panel lumps SYN1
    under "X-linked complex neurodevelopmental disorder" and does not curate
    this arm separately.
  evidence:
  - reference: PMID:28973667
    reference_title: "A novel SYN1 missense mutation in non-syndromic X-linked intellectual disability affects synaptic vesicle life cycle, clustering and mobility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a missense mutation (c.236 C > G; p.S79W) in the SYN1 gene
      coding for synapsin I in the MRX50 family, affected by non-syndromic
      X-linked intellectual disability.
    explanation: >-
      Ties the causal gene and allele directly to the numbered MRX50 family
      and to the non-syndromic designation this row carries.
  - reference: PMID:28973667
    reference_title: "A novel SYN1 missense mutation in non-syndromic X-linked intellectual disability affects synaptic vesicle life cycle, clustering and mobility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The S79W mutation segregates with the disease in the MRX50 family and
      all affected members display intellectual disability as sole clinical
      manifestation.
    explanation: >-
      The explicit statement of sole-feature presentation, which is the
      defining criterion for membership of this class.
- name: MRX72
  display_name: Intellectual disability, X-linked 72 (RAB39B)
  classification: molecular
  subtype_term:
    preferred_term: intellectual disability, X-linked 72
    term:
      id: MONDO:0010289
      label: intellectual disability, X-linked 72
  genes:
  - preferred_term: RAB39B
    term:
      id: hgnc:16499
      label: RAB39B
  description: >-
    Null alleles of RAB39B, a neuronal-specific small GTPase of the Golgi
    compartment, identified in two male patients - one of them in the MRX72
    family, where a 5' splice-site change abolished normal splicing. Its
    downregulation alters neurite growth cone number and morphology and
    reduces presynaptic boutons, placing the subtype in the vesicular
    trafficking theme. Intellectual disability was accompanied by autism
    spectrum disorder, epileptic seizures and macrocephaly in some, not all,
    affected family members, which is the variable-comorbidity pattern this
    class tolerates rather than a reproducible syndromic signature. The row
    carries a live caveat: the ClinGen Intellectual Disability and Autism
    Gene Curation Expert Panel curates RAB39B as Definitive against an
    early-onset parkinsonism-intellectual disability syndrome
    (MONDO:0010709), a separate MONDO term with no dismech entry, rather than
    against this one. Parkinsonism is not reported in the founding MRX72
    publication, so the two entities are separated here by phenotype and age
    of onset rather than by allele, and this row should not be read as
    covering the parkinsonism entity.
  evidence:
  - reference: PMID:20159109
    reference_title: "Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A second mutation, in the MRX72 family, altered the 5' splice site
      (c.215+1G > A) and normal splicing.
    explanation: >-
      Ties RAB39B to the numbered MRX72 family that this subtype term denotes,
      and states the allele class.
  - reference: PMID:20159109
    reference_title: "Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations segregate with the disease in the families, and in some family
      members intellectual disabilities were associated with autism spectrum
      disorder, epileptic seizures, and macrocephaly.
    explanation: >-
      Documents the associated features and, critically for the scope call,
      that they occur in only some family members rather than reproducibly.
  - reference: PMID:20159109
    reference_title: "Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Its downregulation leads to an alteration in the number and morphology
      of neurite growth cones and a significant reduction in presynaptic
      buttons, suggesting that RAB39B is required for synapse formation and
      maintenance.
    explanation: >-
      Supplies the cellular mechanism linking this gene to the entry's shared
      synaptic endpoint.
- name: MRX90
  display_name: Intellectual disability, X-linked 90 (DLG3)
  classification: molecular
  subtype_term:
    preferred_term: intellectual disability, X-linked 90
    term:
      id: MONDO:0010452
      label: intellectual disability, X-linked 90
  genes:
  - preferred_term: DLG3
    term:
      id: hgnc:2902
      label: DLG3
  description: >-
    Truncating variants in DLG3, which encodes synapse-associated protein 102
    (SAP102), found in 4 of 329 families screened for moderate to severe
    X-linked intellectual disability - among the higher per-gene yields in the
    class. SAP102 is a membrane-associated guanylate kinase localised to the
    postsynaptic density of excitatory synapses, whose PDZ domains bind the
    NR2 subunits of the NMDA receptor. Every reported allele truncates within
    or before the third PDZ domain, so the proposed mechanism is loss of NMDA
    receptor targeting and downstream signalling, which is the most direct
    molecular route to the impaired synaptic plasticity this entry models as
    the shared endpoint. Together with SYP this is one of only two genes in
    the whole checklist that the ClinGen Intellectual Disability and Autism
    Gene Curation Expert Panel curates against this entry's own MONDO term
    rather than against a broader neurodevelopmental anchor, and it holds the
    Definitive classification.
  evidence:
  - reference: PMID:15185169
    reference_title: Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified truncating mutations in the human DLG3
      (neuroendocrine dlg) gene in 4 of 329 families with moderate to severe
      X-linked mental retardation.
    explanation: >-
      Establishes the gene assignment and gives the per-cohort yield quoted in
      this row's description.
  - reference: PMID:15185169
    reference_title: Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutations identified in this study all introduce premature stop
      codons within or before the third PDZ domain, and it is likely that this
      impairs the ability of SAP102 to interact with the NMDA receptor and/or
      other proteins involved in downstream NMDA receptor signaling pathways.
    explanation: >-
      Supplies the allele class and the proposed loss-of-function mechanism at
      the NMDA receptor, stated by the authors as a likelihood rather than a
      demonstration.
- name: MRX96
  display_name: Intellectual disability, X-linked 96 (SYP)
  classification: molecular
  subtype_term:
    preferred_term: intellectual disability, X-linked 96
    term:
      id: MONDO:0010429
      label: intellectual disability, X-linked 96
  genes:
  - preferred_term: SYP
    term:
      id: hgnc:11506
      label: SYP
  description: >-
    SYP, encoding synaptophysin, was one of nine genes implicated in X-linked
    intellectual disability by the systematic resequencing of X-chromosome
    coding exons in 208 families. Synaptophysin is an integral
    synaptic vesicle protein accounting for roughly a tenth of total synaptic
    vesicle protein cargo; four separate SYP variants were found in affected
    families. Functional follow-up in synaptophysin-knockout mouse neurons
    showed that the patient variants fail to support efficient retrieval of
    synaptobrevin II, giving this subtype a defined lesion in the synaptic
    vesicle cycle. The ClinGen Intellectual Disability and Autism Gene
    Curation Expert Panel curates SYP against this entry's own MONDO term and
    classifies the relationship as Moderate, so the gene assignment is
    supported but not yet definitive.
  evidence:
  - reference: PMID:19377476
    reference_title: "A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The screen has discovered nine genes implicated in XLMR, including SYP,
      ZNF711 and CASK reported here, confirming the power of this strategy.
    explanation: >-
      The primary gene-discovery statement for both this row and the ZNF711
      row, from the screen that reported them.
  - reference: PMID:23966691
    reference_title: X-linked intellectual disability-associated mutations in synaptophysin disrupt synaptobrevin II retrieval.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Synaptophysin has been implicated in X-linked intellectual disability,
      with a recent study identifying four separate synaptophysin gene
      mutations in families affected by the disorder.
    explanation: >-
      Independent restatement of the human genetic finding, giving the number
      of variant families. Graded HUMAN_CLINICAL for the evidence the sentence
      describes with quote_role BACKGROUND because the citing paper is a
      mouse-neuron functional study restating somebody else's human genetics
      in its introduction.
  - reference: PMID:23966691
    reference_title: X-linked intellectual disability-associated mutations in synaptophysin disrupt synaptobrevin II retrieval.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Two distinct truncating mutants were mislocalized throughout the axon
      and phenocopied the arrest of sybII retrieval in synaptophysin knock-out
      cultures.
    explanation: >-
      Functional consequence of the patient alleles in cultured neurons,
      supplying the mechanism this row attributes to the subtype.
- name: MRX97
  display_name: Intellectual disability, X-linked 97 (ZNF711)
  classification: molecular
  subtype_term:
    preferred_term: intellectual disability, X-linked 97
    term:
      id: MONDO:0010430
      label: intellectual disability, X-linked 97
  genes:
  - preferred_term: ZNF711
    term:
      id: hgnc:13128
      label: ZNF711
  description: >-
    ZNF711 was implicated by the same 208-family X-chromosome resequencing
    screen that reported SYP, and was subsequently confirmed in two large
    four-generation pedigrees with eleven affected males, bringing the total
    to four families. The consistent picture is mild to moderate intellectual
    disability with poor speech; autistic features and mild facial
    dysmorphisms occur in some patients but not reproducibly, which is why the
    reporting authors themselves conclude the phenotype is non-syndromic. Note
    that this subtype is distinct from contiguous-gene deletions at Xq21 that
    remove ZNF711 along with neighbouring genes, which dismech models
    elsewhere as Choroideremia-Deafness-Obesity_Syndrome.
  evidence:
  - reference: PMID:27993705
    reference_title: Mutations in two large pedigrees highlight the role of ZNF711 in X-linked intellectual disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we present two large four-generation families with a total of 11
      males affected with ID caused by mutations in ZNF711, thereby expanding
      the total number of families with ID and a ZNF711 mutation to four.
    explanation: >-
      Gives the replication that carries this gene assignment beyond its
      single discovery screen, and the family count quoted in the description.
  - reference: PMID:27993705
    reference_title: Mutations in two large pedigrees highlight the role of ZNF711 in X-linked intellectual disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with mutations in ZNF711 all present with mild to moderate ID
      and poor speech accompanied by additional features in some patients,
      including autistic features and mild facial dysmorphisms, suggesting
      that ZNF711 mutations cause non-syndromic ID.
    explanation: >-
      The authors' own non-syndromic assignment, together with the qualifier
      that additional features appear only in some patients - the exact
      distinction this class turns on.
- name: MRX101
  display_name: Intellectual disability, X-linked 101 (MID2)
  classification: molecular
  subtype_term:
    preferred_term: intellectual disability, X-linked 101
    term:
      id: MONDO:0010489
      label: intellectual disability, X-linked 101
  genes:
  - preferred_term: MID2
    term:
      id: hgnc:7096
      label: MID2
  description: >-
    A missense variant in MID2, encoding an E3 ubiquitin ligase, reported as
    the likely cause of X-linked intellectual disability in one large Indian
    kindred, where it was present in all affected males and obligate carriers
    and absent from unaffected males and from 200 population controls. The
    variant abolishes the function of the protein's COS domain, and the mutant
    protein accumulates in the cytoplasm instead of binding the cytoskeleton.
    This row rests on a single large pedigree plus one further variant found
    by screening 480 unrelated individuals, and MID2 has no ClinGen
    gene-disease validity curation, so the assignment is thinner than most in
    this entry and is recorded with that caveat. It is the ubiquitin-pathway
    theme's entry point in the class, and the authors emphasise that the MID2
    phenotype differs from that reported for its paralogue MID1.
  evidence:
  - reference: PMID:24115387
    reference_title: Targeted deep resequencing identifies MID2 mutation for X-linked intellectual disability with varied disease severity in a large kindred from India.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a novel missense mutation (c.1040G>A, p.Arg347Gln) in MID2,
      which encodes ubiquitin ligase E3, as the likely cause of X-linked
      mental retardation in a large kindred.
    explanation: >-
      The gene assignment, stated by the authors themselves as a likelihood
      rather than a certainty - the hedge this row preserves.
  - reference: PMID:24115387
    reference_title: Targeted deep resequencing identifies MID2 mutation for X-linked intellectual disability with varied disease severity in a large kindred from India.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation was observed in all affected and obligate carriers but not
      in any unaffected males of the family or in population controls (n =
      200).
    explanation: >-
      The segregation and control data that constitute the evidence base for
      this subtype, and the control count quoted in the description.
- name: MRX103
  display_name: Intellectual disability, X-linked 103 (KLHL15)
  classification: molecular
  subtype_term:
    preferred_term: intellectual disability, X-linked 103
    term:
      id: MONDO:0010508
      label: intellectual disability, X-linked 103
  genes:
  - preferred_term: KLHL15
    term:
      id: hgnc:29347
      label: KLHL15
  description: >-
    KLHL15 was one of seven novel and validated X-linked intellectual
    disability genes identified by X-exome sequencing of 405 unresolved
    families - the study that also delivered FRMPD4 and USP27X in this entry.
    A protein-truncating variant was found in a large family, with further
    support from an unrelated family carrying a partial KLHL15 deletion.
    KLHL15 is a kelch-like protein that acts as a substrate adaptor for
    Cul3-based E3 ubiquitin ligases, targeting a brain-specific regulatory
    subunit of protein phosphatase 2A for proteasomal degradation, so like
    MID2 and USP27X it belongs to the ubiquitin-proteasome theme. The
    phenotype is not uniformly pure: the same report notes a KLHL15 partial
    deletion described in a proband with severe intellectual disability,
    epilepsy and cortical developmental anomalies, and KLHL15 has no ClinGen
    gene-disease validity curation.
  evidence:
  - reference: PMID:25644381
    reference_title: X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 19 families, we detected likely causative protein truncating and
      missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2,
      FRMPD4, KLHL15, LAS1L, RLIM and USP27X)
    explanation: >-
      The gene-discovery statement underlying this row and the USP27X row, and
      one of the two independent lines behind the FRMPD4 row.
  - reference: PMID:25644381
    reference_title: X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further support for KLHL15 being implicated in XLID comes from an
      unrelated XLID family, which carries a small deletion that removes part
      of KLHL15
    explanation: >-
      The second, independent family that carries this gene assignment past a
      single observation.
- name: MRX104
  display_name: Intellectual disability, X-linked 104 (FRMPD4)
  classification: molecular
  subtype_term:
    preferred_term: intellectual disability, X-linked 104
    term:
      id: MONDO:0010509
      label: intellectual disability, X-linked 104
  genes:
  - preferred_term: FRMPD4
    term:
      id: hgnc:29007
      label: FRMPD4
  description: >-
    Deleterious FRMPD4 variants - an exon deletion, a nonsense change, a
    frameshift and a conserved-residue missense - in ten affected males from
    four unrelated families. FRMPD4 is a neural scaffolding protein that binds
    PSD-95 to promote dendritic spine morphogenesis and regulates mGluR1/5
    signalling through Homer, so this subtype sits at the postsynaptic
    scaffold alongside DLG3. The frameshift allele disrupts binding to both
    PSD-95 and HOMER1 and fails to increase spine density in transfected
    hippocampal neurons, and knockout mice show hippocampus-dependent spatial
    learning deficits. Two qualifications belong on this row: the reporting
    authors describe the entity as a new X-linked intellectual disability
    syndrome, with language delay, seizures and behavioural or psychiatric
    disturbance alongside moderate-to-severe intellectual disability, and the
    ClinGen Intellectual Disability and Autism Gene Curation Expert Panel
    curates FRMPD4 as Definitive against "X-linked complex neurodevelopmental
    disorder" rather than against this class. OMIM and MONDO nonetheless
    number the entity within the non-syndromic series, and it is recorded here
    on that basis with the comorbidity stated rather than suppressed. A third
    point matters for the evidence audit this entry runs on itself: of the
    fourteen genes admitted in this enumeration pass, FRMPD4 is the only one
    named in either list that the 2013 reassessment against 10,563 control X
    chromosomes singles out, and it falls in the fifteen for which replication
    studies were warranted rather than in the ten whose involvement was
    questioned. Both reports cited on this row postdate that flag and supply
    the independent families it asked for.
  evidence:
  - reference: PMID:29267967
    reference_title: FRMPD4 mutations cause X-linked intellectual disability and disrupt dendritic spine morphogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These mutations were found to be associated with ID in ten affected male
      patients from four unrelated families, following an apparent X-linked
      mode of inheritance.
    explanation: >-
      The cohort and inheritance pattern on which the gene assignment rests.
  - reference: PMID:29267967
    reference_title: FRMPD4 mutations cause X-linked intellectual disability and disrupt dendritic spine morphogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features of these patients consisted of moderate to severe ID,
      language delay and seizures alongside with behavioral and/or psychiatric
      disturbances.
    explanation: >-
      The phenotype statement behind this row's caveat that the presentation
      is not confined to isolated intellectual disability.
  - reference: PMID:29267967
    reference_title: FRMPD4 mutations cause X-linked intellectual disability and disrupt dendritic spine morphogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In-depth functional studies showed that a frame-shift mutation,
      FRMPD4p.Cys618ValfsX8, results in a disruption of FRMPD4 binding with
      PSD-95 and HOMER1, and a failure to increase spine density in transfected
      hippocampal neurons.
    explanation: >-
      The molecular lesion at the postsynaptic scaffold that this row
      attributes to the subtype.
  - reference: PMID:23871722
    reference_title: XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also highlight 15 other genes (CCDC22, CLIC2, CNKSR2, FRMPD4, HCFC1,
      IGBP1, KIAA2022, KLF8, MAOA, NAA10, NLGN3, RPL10, SHROOM4, ZDHHC15, and
      ZNF261) for which replication studies are warranted.
    explanation: >-
      Records that FRMPD4 sits in the "replication warranted" set of the 2013
      control-chromosome reassessment rather than in the questioned set. Cited
      as support for this row's caveat, not against the gene assignment - the
      two reports this row rests on both postdate the reassessment.
- name: MRX105
  display_name: Intellectual disability, X-linked 105 (USP27X)
  classification: molecular
  subtype_term:
    preferred_term: intellectual disability, X-linked 105
    term:
      id: MONDO:0010510
      label: intellectual disability, X-linked 105
  genes:
  - preferred_term: USP27X
    term:
      id: hgnc:13486
      label: USP27X
  description: >-
    USP27X, encoding ubiquitin-specific peptidase 27, was identified in the
    same X-exome screen of 405 unresolved families as KLHL15 and FRMPD4, with
    a second unrelated family carrying a missense variant substituting a
    highly conserved tryptophan. The gene's function in neurons is largely
    uncharacterised - its only known interaction partner is USP22, required
    for glial and neuronal development in flies - so this subtype currently
    has a gene assignment without a worked-out mechanism, and the entry wires
    it to the class's shared convergent node rather than to a specific
    pathway. The ClinGen Intellectual Disability and Autism Gene Curation
    Expert Panel classifies USP27X as Moderate against "X-linked complex
    neurodevelopmental disorder".
  evidence:
  - reference: PMID:25644381
    reference_title: X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 19 families, we detected likely causative protein truncating and
      missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2,
      FRMPD4, KLHL15, LAS1L, RLIM and USP27X)
    explanation: >-
      The gene-discovery statement that assigns USP27X to this class.
  - reference: PMID:25644381
    reference_title: X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The unrelated family L75 with four affected males (Figure 2f) carries a
      potentially deleterious missense variant in USP27X, which substitutes a
      highly conserved tryptophane by a histidine residue
    explanation: >-
      The second family behind this assignment, quoted with the authors' own
      "potentially deleterious" hedge preserved.
- name: MRX108
  display_name: Intellectual developmental disorder, X-linked 108 (SLC9A7)
  classification: molecular
  subtype_term:
    preferred_term: intellectual developmental disorder, X-linked 108
    term:
      id: MONDO:0026723
      label: intellectual developmental disorder, X-linked 108
  genes:
  - preferred_term: SLC9A7
    term:
      id: hgnc:17123
      label: SLC9A7
  description: >-
    A recurrent missense variant (p.Leu515Phe) in the alkali cation/proton
    exchanger SLC9A7, segregating with multigenerational non-syndromic
    intellectual disability in two unrelated families. SLC9A7 resides in the
    trans-Golgi network and post-Golgi vesicles; the mutant protein is
    correctly targeted but alkalinises those compartments and impairs N-linked
    oligosaccharide maturation of exported cargo, which the authors read as a
    gain of function. Unusually for a class defined by the absence of
    biochemical features, it comes with a laboratory readout: patient sera
    show an abnormal transferrin N-glycosylation profile, the standard
    diagnostic marker for congenital disorders of glycosylation. SLC9A7 has no
    ClinGen gene-disease validity curation.
  evidence:
  - reference: PMID:30335141
    reference_title: A recurrent missense variant in SLC9A7 causes nonsyndromic X-linked intellectual disability with alteration of Golgi acidification and aberrant glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report two unrelated families with multigenerational nonsyndromic
      intellectual disability (ID) segregating with a recurrent de novo
      missense variant (c.1543C>T:p.Leu515Phe) in the alkali cation/proton
      exchanger gene SLC9A7 (also commonly referred to as NHE7).
    explanation: >-
      Establishes the gene, the recurrent allele, the two-family segregation
      and the explicitly non-syndromic presentation.
  - reference: PMID:30335141
    reference_title: A recurrent missense variant in SLC9A7 causes nonsyndromic X-linked intellectual disability with alteration of Golgi acidification and aberrant glycosylation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This correlated with alkalinization of the TGN/post-Golgi compartments,
      suggestive of a gain-of-function.
    explanation: >-
      The functional consequence, quoted with the authors' own "suggestive"
      hedge on the gain-of-function reading.
- name: IDX110
  display_name: Intellectual developmental disorder, X-linked 110 (FGF13)
  classification: molecular
  subtype_term:
    preferred_term: intellectual developmental disorder, X-linked 110
    term:
      id: MONDO:0859086
      label: intellectual developmental disorder, X-linked 110
  genes:
  - preferred_term: FGF13
    term:
      id: hgnc:3670
      label: FGF13
  description: >-
    A single-nucleotide variant in the 5' untranslated region of FGF13,
    shared by three male children with severe intellectual disability in a
    screen of Chinese Han children. The mechanism is translational rather than
    coding: the variant reduces FGF13 translation by weakening the interaction
    between the 5' UTR and polypyrimidine-tract-binding protein 2, and FGF13
    protein stabilises microtubules in developing neurons. Mice carrying the
    homologous point mutation show delayed neuronal migration during cortical
    development and weakened learning and memory. This row rests on one report
    of three male children plus its mouse model, with no
    ClinGen gene-disease validity curation and no independent replicating
    family found by a PubMed title search on FGF13 combined with intellectual
    disability, mental retardation or neurodevelopmental (run 2026-09-23),
    which returns this report alone. It is therefore the thinnest gene
    assignment admitted to the entry and should be revisited when a second
    cohort is published.
  evidence:
  - reference: PMID:34184986
    reference_title: "5'-UTR SNP of FGF13 causes translational defect and intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We screened gene mutations in Chinese Han children suffering from severe
      ID and found a single-nucleotide polymorphism (SNP) in the
      5'-untranslated region (5'-UTR) of fibroblast growth factor 13 (FGF13)
      mRNA (NM_001139500.1:c.-32c>G) shared by three male children.
    explanation: >-
      The whole human evidence base for this subtype, stated with its cohort
      size, which is why the description carries an explicit thinness caveat.
  - reference: PMID:34184986
    reference_title: "5'-UTR SNP of FGF13 causes translational defect and intellectual disability."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mice carrying the homologous point mutation in 5'-UTR of Fgf13 showed
      delayed neuronal migration during cortical development, and weakened
      learning and memory.
    explanation: >-
      The in vivo support for causality of the same allele, graded
      MODEL_ORGANISM because the experiment is a mouse knock-in.
- name: IDX112
  display_name: Intellectual developmental disorder, X-linked 112 (ZMYM3)
  classification: molecular
  subtype_term:
    preferred_term: intellectual developmental disorder, X-linked 112
    term:
      id: MONDO:0957496
      label: intellectual developmental disorder, X-linked 112
  genes:
  - preferred_term: ZMYM3
    term:
      id: hgnc:13054
      label: ZMYM3
  description: >-
    Protein-altering variants in ZMYM3, a transcriptional coregulator and
    component of the KDM1A-RCOR1 chromatin-modifying complex, in a
    MatchMaker Exchange cohort of 27 individuals - the largest cohort behind
    any row in this entry. Almost all variants are missense, several recurring
    at the same two residues, and a ChIP-seq experiment on one of them shows
    dramatically reduced genomic occupancy consistent with a hypomorphic
    effect. This places the subtype in the transcriptional-control theme
    alongside ARX and ZNF711 rather than at the synapse. The reported
    phenotype includes developmental delay, intellectual disability and
    behavioural abnormalities, with a specific facial gestalt in a subset of
    males only; the authors state that they cannot perform statistical
    evaluations to definitively support causation and rest the case on the
    totality of the evidence, and ZMYM3 has no ClinGen gene-disease validity
    curation.
  evidence:
  - reference: PMID:36586412
    reference_title: "Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using the MatchMaker Exchange, we assembled a cohort of 27 individuals
      with rare, protein-altering variation in the transcriptional coregulator
      ZMYM3, located on the X chromosome.
    explanation: >-
      Establishes the gene, its molecular class and the cohort size quoted in
      the description.
  - reference: PMID:36586412
    reference_title: "Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overlapping features included developmental delay, intellectual
      disability, behavioral abnormalities, and a specific facial gestalt in a
      subset of males.
    explanation: >-
      The phenotype, including the qualifier that the facial gestalt appears
      in only a subset - the basis for admitting this term to the
      non-syndromic class as MONDO and OMIM do.
  - reference: PMID:36586412
    reference_title: "Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      ZMYM3 is relatively intolerant to variation in the general population,
      is widely expressed across human tissues, and encodes a component of the
      KDM1A-RCOR1 chromatin-modifying complex.
    explanation: >-
      The constraint and expression argument supporting pathogenicity, graded
      COMPUTATIONAL because population-constraint intolerance is derived from
      in-silico analysis of variation databases.

pathophysiology:
- name: X-Linked Gene Disruption
  biological_scale: MOLECULAR
  description: >-
    Rare germline loss-of-function, hypomorphic, repeat-expansion, or
    copy-number variants in any one of a large set of genes on the X
    chromosome remove or reduce the activity of the encoded product in the
    developing and mature brain. The class is clinically homogeneous but
    genetically heterogeneous: variants at many different loci converge on the
    same single clinical outcome, and each individual gene accounts for only a
    small fraction of cases. The X chromosome is disproportionately
    represented among intellectual-disability genes relative to its size.
  evidence:
  - reference: PMID:9731525
    reference_title: "PAK3 mutation in nonsyndromic X-linked mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nonsyndromic X-linked mental retardation (MRX) syndromes are clinically
      homogeneous but genetically heterogeneous disorders, whose genetic bases
      are largely unknown.
    explanation: >-
      States the defining architecture of the class - one phenotype, many
      loci - which is why the numbered MRX series was defined by linkage
      rather than by clinical features.
  - reference: PMID:10655063
    reference_title: "A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At least five MRX genes have been identified by positional cloning, but
      each accounts for only 0.5%-1.0% of MRX cases.
    explanation: >-
      Quantifies the per-gene contribution, establishing that no single gene
      dominates this class.
  - reference: PMID:29696803
    reference_title: "X-linked intellectual disability update 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The X-chromosome comprises only about 5% of the human genome but
      accounts for about 15% of the genes currently known to be associated
      with intellectual disability.
    explanation: >-
      Quantifies the disproportionate contribution of the X chromosome to
      intellectual-disability genetics, the observation that motivated the
      field.
  downstream:
  - target: Hemizygous Male Expression of the Mutant Allele
    causal_link_type: DIRECT
    description: >-
      A variant on the single male X chromosome is expressed without a
      compensating allele. Note this edge encodes a dosage/conditioning
      relationship (hemizygosity is a property of male karyotype, not an event
      caused by the variant) rather than a downstream biochemical step;
      `DIRECT` is used because CausalLinkTypeEnum offers no conditioning
      value.

- name: Hemizygous Male Expression of the Mutant Allele
  biological_scale: CELLULAR
  description: >-
    Males carry one X chromosome, so a loss-of-function allele is expressed in
    every cell with no second copy to buffer it. Heterozygous females are
    mosaic, because random X-chromosome
    inactivation silences one X per cell, so the mutant allele is expressed in
    only a subset of cells; such carriers are typically unaffected or mildly
    affected, and in several subtypes completely skewed X-inactivation
    silences the mutant X entirely. This dosage asymmetry is the mechanistic
    basis of the male excess observed among people with intellectual
    disability, and the mosaicism is the principal obstacle to studying the
    circuit pathophysiology in females.
  evidence:
  - reference: PMID:23871722
    reference_title: "XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Because of the unbalanced sex ratio (1.3-1.4 to 1) observed in
      intellectual disability (ID) and the identification of large ID-affected
      families showing X-linked segregation, much attention has been focused
      on the genetics of X-linked ID (XLID).
    explanation: >-
      Quantifies the male excess that hemizygous expression explains and that
      motivated the field's focus on the X chromosome.
  - reference: PMID:38424476
    reference_title: "Overcoming genetic and cellular complexity to study the pathophysiology of X-linked intellectual disabilities."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This mosaic expression produces substantial complexity, especially when
      attempting to study the already complicated neural circuits that underly
      behavior, thus impeding the understanding of disease-related
      pathophysiology and the development of therapeutics.
    explanation: >-
      Establishes the consequence of female mosaicism for mechanistic study
      and therapeutic development in this class. Tagged OTHER: the quoted
      sentence is a methodological statement about the difficulty of studying
      mosaic neural circuits, not a human clinical observation.
  - reference: PMID:11889465
    reference_title: "FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All carrier females with either point mutations or genomic deletions in
      FACL4 showed a completely skewed X-inactivation, suggesting that the
      gene influences survival advantage.
    explanation: >-
      Demonstrates the complete X-inactivation skewing that spares carrier
      females in this class.
  downstream:
  - target: Convergent Disruption of Neuronal Function
    causal_link_type: DIRECT
    description: >-
      Loss of the gene product in neurons impairs the synaptic processes it
      supports.

- name: Convergent Disruption of Neuronal Function
  genes:
  - preferred_term: PAK3
    term:
      id: hgnc:8592
      label: PAK3
  - preferred_term: GDI1
    term:
      id: hgnc:4226
      label: GDI1
  - preferred_term: IL1RAPL1
    term:
      id: hgnc:5996
      label: IL1RAPL1
  - preferred_term: TSPAN7
    term:
      id: hgnc:11854
      label: TSPAN7
  - preferred_term: FTSJ1
    term:
      id: hgnc:13254
      label: FTSJ1
  - preferred_term: ACSL4
    term:
      id: hgnc:3571
      label: ACSL4
  - preferred_term: AFF2
    term:
      id: hgnc:3776
      label: AFF2
  - preferred_term: ARX
    term:
      id: hgnc:18060
      label: ARX
  - preferred_term: SLC9A7
    term:
      id: hgnc:17123
      label: SLC9A7
  - preferred_term: IQSEC2
    term:
      id: hgnc:29059
      label: IQSEC2
  - preferred_term: RPS6KA3
    term:
      id: hgnc:10432
      label: RPS6KA3
  - preferred_term: SYN1
    term:
      id: hgnc:11494
      label: SYN1
  - preferred_term: RAB39B
    term:
      id: hgnc:16499
      label: RAB39B
  - preferred_term: DLG3
    term:
      id: hgnc:2902
      label: DLG3
  - preferred_term: SYP
    term:
      id: hgnc:11506
      label: SYP
  - preferred_term: ZNF711
    term:
      id: hgnc:13128
      label: ZNF711
  - preferred_term: MID2
    term:
      id: hgnc:7096
      label: MID2
  - preferred_term: KLHL15
    term:
      id: hgnc:29347
      label: KLHL15
  - preferred_term: FRMPD4
    term:
      id: hgnc:29007
      label: FRMPD4
  - preferred_term: USP27X
    term:
      id: hgnc:13486
      label: USP27X
  - preferred_term: FGF13
    term:
      id: hgnc:3670
      label: FGF13
  - preferred_term: ZMYM3
    term:
      id: hgnc:13054
      label: ZMYM3
  biological_scale: CELLULAR
  description: >-
    Although the causal genes do not share a single pathway, their products
    fall repeatedly into a limited set of themes that converge on the same
    functional endpoint: Rho GTPase signalling to the actin cytoskeleton
    (PAK3), Rab-dependent synaptic vesicle recycling (GDI1), proposed roles in excitatory synapse
    formation and neurite outgrowth (IL1RAPL1, TSPAN7 - both inferred rather
    than directly demonstrated in the cited reports), tRNA anticodon-loop modification and translational fidelity
    (FTSJ1), fatty-acid metabolism (ACSL4), Golgi/trans-Golgi-network pH
    regulation and glycosylation (SLC9A7), transcriptional activation (AFF2,
    silenced by the FRAXE repeat expansion), and telencephalic transcriptional
    control (ARX). Most of these arms act on synapse formation, maintenance,
    and plasticity, and synaptic convergence is the field's dominant framing
    of the class. It is not, however, established for all of them: the
    tRNA-modification (FTSJ1), fatty-acid (ACSL4), Golgi-pH (SLC9A7), and
    transcriptional (AFF2) arms have documented molecular and cellular
    consequences but no cited evidence of a synaptic endpoint, so the node is
    deliberately named for neuronal rather than synaptic function. What is shared across every arm is that
    convergence happens at the level of neuronal cell biology rather than
    through a common molecular pathway - which is why no single
    pathway-directed therapy addresses the class. Enumerating the rest of the
    numbered series adds further themes without disturbing that conclusion:
    postsynaptic scaffolding at the NMDA receptor and the dendritic spine
    (DLG3, FRMPD4), synaptic vesicle clustering, mobility and cargo retrieval
    (SYN1, SYP), presynaptic terminal formation and maintenance from the Golgi
    (RAB39B), ubiquitin-proteasome substrate handling (MID2, KLHL15, USP27X),
    chromatin and transcriptional coregulation (ZNF711, ZMYM3), Arf-family
    guanine-nucleotide exchange (IQSEC2), serine-threonine kinase signalling
    (RPS6KA3) and microtubule stabilisation in developing neurons (FGF13). The
    ubiquitin arm is the clearest illustration that convergence here is
    thematic rather than directional: MID2 and KLHL15 are ubiquitin-ligase
    pathway components whose loss impairs degradation of specific substrates,
    whereas USP27X is a deubiquitinase, so the arm has no single direction and
    its process annotation deliberately carries no modifier. USP27X is also
    the one gene admitted here with essentially no characterised neuronal
    function, so for that arm this node records convergence without a
    mechanism.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
    modifier: DECREASED
  - preferred_term: regulation of synapse structure or activity
    term:
      id: GO:0050803
      label: regulation of synapse structure or activity
    modifier: DECREASED
  - preferred_term: Rho protein signal transduction
    term:
      id: GO:0007266
      label: Rho protein signal transduction
    modifier: DECREASED
  - preferred_term: vesicle-mediated transport
    term:
      id: GO:0016192
      label: vesicle-mediated transport
    modifier: DECREASED
  - preferred_term: tRNA modification
    term:
      id: GO:0006400
      label: tRNA modification
    modifier: DECREASED
  - preferred_term: Golgi and post-Golgi pH regulation
    term:
      id: GO:0051453
      label: regulation of intracellular pH
    modifier: DECREASED
  - preferred_term: glycosylation of exported cargo
    term:
      id: GO:0009101
      label: glycoprotein biosynthetic process
    modifier: DECREASED
  - preferred_term: FMR2/AFF2-dependent transcriptional activation
    term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    modifier: DECREASED
  - preferred_term: postsynaptic density organization
    term:
      id: GO:0097106
      label: postsynaptic density organization
    modifier: DECREASED
  - preferred_term: synaptic vesicle endocytosis and cargo retrieval
    term:
      id: GO:0048488
      label: synaptic vesicle endocytosis
    modifier: DECREASED
  - preferred_term: ubiquitin-proteasome substrate handling
    term:
      id: GO:0006511
      label: ubiquitin-dependent protein catabolic process
  - preferred_term: chromatin and transcriptional coregulation
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: DECREASED
  - preferred_term: microtubule stabilisation in developing neurons
    term:
      id: GO:0000226
      label: microtubule cytoskeleton organization
    modifier: DECREASED
  evidence:
  - reference: PMID:9731525
    reference_title: "PAK3 mutation in nonsyndromic X-linked mental retardation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PAK proteins are crucial effectors linking Rho GTPases to cytoskeletal
      reorganization and to nuclear signalling.
    explanation: >-
      Establishes the Rho GTPase-to-cytoskeleton arm of the convergence.
      Tagged OTHER: this is a background statement of established protein
      function, not a result generated by the cited study.
  - reference: PMID:9731525
    reference_title: "PAK3 mutation in nonsyndromic X-linked mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Signal transduction through Rho GTPases and PAK3 may be critical for
      human cognitive function.
    explanation: >-
      Connects the Rho GTPase theme directly to the cognitive endpoint.
  - reference: PMID:9620768
    reference_title: "Mutations in GDI1 are responsible for X-linked non-specific mental retardation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rab GDP-dissociation inhibitors (GDI) are evolutionarily conserved
      proteins that play an essential role in the recycling of Rab GTPases
      required for vesicular transport through the secretory pathway.
    explanation: >-
      Establishes the vesicle-trafficking arm of the convergence. Tagged
      OTHER: a background statement of established protein function rather
      than a result of the cited study.
  - reference: PMID:26310293
    reference_title: "Defects in tRNA Anticodon Loop 2'-O-Methylation Are Implicated in Nonsyndromic X-Linked Intellectual Disability due to Mutations in FTSJ1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      tRNA modifications are crucial for efficient and accurate protein
      synthesis, and modification defects are frequently associated with
      disease.
    explanation: >-
      Establishes the translational-fidelity arm of the convergence, which is
      mechanistically distinct from the synaptic-structural arms. Tagged
      OTHER: a general statement about tRNA biology rather than a result of
      the cited study.
  - reference: PMID:30335141
    reference_title: "A recurrent missense variant in SLC9A7 causes nonsyndromic X-linked intellectual disability with alteration of Golgi acidification and aberrant glycosylation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These data implicate a crucial role for SLC9A7 in the regulation of
      TGN/post-Golgi pH homeostasis and glycosylation of exported cargo, which
      may underlie the cellular pathophysiology and neurodevelopmental
      deficits associated with this particular nonsyndromic form of X-linked
      ID.
    explanation: >-
      Establishes the Golgi-pH/glycosylation arm of the convergence, the most
      recently characterised theme in this class.
  - reference: PMID:11355014
    reference_title: "Fragile XE-associated familial mental retardation protein 2 (FMR2) acts as a potent transcription activator."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our results show that FMR2 is a potent transcription activator and that
      its function is conserved.
    explanation: >-
      Establishes the transcriptional arm of the convergence and the molecular
      function lost when the FRAXE expansion silences AFF2/FMR2. Tagged
      IN_VITRO: the activation was measured in yeast and mammalian cell
      reporter assays. GO:0045893 (positive regulation of DNA-templated
      transcription) is used rather than the RNA-polymerase-II-specific term
      because the reporter assays demonstrate transcription activation without
      resolving promoter class.
  - reference: PMID:11355014
    reference_title: "Fragile XE-associated familial mental retardation protein 2 (FMR2) acts as a potent transcription activator."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Expansion of the FRAXE CCG repeat to a full mutation is associated with
      methylation and transcriptional silencing of the FMR2 gene, and as a
      consequence, mild-to-borderline mental retardation.
    explanation: >-
      Connects the loss of that transcriptional activity to the cognitive
      endpoint, which is what places this arm on the convergence node rather
      than leaving it as isolated protein biochemistry. Tagged OTHER rather
      than HUMAN_CLINICAL: this is the abstract's opening background sentence,
      and the study itself reports no human clinical data (its MeSH terms are
      HeLa cells and Saccharomyces cerevisiae).
  downstream:
  - target: Impaired Synaptic Plasticity in Learning and Memory Circuits
    causal_link_type: DIRECT
    description: >-
      Disrupted synapse formation, transmission, and recycling degrade
      activity-dependent plasticity.

- name: Impaired Synaptic Plasticity in Learning and Memory Circuits
  biological_scale: TISSUE
  description: >-
    The convergent synaptic lesion degrades activity-dependent plasticity in
    the hippocampal and cortical circuits that support learning and memory.
    Several causal genes are selectively or highly expressed in exactly these
    structures - IL1RAPL1 in the postnatal hippocampal memory system, PAK3 in
    postmitotic neurons of developing and postnatal cerebral cortex and
    hippocampus, TSPAN7 in cerebral cortex and hippocampus - which is the
    anatomical reason a diffuse molecular lesion produces a circumscribed
    cognitive phenotype.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  - preferred_term: hippocampus
    term:
      id: UBERON:0002421
      label: hippocampal formation
  biological_processes:
  - preferred_term: regulation of synaptic plasticity
    term:
      id: GO:0048167
      label: regulation of synaptic plasticity
    modifier: DECREASED
  - preferred_term: dendritic spine morphogenesis
    term:
      id: GO:0060997
      label: dendritic spine morphogenesis
    modifier: DECREASED
  evidence:
  - reference: PMID:9731525
    reference_title: "PAK3 mutation in nonsyndromic X-linked mental retardation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Immunofluorescence analysis showed that PAK3 protein is highly expressed
      in postmitotic neurons of the developing and postnatal cerebral cortex
      and hippocampus.
    explanation: >-
      Localises a causal gene product to the cortical and hippocampal circuits
      that carry the cognitive phenotype. Tagged MODEL_ORGANISM: the
      immunofluorescence was performed in animal tissue (the paper's MeSH
      terms include Mice and Rats), not in patients.
  - reference: PMID:10655063
    reference_title: "A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      RNA in situ hybridization showed that TM4SF2 is highly expressed in the
      central nervous system, including the cerebral cortex and hippocampus.
    explanation: >-
      Independent confirmation that causal genes in this class are enriched in
      the same learning-and-memory circuits. Tagged IN_VITRO: an in situ
      hybridisation tissue-expression assay rather than a clinical
      observation.
  - reference: PMID:9620768
    reference_title: "Mutations in GDI1 are responsible for X-linked non-specific mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results show that both functional and developmental alterations in
      the neuron may account for the severe impairment of learning abilities
      as a consequence of mutations in GDI1, emphasizing its critical role in
      development of human intellectual and learning abilities.
    explanation: >-
      Links the vesicle-recycling lesion to impaired learning through both
      functional and developmental neuronal alterations.
  downstream:
  - target: Static Cognitive Impairment Without Structural Brain Malformation
    causal_link_type: DIRECT
    description: >-
      Degraded plasticity in an anatomically normal brain manifests as
      non-progressive intellectual disability.

- name: Static Cognitive Impairment Without Structural Brain Malformation
  biological_scale: ORGANISM
  description: >-
    The endpoint of the class: non-progressive impairment of intellectual
    functioning and adaptive behaviour in a brain that is structurally normal
    on imaging and free of any consistently reproducible dysmorphic,
    metabolic, or systemic sign. This is a mis-tuned rather than a mis-built
    or damaged circuit, which is why brain MRI is characteristically
    unremarkable and why - in the absence of any distinguishing feature -
    molecular testing rather than clinical recognition is the only route to a
    specific diagnosis. The class is conventionally described as static and
    non-progressive, with developmental regression arguing against the
    diagnosis; note that none of the evidence cited on this node speaks to
    temporal course, so the staticity claim rests on clinical convention
    rather than on a source quoted here.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:9731525
    reference_title: "PAK3 mutation in nonsyndromic X-linked mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRI analysis showed no gross defects in brain development.
    explanation: >-
      Documents the structurally normal brain that defines the non-syndromic
      endpoint.
  - reference: PMID:11971879
    reference_title: "ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The absence of detectable brain malformations in patients suggests that
      ARX may have an essential role, in mature neurons, required for the
      development of cognitive abilities.
    explanation: >-
      Independent confirmation, in a second subtype, that the lesion is
      functional rather than malformative.
  - reference: PMID:22002931
    reference_title: "Novel GDI1 mutation in a large family with nonsyndromic X-linked intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present family supports the lack of additional phenotypic features
      in patients with GDI1 mutations, rendering a clinical diagnosis of
      GDI1-associated XLID impossible.
    explanation: >-
      States the diagnostic consequence of a phenotype with no distinguishing
      features.
  downstream:
  - target: Intellectual disability
    causal_link_type: DIRECT
    description: >-
      The clinical expression of this endpoint node. Impaired intellectual
      functioning is what the class is defined by, and in the strictest
      members of the series it is the only feature present, so the terminal
      mechanism node and this phenotype stand in a direct relation with no
      intervening step. The remaining phenotypes in this entry - global
      developmental delay, speech and language delay, behavioural and autistic
      features, and seizures - are deliberately left unwired: they appear in
      some subtypes and not others, and assigning each to a mechanism node
      requires per-subtype evidence this pass did not gather.
    evidence:
    - reference: PMID:10471494
      reference_title: "A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Non-overlapping deletions and a nonsense mutation in this gene were
        identified in patients with cognitive impairment only.
      explanation: >-
        Cognitive impairment as the sole clinical consequence of the molecular
        lesion, which is the claim this edge makes.
    - reference: PMID:22002931
      reference_title: "Novel GDI1 mutation in a large family with nonsyndromic X-linked intellectual disability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the affected male family members had nonsyndromic intellectual
        disability, that is, they had neither abnormal body measurements nor
        any other significant clinical problems
      explanation: >-
        Independent confirmation in a second subtype that the endpoint
        presents as intellectual disability with nothing else attached.

phenotypes:
- category: Neurologic
  name: Intellectual disability
  description: >-
    Impaired intellectual functioning and adaptive behaviour, present as the
    only consistent shared feature of the class. Severity spans mild to severe
    depending on the gene and allele. Because the class aggregates many
    individually rare gene-defined disorders, severity cannot be meaningfully
    quantified at the group level.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:10471494
    reference_title: "A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Non-overlapping deletions and a nonsense mutation in this gene were
      identified in patients with cognitive impairment only.
    explanation: >-
      Documents cognitive impairment as the sole clinical feature, which is
      the definition of the non-syndromic class. The VERY_FREQUENT band
      follows from the phenotype being definitional rather than variable.
  - reference: PMID:22002931
    reference_title: "Novel GDI1 mutation in a large family with nonsyndromic X-linked intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the affected male family members had nonsyndromic intellectual
      disability, that is, they had neither abnormal body measurements nor any
      other significant clinical problems
    explanation: >-
      Independent confirmation that intellectual disability is the isolated
      finding in a second subtype.
- category: Neurologic
  name: Absence of distinctive clinical or biochemical features
  description: >-
    The defining negative finding of the class. Affected males have no
    distinctive dysmorphic, malformative, or biochemical abnormality that is
    reproducible across families, which is why the historical MRX families
    were numbered by linkage interval rather than named for a phenotype, and
    why molecular testing is the only route to a specific diagnosis. This is a
    statement about consistency across cases, not about every individual
    patient having isolated intellectual disability. No `phenotype_term` is
    bound: this is a meta-statement about the ABSENCE of consistent
    additional features, so binding it to HP:0001249 would both double-count
    intellectual disability in graph export and assert the opposite of what
    the entry means. HPO has no term for "no consistent additional feature".
  evidence:
  - reference: PMID:10655063
    reference_title: "A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They can be categorized into syndromic (MRXS) and nonspecific (MRX)
      forms. In MRX forms, affected patients have no distinctive clinical or
      biochemical features.
    explanation: >-
      States the defining negative criterion separating this class from the
      syndromic (MRXS) forms.
  - reference: PMID:31898314
    reference_title: "Non-syndromic X linked intellectual disability: Current knowledge in light of the recent advances in molecular and functional studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classically, XLID has been subdivided in syndromic intellectual
      disability (S-XLID)-where intellectual disability (ID) is always
      associated with other recognizable physical and/or neurological
      features-and non-specific or non-syndromic intellectual disability
      (NS-XLID) where the only common feature is ID.
    explanation: >-
      The dedicated NS-XLID review's definition of the class, stating
      precisely that the defining property is ID being the only COMMON
      feature - a statement about consistency across cases rather than about
      isolation in each patient.
- category: Neurologic
  name: Global developmental delay
  description: >-
    Delay across developmental domains in early childhood, the presentation
    that precedes a formal diagnosis of intellectual disability before an IQ
    can reliably be measured. More typical of paediatric case series; adult
    historical families are usually described in terms of intellectual
    disability directly. No evidence item is attached: none of the cited
    sources reports a formal developmental-delay ascertainment in this class,
    so the phenotype is recorded as clinical context only, per the evidence
    SOP's option to keep the description without an evidence block rather
    than attach a snippet that does not make the claim.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
- category: Neurologic
  name: Delayed speech and language development
  description: >-
    Speech and language delay is common in several gene-defined forms,
    including SLC9A7-related disease, but is strongly gene-dependent and not
    universal across the class. No frequency band is recorded: the class
    aggregates many gene-defined disorders and no source quantifies the
    proportion affected at group level. No evidence item is attached either -
    the speech phenotype in the SLC9A7 families is reported in the paper's full
    text rather than its abstract, and the cached record for PMID:30335141 is
    abstract-only, so there is no verifiable snippet to quote. Recorded as
    clinical context pending a quotable source.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
- category: Behavioral
  name: Atypical behavior
  description: >-
    Behavioural problems and psychiatric features are reported in subsets of
    families, most clearly documented in IL1RAPL1 deletion families. Their
    presence marks the point at which a nominally non-syndromic subtype begins
    to acquire additional features, and is one reason the class boundary is
    regarded as blurred. No frequency band is recorded: the source reports two
    families without a denominator, which does not support a quantitative
    band. Autistic features are deliberately NOT claimed here even though they
    fall under this term: they are recorded separately below under the child
    term HP:0000729, on independent cohort evidence with its own denominator.
    The parent and child entries are both retained because they rest on
    different sources and make different claims - not to state the same
    finding twice.
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:21484992
    reference_title: "Deletion of the immunoglobulin domain of IL1RAPL1 results in nonsyndromic X-linked intellectual disability associated with behavioral problems and mild dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified an additional two families with deletions of a
      portion of the gene that give rise to cognitive impairment, as well as
      some behavioral problems and mild dysmorphism.
    explanation: >-
      Documents behavioural problems in a subset of IL1RAPL1 families. No
      frequency is asserted: this is a subset finding within two reported
      families, not a quantified class-wide feature.
- category: Behavioral
  name: Autistic behavior
  description: >-
    Autism spectrum features are reported in a substantial minority of
    patients ascertained as suggestive non-syndromic XLID: nearly 30% of the
    61 males in the Basque targeted-panel cohort, in a group explicitly
    characterised in the same sentence as showing an unspecific (that is,
    non-syndromic) phenotype. Read the denominator carefully - those 61 males
    are a REFERRAL population selected on X-linked family history and normal
    FMR1 testing, and only 16 of them received a candidate variant, so most of
    the denominator carries no molecular XLID diagnosis. The figure therefore
    describes the population in which this class is looked for, not a
    genetically confirmed case series. This is the more specific sibling of
    the `Atypical behavior` entry above, which carries the parent HPO term and
    the independent IL1RAPL1-family evidence.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:31906484
    reference_title: "Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most of the selected patients did not have relevant dysmorphic features,
      confirming that they show an unspecific phenotype. However, autism
      spectrum disorders were present in nearly 30% of them.
    explanation: >-
      Quantifies autistic features in a cohort selected for suggestive
      non-syndromic XLID, in the same sentence in which the authors
      characterise that cohort as phenotypically unspecific - so the figure is
      drawn from the non-syndromic population this entry is about, though the
      authors write "most", not all, of the patients lacked relevant
      dysmorphic features. OCCASIONAL (5-29%) is the conservative reading of
      "nearly 30%", which sits exactly on the OCCASIONAL/FREQUENT boundary;
      the band would be FREQUENT if the true value were at or above 30%.
- category: Neurologic
  name: Seizure
  description: >-
    Seizures occur in a minority of affected males - almost 15% of the
    X-linked group in the Basque suggestive non-syndromic XLID cohort, that
    group being the roughly 47 probands ascertained on X-linked family history
    rather than the full 61-patient cohort - and are a designated variable
    feature of the ARX-related subtype, which is named "with or without
    seizures". The same referral-population caveat recorded on the
    `Autistic behavior` entry applies. They are not a defining feature of the
    class. When prominent and early, they should prompt consideration of the
    syndromic ARX entities (West syndrome, Ohtahara syndrome) instead. Note
    that the ARX-specific literature quote available here enumerates those
    SYNDROMIC ARX entities, which this entry deliberately excludes, so it is
    not attached: the frequency band rests on the cohort figure below, and the
    ARX designation rests on the MONDO subtype label itself
    ("intellectual disability, X-linked, with or without seizures,
    ARX-related", MONDO:0010317). The entry is therefore recorded at class
    level rather than scoped to the ARX subtype, because the quantitative
    evidence is a class-level cohort figure.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  phenotype_contexts:
  - subtype: ARX-related
    notes: >-
      Seizures are a designated variable feature of this subtype, whose MONDO
      label is "intellectual disability, X-linked, with or without seizures,
      ARX-related" (MONDO:0010317). No frequency is recorded for the context:
      the label establishes that seizures vary within the subtype without
      quantifying them, and the only ARX-specific seizure quote available
      enumerates the syndromic ARX entities this entry excludes. The context
      exists so the subtype association survives structurally now that the
      phenotype itself is recorded at class level on cohort evidence.
  evidence:
  - reference: PMID:31906484
    reference_title: "Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Almost 15% of the patients in the X-linked group also reported having
      epilepsy.
    explanation: >-
      Quantifies epilepsy in the X-linked-family arm of a cohort selected for
      suggestive non-syndromic XLID, supporting the OCCASIONAL band (5-29%).

genetic:
- name: IL1RAPL1
  gene_term:
    preferred_term: IL1RAPL1
    term:
      id: hgnc:5996
      label: IL1RAPL1
  relationship_type: CAUSATIVE
  subtype: MRX21
  notes: >-
    Interleukin-1 receptor accessory protein-like 1 at Xp22.1-21.3. Deletions
    and nonsense variants cause non-syndromic X-linked intellectual
    disability; the protein is highly expressed in postnatal hippocampus and
    organises excitatory synapse formation.
  evidence:
  - reference: PMID:10471494
    reference_title: "A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thorough investigation of an MRX critical region in Xp22.1-21.3 enabled
      us to identify a new gene expressed in brain that is responsible for a
      non-specific form of X-linked mental retardation.
    explanation: >-
      Establishes IL1RAPL1 as causal for the non-specific (non-syndromic)
      form.
- name: PAK3
  gene_term:
    preferred_term: PAK3
    term:
      id: hgnc:8592
      label: PAK3
  relationship_type: CAUSATIVE
  subtype: MRX30
  notes: >-
    p21-activated serine-threonine kinase at Xq22. Truncating variants disrupt
    kinase function and abolish Rho GTPase-to-cytoskeleton signalling in
    postmitotic cortical and hippocampal neurons.
  evidence:
  - reference: PMID:9731525
    reference_title: "PAK3 mutation in nonsyndromic X-linked mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation produces premature termination, disrupting kinase function.
    explanation: >-
      Establishes the loss-of-function mechanism of the causal PAK3 allele.
- name: GDI1
  gene_term:
    preferred_term: GDI1
    term:
      id: hgnc:4226
      label: GDI1
  relationship_type: CAUSATIVE
  subtype: MRX41
  notes: >-
    Rab GDP-dissociation inhibitor alpha. Missense (L92P) and null alleles
    impair recycling of RAB3A and synaptic vesicle traffic. Associated with a
    strictly non-syndromic phenotype across independent families.
  evidence:
  - reference: PMID:9620768
    reference_title: "Mutations in GDI1 are responsible for X-linked non-specific mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One of the mutations caused a non-conservative substitution (L92P) which
      reduced binding and recycling of RAB3A, the second was a null mutation.
    explanation: >-
      Characterises both the missense and null mechanisms at this locus.
- name: TSPAN7
  gene_term:
    preferred_term: TSPAN7
    term:
      id: hgnc:11854
      label: TSPAN7
  relationship_type: CAUSATIVE
  subtype: MRX58
  notes: >-
    Tetraspanin 7 (formerly TM4SF2) at Xp11.4, implicated by a disrupting X;2
    translocation breakpoint and by point variants in MRX families.
  evidence:
  - reference: PMID:10655063
    reference_title: "A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further investigation led to identification of TM4SF2 mutations in 2 of
      33 other MRX families.
    explanation: >-
      Provides the independent point-variant evidence beyond the index
      translocation.
- name: FTSJ1
  gene_term:
    preferred_term: FTSJ1
    term:
      id: hgnc:13254
      label: FTSJ1
  relationship_type: CAUSATIVE
  subtype: MRX9
  notes: >-
    tRNA 2'-O-methyltransferase, the human TRM7 homolog. Loss-of-function
    alleles abolish Cm32 and Gm34 modification of the tRNA anticodon loop; a
    p.A26P missense allele produces a selective Gm34 defect, giving an
    allele-specific biochemical readout.
  evidence:
  - reference: PMID:26310293
    reference_title: "Defects in tRNA Anticodon Loop 2'-O-Methylation Are Implicated in Nonsyndromic X-Linked Intellectual Disability due to Mutations in FTSJ1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Additionally, tRNA(Phe) from an NSXLID patient with a novel
      FTSJ1-p.A26P missense allele specifically lacks Gm34 , but has normal
      levels of Cm32 and o2yW37 .
    explanation: >-
      Demonstrates allele-specific biochemical consequences at this locus.
- name: ACSL4
  gene_term:
    preferred_term: ACSL4
    term:
      id: hgnc:3571
      label: ACSL4
  relationship_type: CAUSATIVE
  subtype: MRX63
  notes: >-
    Fatty acid-CoA ligase 4 (FACL4) at Xq22.3. Missense and splice-site null
    alleles reduce enzymatic activity in patient lymphoblastoid lines. Mapped
    by narrowing the ATS-MR contiguous-gene deletion interval to roughly
    380 kb.
  evidence:
  - reference: PMID:11889465
    reference_title: "FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Analysis of enzymatic activity in lymphoblastoid cell lines from
      affected individuals of both families revealed low levels compared with
      normal cells, indicating that both mutations are null mutations.
    explanation: >-
      Provides the functional confirmation that both alleles are null.
- name: ARX
  gene_term:
    preferred_term: ARX
    term:
      id: hgnc:18060
      label: ARX
  relationship_type: CAUSATIVE
  subtype: ARX-related
  notes: >-
    Aristaless-related homeobox transcription factor with telencephalon- and
    ventral-thalamus-restricted expression. Polyalanine expansions and certain
    missense alleles give the non-syndromic phenotype modelled here; other
    alleles in the same gene cause distinct syndromic entities.
  evidence:
  - reference: PMID:11971879
    reference_title: "ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to other genes involved in XLMR, ARX expression is specific
      to the telencephalon and ventral thalamus.
    explanation: >-
      Characterises the restricted expression domain that distinguishes ARX
      from the broadly expressed genes in this class.
- name: AFF2
  gene_term:
    preferred_term: AFF2
    term:
      id: hgnc:3776
      label: AFF2
  relationship_type: CAUSATIVE
  subtype: FRAXE
  notes: >-
    AF4/FMR2 family member 2 at the FRAXE folate-sensitive fragile site in
    Xq28. Silenced by CCG repeat expansion and methylation, giving the
    repeat-expansion route into this class. Found in non-syndromal (IDX)
    families that were never assigned an IDX number.
  evidence:
  - reference: PMID:29696803
    reference_title: "X-linked intellectual disability update 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence variants in 11 genes (KLF8, AFF2, SLC6A8, NDUFA1, ALG13, SRPX2,
      ATRX, NLGN3, FGDY, CDKL5, and NLGN4) have been found in families with
      IDX but in whom IDX numbers were never assigned.
    explanation: >-
      Places AFF2 among the genes causing non-syndromal X-linked intellectual
      disability.
- name: SLC9A7
  gene_term:
    preferred_term: SLC9A7
    term:
      id: hgnc:17123
      label: SLC9A7
  relationship_type: CAUSATIVE
  subtype: MRX108
  notes: >-
    Alkali cation/proton exchanger (NHE7) at Xp11.3, resident in the
    trans-Golgi network and post-Golgi vesicles. A recurrent p.Leu515Phe
    missense variant in two unrelated multigenerational families alkalinises
    the TGN and impairs N-glycosylation of exported cargo, with an abnormal
    serum transferrin glycosylation profile in patients. The most recently
    characterised mechanistic theme in this class; not curated as a formal
    subtype here because a corresponding MONDO descendant term was not
    confirmed.
  evidence:
  - reference: PMID:30335141
    reference_title: "A recurrent missense variant in SLC9A7 causes nonsyndromic X-linked intellectual disability with alteration of Golgi acidification and aberrant glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report two unrelated families with multigenerational nonsyndromic
      intellectual disability (ID) segregating with a recurrent de novo
      missense variant (c.1543C>T:p.Leu515Phe) in the alkali cation/proton
      exchanger gene SLC9A7 (also commonly referred to as NHE7).
    explanation: >-
      Establishes SLC9A7 as causal for a non-syndromic form in two independent
      families.
  - reference: PMID:30335141
    reference_title: "A recurrent missense variant in SLC9A7 causes nonsyndromic X-linked intellectual disability with alteration of Golgi acidification and aberrant glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mass spectrometry analysis of patient sera also revealed an abnormal
      N-glycosylation profile for transferrin, a clinical diagnostic marker
      for congenital disorders of glycosylation.
    explanation: >-
      Provides a measurable biochemical readout for this form, unusual in a
      class defined by the absence of biochemical features.
- name: IQSEC2
  gene_term:
    preferred_term: IQSEC2
    term:
      id: hgnc:29059
      label: IQSEC2
  relationship_type: CAUSATIVE
  subtype: MRX1
  notes: >-
    IQ motif and Sec7 domain ArfGEF 2, a guanine nucleotide exchange factor
    for the ADP-ribosylation factor family of small GTPases. It is the causal
    gene of MRX1, the index family of the numbered series, found by
    systematic X-chromosome exome resequencing more than two decades after
    that family was mapped. The allelic spectrum reaches beyond isolated
    intellectual disability - MONDO carries "IQSEC2-related syndromic
    intellectual disability" among this term's exact synonyms - and those
    presentations are not curated here.
  evidence:
  - reference: PMID:20473311
    reference_title: Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first family identified as having a nonsyndromic intellectual
      disability was mapped in 1988. Here we show that a mutation of IQSEC2,
      encoding a guanine nucleotide exchange factor for the ADP-ribosylation
      factor family of small GTPases, caused this disorder.
    explanation: >-
      Establishes IQSEC2 as causal for the non-syndromic form and gives the
      protein function recorded in these notes.
- name: RPS6KA3
  gene_term:
    preferred_term: RPS6KA3
    term:
      id: hgnc:10432
      label: RPS6KA3
  relationship_type: CAUSATIVE
  subtype: MRX19
  notes: >-
    Ribosomal protein S6 kinase, 90 kDa, polypeptide 3 (RSK2), a
    serine-threonine kinase located at Xp22.2. Single-amino-acid deletions and
    proximal-domain missense variants produce an attenuated, non-syndromic
    phenotype, while other alleles of the same gene cause Coffin-Lowry
    syndrome, curated separately in dismech.
  evidence:
  - reference: PMID:17100996
    reference_title: Mutations in the RSK2(RPS6KA3) gene cause Coffin-Lowry syndrome and nonsyndromic X-linked mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In two families, the clinical diagnosis had been nonsyndromic X-linked
      mental retardation.
    explanation: >-
      Establishes that RPS6KA3 variants are found in families diagnosed as
      non-syndromic, which is what admits this gene to this entry.
  - reference: PMID:17100996
    reference_title: Mutations in the RSK2(RPS6KA3) gene cause Coffin-Lowry syndrome and nonsyndromic X-linked mental retardation.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disorder is now recognized to be due to mutations in a serine
      threonine kinase RSK2(RPS6KA3) located at Xp22.2
    explanation: >-
      Source for the kinase function and the Xp22.2 location recorded in these
      notes. Marked BACKGROUND because the sentence is the paper's
      introductory framing of previously established Coffin-Lowry genetics,
      not its own result.
- name: SYN1
  gene_term:
    preferred_term: SYN1
    term:
      id: hgnc:11494
      label: SYN1
  relationship_type: CAUSATIVE
  subtype: MRX50
  notes: >-
    Synapsin I, a neuronal phosphoprotein regulating neurotransmitter release
    and neuronal development. The MRX50 allele is a missense change in the
    B-domain region involved in recognition of highly curved membranes; it
    reduces synaptic vesicle mobility and increases vesicle clustering at
    presynaptic terminals. Distinct SYN1 alleles cause the epilepsy/autism
    entity curated separately as SYN1-Related_Disorder.
  evidence:
  - reference: PMID:28973667
    reference_title: "A novel SYN1 missense mutation in non-syndromic X-linked intellectual disability affects synaptic vesicle life cycle, clustering and mobility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a missense mutation (c.236 C > G; p.S79W) in the SYN1 gene
      coding for synapsin I in the MRX50 family, affected by non-syndromic
      X-linked intellectual disability.
    explanation: >-
      Establishes SYN1 as causal in the numbered MRX50 family with a
      non-syndromic presentation.
  - reference: PMID:28973667
    reference_title: "A novel SYN1 missense mutation in non-syndromic X-linked intellectual disability affects synaptic vesicle life cycle, clustering and mobility."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In addition, the presence of S79W Synapsin I strongly reduces the
      mobility of synaptic vesicles, with possible implications for the
      regulation of neurotransmitter release and synaptic plasticity.
    explanation: >-
      The functional consequence of the causal allele recorded in these notes,
      demonstrated in cultured knockout hippocampal neurons.
- name: RAB39B
  gene_term:
    preferred_term: RAB39B
    term:
      id: hgnc:16499
      label: RAB39B
  relationship_type: CAUSATIVE
  subtype: MRX72
  notes: >-
    A neuronal-specific small GTPase of the RAB family localised to the Golgi
    compartment. Null alleles - a near-start stop codon in one family and a
    5' splice-site change in the MRX72 family - produce no protein, and
    downregulation reduces presynaptic boutons and disturbs neurite growth
    cones. The same gene is curated by ClinGen against an early-onset
    parkinsonism-intellectual disability syndrome (MONDO:0010709), a separate
    entity that is not curated here.
  evidence:
  - reference: PMID:20159109
    reference_title: "Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One mutation in family X (D-23) introduced a stop codon seven amino
      acids after the start codon (c.21C > A; p.Y7X). A second mutation, in
      the MRX72 family, altered the 5' splice site (c.215+1G > A) and normal
      splicing. Neither instance produced a protein.
    explanation: >-
      Establishes both causal alleles and the loss-of-function mechanism
      recorded in these notes.
  - reference: PMID:20159109
    reference_title: "Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that RAB39B, a novel RAB GTPase of unknown function, is a
      neuronal-specific protein that is localized to the Golgi compartment.
    explanation: >-
      Source for the protein family, neuronal specificity and Golgi
      localisation recorded in these notes and in the MRX72 subtype row.
- name: DLG3
  gene_term:
    preferred_term: DLG3
    term:
      id: hgnc:2902
      label: DLG3
  relationship_type: CAUSATIVE
  subtype: MRX90
  notes: >-
    Discs large MAGUK scaffold protein 3, encoding synapse-associated protein
    102 (SAP102), a membrane-associated guanylate kinase of the postsynaptic
    density of excitatory synapses whose PDZ domains bind the NR2 subunits of
    the NMDA receptor. Truncating alleles remove the third PDZ domain and are
    proposed to disrupt NMDA receptor targeting and signalling.
  evidence:
  - reference: PMID:15185169
    reference_title: Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified truncating mutations in the human DLG3
      (neuroendocrine dlg) gene in 4 of 329 families with moderate to severe
      X-linked mental retardation.
    explanation: >-
      Establishes DLG3 as causal, with the cohort yield that supports the
      gene assignment.
  - reference: PMID:15185169
    reference_title: Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DLG3 encodes synapse-associated protein 102 (SAP102), a member of the
      membrane-associated guanylate kinase protein family.
    explanation: >-
      Source for the protein identity and family recorded in these notes.
- name: SYP
  gene_term:
    preferred_term: SYP
    term:
      id: hgnc:11506
      label: SYP
  relationship_type: CAUSATIVE
  subtype: MRX96
  notes: >-
    Synaptophysin, an integral synaptic vesicle protein that accounts for
    about a tenth of total synaptic vesicle protein cargo and is required for
    efficient retrieval of synaptobrevin II from the plasma membrane during
    endocytosis. Patient variants either mislocalise throughout the axon or
    reach the nerve terminal without supporting that retrieval.
  evidence:
  - reference: PMID:19377476
    reference_title: "A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The screen has discovered nine genes implicated in XLMR, including SYP,
      ZNF711 and CASK reported here, confirming the power of this strategy.
    explanation: >-
      The gene-discovery statement assigning SYP to X-linked intellectual
      disability.
  - reference: PMID:23966691
    reference_title: X-linked intellectual disability-associated mutations in synaptophysin disrupt synaptobrevin II retrieval.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Synaptophysin is an integral synaptic vesicle (SV) protein that accounts
      for ∼10% of total SV protein cargo.
    explanation: >-
      Source for the protein identity and abundance recorded in these notes.
- name: ZNF711
  gene_term:
    preferred_term: ZNF711
    term:
      id: hgnc:13128
      label: ZNF711
  relationship_type: CAUSATIVE
  subtype: MRX97
  notes: >-
    ZNF711, a chromatin-associated transcription factor that interacts with the
    X-linked intellectual disability protein PHF8 and binds a subset of PHF8
    target genes. Implicated by the 208-family X-chromosome resequencing screen
    and confirmed in two large four-generation pedigrees. Affected males have
    mild to moderate intellectual disability with poor speech; autistic
    features and mild facial dysmorphism occur in some but not all patients.
  evidence:
  - reference: PMID:27993705
    reference_title: Mutations in two large pedigrees highlight the role of ZNF711 in X-linked intellectual disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with mutations in ZNF711 all present with mild to moderate ID
      and poor speech accompanied by additional features in some patients,
      including autistic features and mild facial dysmorphisms, suggesting
      that ZNF711 mutations cause non-syndromic ID.
    explanation: >-
      Establishes the phenotype and the authors' non-syndromic assignment
      recorded in these notes.
  - reference: PMID:20346720
    reference_title: A functional link between the histone demethylase PHF8 and the transcription factor ZNF711 in X-linked mental retardation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, PHF8 interacts with another XMLR protein, ZNF711, which
      binds to a subset of PHF8 target genes, including the XLMR gene JARID1C.
    explanation: >-
      Source for describing ZNF711 as a chromatin-associated transcription
      factor and for its functional link to two other X-linked intellectual
      disability genes. Quoted verbatim, including the source's "XMLR"
      typographical error.
  - reference: PMID:19377476
    reference_title: "A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The screen has discovered nine genes implicated in XLMR, including SYP,
      ZNF711 and CASK reported here, confirming the power of this strategy.
    explanation: >-
      The 208-family resequencing screen that first implicated ZNF711, cited
      here so the claim in these notes does not depend on an evidence item
      attached to a different row.
- name: MID2
  gene_term:
    preferred_term: MID2
    term:
      id: hgnc:7096
      label: MID2
  relationship_type: CAUSATIVE
  subtype: MRX101
  notes: >-
    Midline 2, an E3 ubiquitin ligase. The reported causal allele abolishes
    the function of the protein's COS domain, and the mutant protein
    accumulates in the cytoplasm instead of binding the cytoskeleton. The
    assignment rests on a single large kindred plus one further variant from
    a 480-individual screen, and has no ClinGen gene-disease validity
    curation.
  evidence:
  - reference: PMID:24115387
    reference_title: Targeted deep resequencing identifies MID2 mutation for X-linked intellectual disability with varied disease severity in a large kindred from India.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a novel missense mutation (c.1040G>A, p.Arg347Gln) in MID2,
      which encodes ubiquitin ligase E3, as the likely cause of X-linked
      mental retardation in a large kindred.
    explanation: >-
      The gene assignment, preserving the authors' "likely cause" hedge.
  - reference: PMID:24115387
    reference_title: Targeted deep resequencing identifies MID2 mutation for X-linked intellectual disability with varied disease severity in a large kindred from India.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      When transiently expressed in HEK293T cell line, the mutation was found
      to abolish the function of the COS domain in the protein.
    explanation: >-
      Source for the molecular consequence recorded in these notes.
- name: KLHL15
  gene_term:
    preferred_term: KLHL15
    term:
      id: hgnc:29347
      label: KLHL15
  relationship_type: CAUSATIVE
  subtype: MRX103
  notes: >-
    Kelch-like family member 15, a substrate adaptor for Cul3-based E3
    ubiquitin ligases that targets a brain-specific regulatory subunit of
    protein phosphatase 2A for proteasomal degradation. Identified by X-exome
    sequencing of 405 unresolved families, with supporting evidence from a
    second family carrying a partial gene deletion. No ClinGen gene-disease
    validity curation exists for this gene.
  evidence:
  - reference: PMID:25644381
    reference_title: X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the poorly characterized KLHL15 gene, encoding a member of the
      kelch-like protein family, we identified a protein-truncating variant
    explanation: >-
      The causal allele class identified in this gene by the discovery study.
  - reference: PMID:25644381
    reference_title: X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      KLHL15-Cul3 specifically targets a brain-specific regulatory subunit of
      the protein phosphatase 2A (PP2A/B'ß) and thereby promotes its
      proteasomal degradation, resulting in the formation of alternative PP2A
      holoenzymes.
    explanation: >-
      Source for the molecular function recorded in these notes.
- name: FRMPD4
  gene_term:
    preferred_term: FRMPD4
    term:
      id: hgnc:29007
      label: FRMPD4
  relationship_type: CAUSATIVE
  subtype: MRX104
  notes: >-
    FERM and PDZ domain containing 4, a neural scaffolding protein that
    interacts with PSD-95 to promote dendritic spine morphogenesis and with
    mGluR1/5 and Homer to regulate mGluR1/5 signalling. Deleterious alleles
    include an exon deletion, a nonsense change, a frameshift and a
    conserved-residue missense variant.
  evidence:
  - reference: PMID:29267967
    reference_title: FRMPD4 mutations cause X-linked intellectual disability and disrupt dendritic spine morphogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations include deletion of an entire coding exon, a nonsense
      mutation, a frame-shift mutation resulting in premature termination of
      translation, and a missense mutation involving a highly conserved amino
      acid residue neighboring FRMPD4-FERM domain.
    explanation: >-
      The allele spectrum recorded in these notes.
  - reference: PMID:29267967
    reference_title: FRMPD4 mutations cause X-linked intellectual disability and disrupt dendritic spine morphogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      FRMPD4 (FERM and PDZ Domain Containing 4) is a neural scaffolding
      protein that interacts with PSD-95 to positively regulate dendritic
      spine morphogenesis, and with mGluR1/5 and Homer to regulate mGluR1/5
      signaling.
    explanation: >-
      Source for the protein function recorded in these notes.
- name: USP27X
  gene_term:
    preferred_term: USP27X
    term:
      id: hgnc:13486
      label: USP27X
  relationship_type: CAUSATIVE
  subtype: MRX105
  notes: >-
    Ubiquitin specific peptidase 27 X-linked. Identified by X-exome sequencing
    of 405 unresolved families, with a second unrelated family carrying a
    conserved-residue missense variant. Its neuronal role is essentially
    uncharacterised: the only known interaction partner is USP22, required for
    glial and neuronal development in flies.
  evidence:
  - reference: PMID:25644381
    reference_title: X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 19 families, we detected likely causative protein truncating and
      missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2,
      FRMPD4, KLHL15, LAS1L, RLIM and USP27X)
    explanation: >-
      The gene-discovery statement assigning USP27X to X-linked intellectual
      disability.
  - reference: PMID:25644381
    reference_title: X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Little is currently known about the functional role of the ubiquitin
      specific peptidase USP27X.
    explanation: >-
      Source for the statement in these notes that the gene's function is
      uncharacterised. Graded OTHER because the sentence reports the state of
      the literature rather than any experimental result.
- name: FGF13
  gene_term:
    preferred_term: FGF13
    term:
      id: hgnc:3670
      label: FGF13
  relationship_type: CAUSATIVE
  subtype: IDX110
  notes: >-
    Fibroblast growth factor 13, which stabilises microtubules in developing
    neurons. The reported causal variant lies in the 5' untranslated region
    and reduces translation of the protein by weakening the interaction
    between that region and polypyrimidine-tract-binding protein 2. The human
    evidence is one report of three male children; no ClinGen gene-disease
    validity curation exists for this gene.
  evidence:
  - reference: PMID:34184986
    reference_title: "5'-UTR SNP of FGF13 causes translational defect and intellectual disability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In both HEK293 cells and patient-derived induced pluripotent stem cells,
      this SNP reduced the translation of FGF13, which stabilizes microtubules
      in developing neurons.
    explanation: >-
      The translational mechanism and the protein's function recorded in these
      notes, demonstrated in cell lines including patient-derived iPSCs.
  - reference: PMID:34184986
    reference_title: "5'-UTR SNP of FGF13 causes translational defect and intellectual disability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, this SNP reduced the interaction between FGF13 5'-UTR and
      polypyrimidine-tract-binding protein 2 (PTBP2), which was required for
      FGF13 translation in cortical neurons.
    explanation: >-
      Source for the PTBP2 interaction recorded in these notes.
- name: ZMYM3
  gene_term:
    preferred_term: ZMYM3
    term:
      id: hgnc:13054
      label: ZMYM3
  relationship_type: CAUSATIVE
  subtype: IDX112
  notes: >-
    Zinc finger MYM-type containing 3, a transcriptional coregulator and
    component of the KDM1A-RCOR1 chromatin-modifying complex. Almost all
    reported variants are missense, several recurring at two residues, and one
    tested variant shows dramatically reduced genomic occupancy consistent
    with a hypomorphic effect. The reporting authors state they cannot
    statistically prove causation and rest the case on the totality of the
    evidence; no ClinGen gene-disease validity curation exists for this gene.
  evidence:
  - reference: PMID:36586412
    reference_title: "Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically
      reduced genomic occupancy, supporting a hypomorphic effect.
    explanation: >-
      The functional consequence recorded in these notes, from a chromatin
      immunoprecipitation experiment.
  - reference: PMID:36586412
    reference_title: "Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Variants in almost all individuals (n = 26) are missense, including six
      that recurrently affect two residues.
    explanation: >-
      Source for the allele spectrum and recurrence recorded in these notes.

diagnosis:
- name: Fragile X (FMR1) repeat testing
  description: >-
    Sizing of the FMR1 CGG trinucleotide repeat, performed before or alongside
    sequencing. It is separated from the sequencing entry below because it is a
    mechanically distinct assay: a repeat expansion is not reliably called by
    exome or panel sequencing, so a normal sequencing result does not exclude
    fragile X syndrome. Fragile X is the most common single XLID entity, and
    excluding it is the conventional first step in a male with intellectual
    disability and a suggestive X-linked family history - in the Basque
    targeted-panel cohort, every one of the 61 patients had already been
    referred for FMR1 testing and shown a normal repeat number before
    enrolment.
  diagnosis_term:
    preferred_term: Molecular Analysis
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:22482801
    reference_title: "Fragile X and X-linked intellectual disability: four decades of discovery."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Over 150 syndromes, the most common of which is the fragile X syndrome,
      have been described.
    explanation: >-
      Establishes fragile X syndrome as the most common of the XLID syndromes,
      which is why its exclusion is the conventional first diagnostic step in
      this population. Tagged OTHER: the source is a historical review and the
      sentence summarises the field rather than reporting a clinical series.
  - reference: PMID:31906484
    reference_title: "Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients were initially referred to the molecular genetics
      laboratory to exclude Fragile X Syndrome.
    explanation: >-
      Documents FMR1 testing as the referral-level first step preceding
      sequencing in a suggestive non-syndromic XLID cohort.
  - reference: PMID:31906484
    reference_title: "Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 61 patients had normal G-banded karyotype and showed normal FMR1
      trinucleotide repeat numbers.
    explanation: >-
      Documents that a normal FMR1 repeat number was, in this cohort, already
      established before enrolment - so fragile X exclusion preceded the
      non-syndromic XLID workup rather than running alongside it. The
      generalisation to practice is the entry's own inference from the
      referral pattern, not a claim of the quoted sentence.
- name: Molecular genetic testing (exome or genome sequencing)
  description: >-
    Because affected individuals have no distinguishing clinical features, a
    specific diagnosis cannot be reached by examination and requires parallel
    molecular testing of all known intellectual-disability genes. The
    contemporary workup is clinical evaluation with a family pedigree,
    fragile X (FMR1) testing (recorded as its own entry above), chromosomal
    microarray, and exome or genome sequencing with segregation analysis; of
    these, only fragile X exclusion and panel sequencing with segregation are
    covered by the evidence cited here, the remainder - chromosomal microarray
    in particular - reflecting standard practice. Targeted XLID panels
    retain a role in pedigrees with suggestive X-linked family history: in one
    cohort of 61 unrelated males with suggestive non-syndromic XLID and
    negative fragile X testing, an 82-gene panel identified 17 candidate
    variants in 16 patients.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:22002931
    reference_title: "Novel GDI1 mutation in a large family with nonsyndromic X-linked intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, this family not only broadens the spectrum of GDI1 mutations but
      also emphasizes the need for parallel testing of all known genes
      associated with ID in patients with an unspecific phenotype.
    explanation: >-
      States the diagnostic strategy the class requires and the reason for it.
  - reference: PMID:31906484
    reference_title: "Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have performed targeted next-generation sequencing of 82 XLID genes
      on 61 non-related male patients with suggestive non-syndromic XLID.
      These patients were initially referred to the molecular genetics
      laboratory to exclude Fragile X Syndrome.
    explanation: >-
      Documents the cohort design and the position of targeted panels after
      fragile X exclusion in this population.
  - reference: PMID:31906484
    reference_title: "Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequencing data analysis identified 17 candidate variants in 16
      patients.
    explanation: >-
      Quantifies the diagnostic yield of a targeted panel in a suggestive
      non-syndromic XLID cohort.
- name: Brain MRI
  description: >-
    Characteristically unremarkable. Its role here is exclusionary - normal
    imaging supports a non-syndromic, non-malformative diagnosis and argues
    against the malformative X-linked entities (for example ARX-related
    lissencephaly) that enter the differential.
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:9731525
    reference_title: "PAK3 mutation in nonsyndromic X-linked mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRI analysis showed no gross defects in brain development.
    explanation: >-
      Documents the normal imaging expected in this class.
- name: X-chromosome inactivation studies in female relatives
  description: >-
    Assessment of X-inactivation skewing in mothers and female relatives.
    Extreme skewing supports an X-linked cause and, in cohorts of females with
    idiopathic intellectual disability, enriches for pathogenic findings on
    subsequent sequencing - 11 of 136 informative women showed at least 90%
    skewing, and exome sequencing found pathogenic variants in 8 of those 11.
    Note that those variants were dominant and included autosomal genes, so
    skewing is an ascertainment aid toward a genetic diagnosis generally, not
    a diagnostic criterion for this class.
  diagnosis_term:
    preferred_term: Molecular Analysis
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:31906484
    reference_title: "Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      and 14 male patients with ID and affected brothers whose mothers show
      skewed X-inactivation
    explanation: >-
      Documents maternal X-inactivation skewing used as an ascertainment
      criterion for suspected X-linked intellectual disability.
  - reference: PMID:36943625
    reference_title: "Skewed X-chromosome Inactivation in Women with Idiopathic Intellectual Disability is Indicative of Pathogenic Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among the 136 patients who were informative, 11 (8%) presented with
      extreme or total XCI skewing (>= 90%), which was significantly higher
      than expected by chance.
    explanation: >-
      Quantifies the enrichment of extreme X-inactivation skewing in women
      with idiopathic intellectual disability.
  - reference: PMID:36943625
    reference_title: "Skewed X-chromosome Inactivation in Women with Idiopathic Intellectual Disability is Indicative of Pathogenic Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All variants were mapped to ID-related genes with dominant phenotypes:
      four variants in the X-linked genes DDX3X (an XCI escape gene; two
      cases), WDR45, and PDHA1, and four variants in the autosomal genes
      KCNB1, CTNNB1, YY1, and ANKRD11.
    explanation: >-
      Important qualification, and the reason this is PARTIAL for this entry:
      half the variants recovered by the skewing-guided strategy were
      autosomal, so the yield is not specific to X-linked - let alone
      non-syndromic X-linked - intellectual disability.

treatments:
- name: Genetic Counseling
  description: >-
    Establishing a molecular diagnosis enables carrier detection in female
    relatives and informs recurrence-risk counselling and reproductive
    options, including prenatal diagnosis and preimplantation genetic testing
    where a familial pathogenic variant is known. Because the mode of
    inheritance is X-linked, carrier females have a 50% chance of transmitting
    the allele to each child, and the counselling yield is high in the large
    multiplex pedigrees characteristic of this class.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:22482801
    reference_title: "Fragile X and X-linked intellectual disability: four decades of discovery."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the same time, it has improved the clinical diagnosis of XLID and
      allowed for carrier detection and prevention strategies through gamete
      donation, prenatal diagnosis, and genetic counseling.
    explanation: >-
      Documents genetic counselling and carrier detection as the established
      clinical payoff of molecular diagnosis in this class.
- name: Supportive Care
  description: >-
    No disease-modifying therapy is established for this class. Management is
    supportive and individualised: developmental, educational, speech-language,
    occupational, physical, and behavioural interventions, with psychiatric and
    antiseizure treatment where indicated. This entry carries the umbrella
    claim and the evidence that care is supportive only; the two most
    consistently named allied-health modalities are additionally recorded as
    their own NCIT-coded entries below, for queryability. Because management is
    phenotype- and gene-specific, the evidence base is largely extrapolated
    from broader neurodevelopmental care rather than generated for this class.
    Gene therapy, selective X-reactivation, and synapse- or circuit-directed
    interventions remain experimental and are mostly not specific to this
    class.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:38424476
    reference_title: "Overcoming genetic and cellular complexity to study the pathophysiology of X-linked intellectual disabilities."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Here, we review a few selected X-linked forms of ID that predominantly
      affect heterozygous females and the current obstacles for developing
      effective therapies for such disorders.
    explanation: >-
      Documents that effective disease-modifying therapies for X-linked
      intellectual disability remain obstructed and under development, which
      is why care is supportive. Tagged OTHER for the same reason as the
      hemizygous-expression node: the sentence states the scope of a review
      rather than reporting a clinical observation.
  - reference: PMID:29696803
    reference_title: "X-linked intellectual disability update 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The progress in identifying genetic and genomic alterations associated
      with XLID has not been matched with insights that improve the
      clinician's ability to form differential diagnoses, that bring into view
      the possibility of curative therapies for patients
    explanation: >-
      States explicitly that gene discovery in this class has not yet
      translated into curative therapy, grounding the supportive-care-only
      position.
- name: Speech and Language Therapy
  description: >-
    Speech-language intervention, including augmentative and alternative
    communication where speech is absent or limited, is a standard component of
    multidisciplinary care and is tied to the group rather than to any single
    causal gene. No evidence block is attached, and this is deliberate: none
    of the references cached for this entry mentions speech-language therapy
    at all - including the two the deep-research report attributed the
    modality list to, one of which is cached as full text - so there is no
    quotable source, and the DR report over-attributed the enumeration.
    Recorded as a queryable NCIT-coded entry under the supportive-care
    umbrella above, not as an evidenced claim.
  treatment_term:
    preferred_term: speech and language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  therapeutic_modality: BEHAVIORAL
- name: Occupational Therapy
  description: >-
    Occupational therapy addressing adaptive, motor, and daily-living skills,
    likewise tied to the group rather than to a specific gene. As with speech
    and language therapy, no evidence block is attached because no cached
    reference for this entry mentions the modality; the entry exists to make
    it queryable rather than to assert a class-specific evidence base.
  treatment_term:
    preferred_term: occupational therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy
  therapeutic_modality: BEHAVIORAL

differential_diagnoses:
- name: Syndromic X-linked intellectual disability (MRXS)
  description: >-
    The primary differential. MRXS entities share X-linked inheritance and
    intellectual disability but add distinguishing physical, neurological, or
    biochemical features. The boundary is explicitly regarded as blurred and
    sometimes arbitrary: 28 of the numbered non-syndromal (IDX) genes are also
    associated with XLID syndromes. Separately curated dismech entries in this
    family (Claes-Jensen, Siderius, Shashi, Turner type) are deliberately not
    modelled as subtypes here.
  evidence:
  - reference: PMID:10655063
    reference_title: "A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They can be categorized into syndromic (MRXS) and nonspecific (MRX)
      forms. In MRX forms, affected patients have no distinctive clinical or
      biochemical features.
    explanation: >-
      States the criterion that separates the two classes.
  - reference: PMID:29696803
    reference_title: "X-linked intellectual disability update 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twenty-eight of the “IDX genes” in Figure 3 have also been associated
      with XLID syndromes.
    explanation: >-
      Quantifies the overlap between the two classes at the gene level,
      showing the differential is often not resolvable by gene identity alone.
- name: Fragile X syndrome
  description: >-
    The most common syndromic XLID entity and the standard exclusion before
    this diagnosis is entertained - patients in non-syndromic XLID cohorts are
    typically referred after negative FMR1 testing. Distinguished by the
    characteristic somatic features and the FMR1 CGG expansion.
  evidence:
  - reference: PMID:31906484
    reference_title: "Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients were initially referred to the molecular genetics
      laboratory to exclude Fragile X Syndrome.
    explanation: >-
      Documents fragile X exclusion as the standard first step before
      non-syndromic XLID is pursued.
- name: Autosomal recessive non-syndromic intellectual disability
  description: >-
    Clinically indistinguishable in an isolated male. Distinguished by
    pedigree structure (affected siblings of both sexes, parental
    consanguinity, no X-linked segregation) and ultimately by molecular
    testing.
- name: Autosomal dominant non-syndromic intellectual disability
  description: >-
    The dominant class, in which sporadic de novo heterozygous variants in
    constraint-intolerant autosomal genes predominate. In a sporadic male with
    no family history this is now a more likely explanation than a novel
    X-linked cause, a reversal of the pre-exome-era prior.

discussions:
- discussion_id: questioned_xlid_gene_assignments
  kind: KNOWLEDGE_GAP
  prompt: >-
    Which of the genes historically assigned to non-syndromic X-linked
    intellectual disability are genuinely causal, given that many were
    nominated from small families before large population control sets were
    available?
  attaches_to:
  - pathophysiology#X-Linked Gene Disruption
  rationale: >-
    Gene lists for this class carry an unusual historical liability. Genes
    were nominated by linkage in individual families at a time when systematic
    sequencing of control X chromosomes was not possible, so rare
    non-disease-causing variants could not be excluded. When 106 proposed XLID
    genes were reassessed against 10,563 control X chromosomes from the NHLBI
    Exome Sequencing Project, ten were specifically questioned because
    truncating or previously published variants occurred at appreciable
    frequency in controls, and a further fifteen were flagged as requiring
    replication. The 2017 authoritative update revisited those 25 challenged
    genes: none of the five highly questionable assignments has been
    confirmed, only ATP6AP2 of the five questionable ones has been confirmed,
    and additional cases have been published for seven of the fifteen needing
    replication - leaving 17 of the 25 still unresolved. This directly affects
    curation of this entry: AGTR2 in particular is frequently cited in older
    reviews as a non-syndromic XLID gene and is among the questioned set, so
    it is deliberately not modelled as a subtype here. Any gene list for this
    class drawn from literature predating the reassessment should be treated
    as provisional.
  proposed_experiments:
  - experiment_id: reassess_questioned_xlid_genes_gnomad
    name: Re-evaluation of questioned XLID genes against contemporary population databases
    description: >-
      Repeat the control-frequency reassessment against gnomAD-scale
      population data, which offers far more X chromosomes than the NHLBI
      cohort, and combine with independent replication cohorts and functional
      assays for the genes still flagged as requiring replication.
  evidence:
  - reference: PMID:23871722
    reference_title: "XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We used this NHLBI cohort to systematically reassess the implication of
      106 genes proposed to be involved in monogenic forms of XLID. We
      particularly question the implication in XLID of ten of them (AGTR2,
      MAGT1, ZNF674, SRPX2, ATP6AP2, ARHGEF6, NXF5, ZCCHC12, ZNF41, and
      ZNF81), in which truncating variants or previously published mutations
      are observed at a relatively high frequency within this cohort.
    explanation: >-
      Names the specific genes whose causal role in this class is in doubt,
      including AGTR2, ZNF41, and ARHGEF6, which appear in older MRX gene
      lists.
  - reference: PMID:23871722
    reference_title: "XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nonetheless, the boundary between true mutations and rare
      non-disease-causing variants often remains elusive. The sequencing of a
      large number of control X chromosomes, required for avoiding
      false-positive results, was not systematically possible in the past.
    explanation: >-
      Explains the methodological reason this class accumulated
      false-positive gene assignments.
  - reference: PMID:29696803
    reference_title: "X-linked intellectual disability update 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 15 assignments in need of replication, additional cases with
      MAOA, HCFC1, CCDC22, CNKSR2, KIAA2022, NAA10 and SHROOM4 sequence
      variants have now been published, leaving 17 of the 25 challenged genes
      unresolved.
    explanation: >-
      Gives the current resolution status of the challenged genes - the direct
      measure of how much of this gap remains open.
  - reference: PMID:19377476
    reference_title: "A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The study has, however, also highlighted issues confronting whole-genome
      sequencing screens, including the observation that loss of function of
      1% or more of X-chromosome genes is compatible with apparently normal
      existence.
    explanation: >-
      Provides the independent, orthogonal reason gene attribution is hard in
      this class: X-chromosome loss-of-function is tolerated more often than
      assumed, so a truncating variant is not self-evidently causal.
- discussion_id: syndromic_nonsyndromic_boundary_stability
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is "non-syndromic" a stable property of a gene, or an artefact of limited
    phenotyping and allele sampling?
  attaches_to:
  - pathophysiology#Static Cognitive Impairment Without Structural Brain Malformation
  rationale: >-
    The class boundary moves in both directions and is explicitly described in
    the authoritative update as blurred, sometimes arbitrary, and difficult to
    defend biologically - retained mainly for historical continuity. IL1RAPL1
    was reported as causing cognitive impairment only, but later families
    showed behavioural problems and mild dysmorphism. ARX shows the converse
    within a single gene: polyalanine expansions give a non-syndromic
    phenotype across nine numbered IDX families while other alleles cause
    lissencephaly with abnormal genitalia, Partington, West, and Ohtahara
    syndromes. Twenty-eight IDX genes are also associated with XLID syndromes.
    Whether a given gene stays in this class therefore depends on how many
    patients have been phenotyped, how deeply, and which alleles they carry -
    not on a fixed biological property. This matters for the KB because
    membership of this entry is provisional for several subtypes, and it is
    the reason FGD1, ZDHHC9, and OPHN1, which are named in older non-syndromic
    gene lists but map to explicitly syndromic MONDO entities, are excluded
    here.
  evidence:
  - reference: PMID:29696803
    reference_title: "X-linked intellectual disability update 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Even though the line dividing the two classes is blurred, sometimes
      arbitrary and difficult to defend from a biological standpoint, it has
      by now acquired quasi-historical value and deserves to be retained.
    explanation: >-
      The authoritative statement that the syndromic/non-syndromic distinction
      is retained for historical rather than biological reasons - the core of
      this knowledge gap.
  - reference: PMID:31898314
    reference_title: "Non-syndromic X linked intellectual disability: Current knowledge in light of the recent advances in molecular and functional studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nevertheless, new advances on the study of these entities have showed
      that this classification is not always clear-cut because distinct
      variants in several of these XLID genes can result in S-XLID as well as
      in NS-XLID.
    explanation: >-
      States the allele-level mechanism behind the unstable boundary directly:
      it is the variant, not the gene, that determines which class a case
      falls into. This is the evidential basis for admitting only the
      non-syndromic arm of the ARX allelic series.
  - reference: PMID:21484992
    reference_title: "Deletion of the immunoglobulin domain of IL1RAPL1 results in nonsyndromic X-linked intellectual disability associated with behavioral problems and mild dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our clinical findings better delineate the phenotypic spectrum
      associated with IL1RAPL1 mutations.
    explanation: >-
      Demonstrates phenotypic expansion of a subtype originally described as
      purely non-syndromic.
  - reference: PMID:29696803
    reference_title: "X-linked intellectual disability update 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is not the case for ARX variants, which have been found in the
      disparate phenotypes of Partington syndrome, West syndrome, X-linked
      lissencephaly with abnormal genitalia, hydranencephaly with abnormal
      genitalia, Proud syndrome, Ohtahara syndrome as well as nonsyndromal
      XLID (IDX 29, 32, 33, 36, 38, 43, 54, 76, 87).
    explanation: >-
      Documents the allelic heterogeneity within ARX that places non-syndromic
      and severely syndromic phenotypes in the same gene.
- discussion_id: nonsyndromic_xlid_group_level_prevalence
  kind: KNOWLEDGE_GAP
  prompt: >-
    What is the population prevalence of non-syndromic X-linked intellectual
    disability as distinct from X-linked intellectual disability as a whole?
  attaches_to:
  - pathophysiology#X-Linked Gene Disruption
  rationale: >-
    The prevalence figures recorded on this entry - approximately 1 in 600
    males, and 5-10% of intellectual disability in males - are for X-linked
    intellectual disability overall, syndromic and non-syndromic combined. No
    robust population prevalence or incidence exists for the non-syndromic
    class alone, because it aggregates many individually rare gene-defined
    disorders whose ascertainment has historically depended on the
    availability of large multiplex pedigrees. This is a genuine measurement
    gap rather than a curation omission, and the recorded rates should not be
    presented as if MONDO:0019181 were a uniform entity with its own
    prevalence.
  proposed_experiments:
  - experiment_id: population_scale_nsxlid_prevalence
    name: Population-scale sequencing estimate of non-syndromic XLID prevalence
    description: >-
      Estimate class prevalence from unselected population-scale exome or
      genome cohorts with linked phenotype data, ascertaining on validated
      causal variants in confirmed non-syndromic XLID genes rather than on
      pedigree structure, which avoids the multiplex-family ascertainment bias
      that inflates familial forms.
  evidence:
  - reference: PMID:10655063
    reference_title: "A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      X-linked forms of mental retardation (MR) affect approximately 1 in 600
      males and are likely to be highly heterogeneous.
    explanation: >-
      The available rate is explicitly for X-linked forms as a whole, not the
      non-syndromic class, which is the substance of this gap.
  - reference: PMID:29696803
    reference_title: "X-linked intellectual disability update 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As to the families with nonsyndromal XLID which have received IDX
      numbers, their total is currently 105 (Figure 3). For 67 of these
      families, the genes have been cloned, 33 have been mapped but the genes
      have not been identified and 5 have reserved IDX numbers (IDX8, 50, 69,
      83 and 86) but have not been published.
    explanation: >-
      Shows the class is enumerated by ascertained families rather than by
      population sampling, which is why no population prevalence exists for
      it.

datasets:
- accession: geo:GSE179384
  title: The ribose methylation enzyme FTSJ1 has a conserved role in neuron morphology and learning performance
  data_type: BULK_RNA_SEQ
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_count: 9
  genes:
  - preferred_term: FTSJ1
    term:
      id: hgnc:13254
      label: FTSJ1
  publication: PMID:36720500
  notes: >-
    Human lymphoblastoid material from patients with FTSJ1 loss of function,
    supporting the MRX9 subtype and the tRNA-modification arm of the
    convergence node. Selected by relevance triage from the dataset-discovery
    candidates as the only DIRECT (disease-named, human, primary-material)
    hit; the remaining candidates were GENE_ONLY matches whose biology is
    unrelated to this disease (for example TSPAN7 in pancreatic beta-cell
    exocytosis, GDI1 in yeast Ypt1 trafficking) and were rejected. No
    evidence block is attached, per the dataset-curation SOP.

notes: >-
  Scope decisions for this entry, recorded so they are auditable.

  Included as subtypes: IL1RAPL1 (MRX21), PAK3 (MRX30), GDI1 (MRX41), TSPAN7
  (MRX58), FTSJ1 (MRX9), ACSL4 (MRX63), AFF2 (FRAXE), and the non-syndromic
  arm of the ARX allelic series. Each maps to a MONDO term that is a
  descendant of MONDO:0019181 and each has a primary publication describing a
  non-syndromic presentation.

  Deliberately excluded: FGD1 (maps to Aarskog-Scott syndrome,
  MONDO:0010589 - classic syndromic facial/skeletal/genital dysmorphism),
  ZDHHC9 (maps to syndromic X-linked intellectual disability, Raymond type,
  MONDO:0010427 - "syndromic" appears in the MONDO label itself), and OPHN1
  (maps to X-linked intellectual disability-cerebellar hypoplasia syndrome,
  MONDO:0010337). All three appear in older non-syndromic gene lists but
  resolve to syndromic MONDO entities, and the curation issue for this entry
  specifies that syndromic X-linked entries stay separate. RLIM/MRX61 is also
  excluded: although MONDO:0010506 sits under this root, the 2018 clinical
  series (PMID:29728705) describes it as a syndromic X-linked intellectual
  disability and behaviour disorder. The concept has since been renamed
  upstream: MONDO:0010506 carries "Tonne-Kalscheuer syndrome" among its exact
  synonyms, and its OMIM xref OMIM:300978 is titled "TONNE-KALSCHEUER
  SYNDROME; TOKAS". It belongs in its own entry, not as a subtype row here.

  AGTR2 is excluded on evidence grounds rather than scope grounds - it is one
  of the ten genes whose involvement in XLID was specifically questioned
  against 10,563 control X chromosomes, and it remains among the unresolved
  set as of the 2017 update (see the questioned_xlid_gene_assignments
  discussion).

  The SLC9A7 subtype term is easy to miss, and a search that misses it will
  wrongly conclude that no such term exists. MONDO:0026723 is the MRX108
  term: its primary label is
  "intellectual developmental disorder, X-linked 108", it carries "MRX108"
  only as a related synonym, and it never names SLC9A7. It is a direct
  subclass of MONDO:0019181, xrefs OMIM:301024, and carries an RO:0004003
  causal-gene edge to hgnc:17123. A search shaped around the gene name, or
  around a disease-style label, returns nothing for it.

  MONDO lists many descendants of MONDO:0019181, most of them numbered MRX
  entries whose causal gene is not recorded in MONDO. The subtypes modelled
  here are the well-characterised, gene-anchored members; the entry still does
  not attempt the full numbered series. For orientation, the 2017 update
  counts 105 non-syndromal families with IDX numbers, 67 of them with a cloned
  gene, against 141 XLID genes overall.

  Twenty further gene-anchored MONDO descendants of this entry's term were
  assessed for membership. Fourteen are modelled as subtype rows: MRX1
  (IQSEC2), MRX19 (RPS6KA3), MRX50 (SYN1), MRX72 (RAB39B), MRX90 (DLG3),
  MRX96 (SYP), MRX97 (ZNF711), MRX101 (MID2), MRX103 (KLHL15), MRX104
  (FRMPD4), MRX105 (USP27X), MRX108 (SLC9A7), IDX110 (FGF13) and IDX112
  (ZMYM3).

  Six were declined, each for a stated reason:

  - MONDO:0010506 (MRX61, RLIM) - now Tonne-Kalscheuer syndrome upstream; see
    the paragraph above. Belongs in its own entry.
  - MONDO:0010393 (MRX93, BRWD3) - the largest series (PMID:31714006, 17
    males) titles the entity "an X-linked syndrome of mild-moderate
    intellectual disability, macrocephaly, and obesity" and reports shared
    facial features, and MONDO itself carries "mental retardation, X-linked,
    with macrocephaly" as a related synonym. A reproducible extra feature is
    exactly what this class excludes. A stub already exists at
    stubs/Intellectual_Disability_X-linked_93.yaml; it should become a
    standalone entry.
  - MONDO:0030907 (MRX106, OGT) - the field has reclassified this entity as
    OGT-CDG, "a new syndromic form of ID, which we propose to classify as a
    novel Congenital Disorder of Glycosylation" (PMID:32080367). dismech
    already carries a large family of standalone entries for congenital
    disorders of glycosylation, which is where it belongs; it is curated as
    the standalone entry OGT-Congenital_Disorder_of_Glycosylation.
  - MONDO:0975828 (IDX114, SRPK3) - the defining report (PMID:39073169) states
    that the eight postnatally ascertained patients shared intellectual
    disability, agenesis of the corpus callosum, abnormal eye movement and
    ataxia, and concludes for a role "in the pathogenesis of syndromic
    X-linked intellectual disability". A feature set shared across the whole
    postnatal cohort is what this class excludes, so it is declined as
    syndromic. See the MONDO disagreement note below.
  - MONDO:0957203 (IDX111, SLITRK2) - declined on evidence grounds, the same
    basis as the AGTR2 exclusion above rather than on scope. The two reports
    are a single patient (PMID:38283150) and a variant series whose own
    conclusion is hedged - "these data suggest that SLITRK2 is involved in
    X-linked neurodevelopmental disorders" (PMID:35840571) - and neither
    asserts a non-syndromic entity. Revisit if a replicating family series
    appears.
  - MONDO:0010487 (MRX99, USP9X) - the male USP9X entity. Declined here
    because PMID:31443933 defines a characteristic phenotype spanning white
    matter disturbance, thin corpus callosum, widened ventricles, hypotonia,
    joint hypermobility, visual defects and dysmorphic features, and concludes
    for "a distinctive neurodevelopmental and behavioral syndrome in male
    subjects". dismech's USP9X_Female-Restricted_Syndromic_Intellectual_Disability
    entry already treats it as a separate disease entry and carries it as a
    differential diagnosis; it should get its own entry rather than a subtype
    row here. See the MONDO disagreement note below.

  MONDO placements worth an upstream report. Two terms are direct subclasses
  of MONDO:0019181, "non-syndromic X-linked
  intellectual disability", whose defining publications describe syndromic
  entities: MONDO:0975828 (IDX114, SRPK3) and MONDO:0010487 (MRX99, USP9X).
  MONDO:0010506 (MRX61, RLIM) is a third instance where the upstream source
  has moved - OMIM now titles it Tonne-Kalscheuer syndrome - and MONDO:0030907
  (MRX106, OGT) is a fourth, the field having reclassified it as OGT-CDG.
  In all four cases the placement follows OMIM's historical MRX numbering
  rather than the current phenotype description; the numbering is not itself
  wrong, but the parent class is.

  ClinGen gene-disease validity classifications are quoted in several subtype
  descriptions. They come from the live ClinGen gene-validity download read on
  2026-09-24 and are not yet cited as CGGV evidence; see dismech#10426. What
  ClinGen holds, in brief: DLG3 (Definitive)
  and SYP (Moderate) are curated against this entry's own MONDO term;
  FRMPD4, SYN1, ZNF711 and IQSEC2 (all Definitive), USP27X (Moderate) and
  SLITRK2 (Limited) against the lumped "X-linked complex neurodevelopmental
  disorder"; RPS6KA3 against Coffin-Lowry syndrome, BRWD3 and USP9X against
  X-linked syndromic intellectual disability, RAB39B against the
  early-onset parkinsonism-intellectual disability syndrome, and OGT against
  MRX106 by the Syndromic Disorders expert panel. FGF13, KLHL15, MID2, RLIM,
  SLC9A7, SRPK3 and ZMYM3 have no ClinGen gene-disease validity record.

  This entry's `disease_term`, MONDO:0019181, is a class term rather than a
  gene-defined leaf standing in for an umbrella, which is what makes it the
  right anchor for the class as modelled here: its MONDO definition reads "In
  contrast to syndromic or specific X-linked intellectual deficiencies (MRXS),
  which also present with associated physical, neurological and/or psychiatric
  manifestations, intellectual deficiency is the only symptom of MRX." Every
  numbered concept assessed for membership above is a direct subclass of it, so
  each is in scope by MONDO's own placement rather than by an over-broad
  anchor.

  This entry completes the non-syndromic intellectual-disability trio with
  Autosomal_Dominant_Non-Syndromic_Intellectual_Disability and
  Autosomal_Recessive_Non-Syndromic_Intellectual_Disability. A Grouping
  uniting the three would be a reasonable follow-up.

  No GeneReviews chapter exists for the umbrella non-syndromic X-linked
  intellectual disability class; GeneReviews coverage in this space is
  organised per syndromic gene (searched 2026-08-12), so the GeneReviews
  phenotype baseline does not apply to this entry. The committed Bookshelf
  index holds no chapter for it in either GeneReviews or StatPearls.

  Deep research was run with Edison (falcon). The NEC preflight returned SKIP
  because MONDO records no causal gene for this umbrella term; the manual
  fallback check was performed - the report's most-discussed genes (SLC9A7,
  IQSEC2, SLC6A8, FMR1, HCFC1) are all genuine X-linked
  intellectual-disability genes and the report is unambiguously about this
  entity, so no Named Entity Confusion was found. Every PMID and snippet used
  from the report was independently fetched and verified against the cached
  reference record before use. Most of those records are abstracts; four
  snippets from PMID:31906484 quote its body text, which is present because
  that record is cached as full text.

  No `clinical_trials:` block is recorded because the search returns nothing
  for this class. A ClinicalTrials.gov query on the condition "X-linked
  intellectual disability" (API v2, run 2026-08-12) returns trials in other
  entities - predominantly syndromic ones such as Rett syndrome, fragile X
  syndrome and the mucopolysaccharidoses, alongside unrelated hits - and no
  disease-modifying interventional trial in non-syndromic XLID, which matches
  the deep-research report's own negative finding. The two studies that do
  name this population are phenotyping and natural-history research rather
  than treatment: NCT02854956 (clinical phenotyping and characterisation of
  neural networks in X-linked mental retardation - registered as
  INTERVENTIONAL, but the intervention is the phenotyping protocol, not a
  therapy; status UNKNOWN) and NCT06500260 (CNKSR2 natural-history study,
  observational). Both were verified against the registry. Listing either as a treatment would
  misrepresent them, so the negative result is recorded here instead.

  Two DR-surfaced phenotypes are deliberately not modelled. Hypotonia
  (HP:0001252) and muscle weakness (HP:0001324) are reported in the SLC9A7
  families, but only in that paper's full text - the cached record for
  PMID:30335141 is abstract-only, so no snippet can support them and the
  claim would be unverifiable. They should be added if an abstract-level
  source is found. Autistic features and seizures, by contrast, WERE added,
  because the Basque cohort paper (PMID:31906484) quantifies both at group
  level in text that is present in the cached record.

  Two of Edison's citation keys resolve to distinct papers by the same Basque
  group, and are cited here under their separately verified identities:
  "tejada2020non-syndromicxlinked" is the dedicated NS-XLID review (Tejada &
  Ibarluzea 2020, Clin Genet, PMID:31898314), and
  "ibarluzea2020targetednextgenerationsequencing" is the 82-gene panel cohort
  study (Ibarluzea et al. 2020, Genes, PMID:31906484). The DOI-to-PMID
  converter returns no PMID for the review's DOI (10.1111/cge.13698), so it
  was recovered by title search; a first pass of this curation conflated the
  two keys, and the review is the source of the class definition, the
  not-clear-cut boundary statement, and the 141-gene count recorded here.

📚

References & Deep Research

References

PMID:31898314

Non-syndromic X linked intellectual disability: Current knowledge in light of the recent advances in molecular and functional studies.

No top-level findings curated for this source.

PMID:29696803

X-linked intellectual disability update 2017.

No top-level findings curated for this source.

PMID:22482801

Fragile X and X-linked intellectual disability: four decades of discovery.

No top-level findings curated for this source.

PMID:23871722

XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing.

No top-level findings curated for this source.

PMID:19377476

A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.

No top-level findings curated for this source.

PMID:15630421

X-linked mental retardation.

No top-level findings curated for this source.

PMID:31906484

Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability.

No top-level findings curated for this source.

PMID:38424476

Overcoming genetic and cellular complexity to study the pathophysiology of X-linked intellectual disabilities.

No top-level findings curated for this source.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record notes

Scope decisions for this entry, recorded so they are auditable. Included as subtypes: IL1RAPL1 (MRX21), PAK3 (MRX30), GDI1 (MRX41), TSPAN7 (MRX58), FTSJ1 (MRX9), ACSL4 (MRX63), AFF2 (FRAXE), and the non-syndromic arm of the ARX allelic series. Each maps to a MONDO term that is a descendant of MONDO:0019181 and each has a primary publication describing a non-syndromic presentation. Deliberately excluded: FGD1 (maps to Aarskog-Scott syndrome, MONDO:0010589 - classic syndromic facial/skeletal/genital dysmorphism), ZDHHC9 (maps to syndromic X-linked intellectual disability, Raymond type, MONDO:0010427 - "syndromic" appears in the MONDO label itself), and OPHN1 (maps to X-linked intellectual disability-cerebellar hypoplasia syndrome, MONDO:0010337). All three appear in older non-syndromic gene lists but resolve to syndromic MONDO entities, and the curation issue for this entry specifies that syndromic X-linked entries stay separate. RLIM/MRX61 is also excluded: although MONDO:0010506 sits under this root, the 2018 clinical series (PMID:29728705) describes it as a syndromic X-linked intellectual disability and behaviour disorder. The concept has since been renamed upstream: MONDO:0010506 carries "Tonne-Kalscheuer syndrome" among its exact synonyms, and its OMIM xref OMIM:300978 is titled "TONNE-KALSCHEUER SYNDROME; TOKAS". It belongs in its own entry, not as a subtype row here. AGTR2 is excluded on evidence grounds rather than scope grounds - it is one of the ten genes whose involvement in XLID was specifically questioned against 10,563 control X chromosomes, and it remains among the unresolved set as of the 2017 update (see the questioned_xlid_gene_assignments discussion). The SLC9A7 subtype term is easy to miss, and a search that misses it will wrongly conclude that no such term exists. MONDO:0026723 is the MRX108 term: its primary label is "intellectual developmental disorder, X-linked 108", it carries "MRX108" only as a related synonym, and it never names SLC9A7. It is a direct subclass of MONDO:0019181, xrefs OMIM:301024, and carries an RO:0004003 causal-gene edge to hgnc:17123. A search shaped around the gene name, or around a disease-style label, returns nothing for it. MONDO lists many descendants of MONDO:0019181, most of them numbered MRX entries whose causal gene is not recorded in MONDO. The subtypes modelled here are the well-characterised, gene-anchored members; the entry still does not attempt the full numbered series. For orientation, the 2017 update counts 105 non-syndromal families with IDX numbers, 67 of them with a cloned gene, against 141 XLID genes overall. Twenty further gene-anchored MONDO descendants of this entry's term were assessed for membership. Fourteen are modelled as subtype rows: MRX1 (IQSEC2), MRX19 (RPS6KA3), MRX50 (SYN1), MRX72 (RAB39B), MRX90 (DLG3), MRX96 (SYP), MRX97 (ZNF711), MRX101 (MID2), MRX103 (KLHL15), MRX104 (FRMPD4), MRX105 (USP27X), MRX108 (SLC9A7), IDX110 (FGF13) and IDX112 (ZMYM3). Six were declined, each for a stated reason: - MONDO:0010506 (MRX61, RLIM) - now Tonne-Kalscheuer syndrome upstream; see the paragraph above. Belongs in its own entry. - MONDO:0010393 (MRX93, BRWD3) - the largest series (PMID:31714006, 17 males) titles the entity "an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity" and reports shared facial features, and MONDO itself carries "mental retardation, X-linked, with macrocephaly" as a related synonym. A reproducible extra feature is exactly what this class excludes. A stub already exists at stubs/Intellectual_Disability_X-linked_93.yaml; it should become a standalone entry. - MONDO:0030907 (MRX106, OGT) - the field has reclassified this entity as OGT-CDG, "a new syndromic form of ID, which we propose to classify as a novel Congenital Disorder of Glycosylation" (PMID:32080367). dismech already carries a large family of standalone entries for congenital disorders of glycosylation, which is where it belongs; it is curated as the standalone entry OGT-Congenital_Disorder_of_Glycosylation. - MONDO:0975828 (IDX114, SRPK3) - the defining report (PMID:39073169) states that the eight postnatally ascertained patients shared intellectual disability, agenesis of the corpus callosum, abnormal eye movement and ataxia, and concludes for a role "in the pathogenesis of syndromic X-linked intellectual disability". A feature set shared across the whole postnatal cohort is what this class excludes, so it is declined as syndromic. See the MONDO disagreement note below. - MONDO:0957203 (IDX111, SLITRK2) - declined on evidence grounds, the same basis as the AGTR2 exclusion above rather than on scope. The two reports are a single patient (PMID:38283150) and a variant series whose own conclusion is hedged - "these data suggest that SLITRK2 is involved in X-linked neurodevelopmental disorders" (PMID:35840571) - and neither asserts a non-syndromic entity. Revisit if a replicating family series appears. - MONDO:0010487 (MRX99, USP9X) - the male USP9X entity. Declined here because PMID:31443933 defines a characteristic phenotype spanning white matter disturbance, thin corpus callosum, widened ventricles, hypotonia, joint hypermobility, visual defects and dysmorphic features, and concludes for "a distinctive neurodevelopmental and behavioral syndrome in male subjects". dismech's USP9X_Female-Restricted_Syndromic_Intellectual_Disability entry already treats it as a separate disease entry and carries it as a differential diagnosis; it should get its own entry rather than a subtype row here. See the MONDO disagreement note below. MONDO placements worth an upstream report. Two terms are direct subclasses of MONDO:0019181, "non-syndromic X-linked intellectual disability", whose defining publications describe syndromic entities: MONDO:0975828 (IDX114, SRPK3) and MONDO:0010487 (MRX99, USP9X). MONDO:0010506 (MRX61, RLIM) is a third instance where the upstream source has moved - OMIM now titles it Tonne-Kalscheuer syndrome - and MONDO:0030907 (MRX106, OGT) is a fourth, the field having reclassified it as OGT-CDG. In all four cases the placement follows OMIM's historical MRX numbering rather than the current phenotype description; the numbering is not itself wrong, but the parent class is. ClinGen gene-disease validity classifications are quoted in several subtype descriptions. They come from the live ClinGen gene-validity download read on 2026-09-24 and are not yet cited as CGGV evidence; see dismech#10426. What ClinGen holds, in brief: DLG3 (Definitive) and SYP (Moderate) are curated against this entry's own MONDO term; FRMPD4, SYN1, ZNF711 and IQSEC2 (all Definitive), USP27X (Moderate) and SLITRK2 (Limited) against the lumped "X-linked complex neurodevelopmental disorder"; RPS6KA3 against Coffin-Lowry syndrome, BRWD3 and USP9X against X-linked syndromic intellectual disability, RAB39B against the early-onset parkinsonism-intellectual disability syndrome, and OGT against MRX106 by the Syndromic Disorders expert panel. FGF13, KLHL15, MID2, RLIM, SLC9A7, SRPK3 and ZMYM3 have no ClinGen gene-disease validity record. This entry's `disease_term`, MONDO:0019181, is a class term rather than a gene-defined leaf standing in for an umbrella, which is what makes it the right anchor for the class as modelled here: its MONDO definition reads "In contrast to syndromic or specific X-linked intellectual deficiencies (MRXS), which also present with associated physical, neurological and/or psychiatric manifestations, intellectual deficiency is the only symptom of MRX." Every numbered concept assessed for membership above is a direct subclass of it, so each is in scope by MONDO's own placement rather than by an over-broad anchor. This entry completes the non-syndromic intellectual-disability trio with Autosomal_Dominant_Non-Syndromic_Intellectual_Disability and Autosomal_Recessive_Non-Syndromic_Intellectual_Disability. A Grouping uniting the three would be a reasonable follow-up. No GeneReviews chapter exists for the umbrella non-syndromic X-linked intellectual disability class; GeneReviews coverage in this space is organised per syndromic gene (searched 2026-08-12), so the GeneReviews phenotype baseline does not apply to this entry. The committed Bookshelf index holds no chapter for it in either GeneReviews or StatPearls. Deep research was run with Edison (falcon). The NEC preflight returned SKIP because MONDO records no causal gene for this umbrella term; the manual fallback check was performed - the report's most-discussed genes (SLC9A7, IQSEC2, SLC6A8, FMR1, HCFC1) are all genuine X-linked intellectual-disability genes and the report is unambiguously about this entity, so no Named Entity Confusion was found. Every PMID and snippet used from the report was independently fetched and verified against the cached reference record before use. Most of those records are abstracts; four snippets from PMID:31906484 quote its body text, which is present because that record is cached as full text. No `clinical_trials:` block is recorded because the search returns nothing for this class. A ClinicalTrials.gov query on the condition "X-linked intellectual disability" (API v2, run 2026-08-12) returns trials in other entities - predominantly syndromic ones such as Rett syndrome, fragile X syndrome and the mucopolysaccharidoses, alongside unrelated hits - and no disease-modifying interventional trial in non-syndromic XLID, which matches the deep-research report's own negative finding. The two studies that do name this population are phenotyping and natural-history research rather than treatment: NCT02854956 (clinical phenotyping and characterisation of neural networks in X-linked mental retardation - registered as INTERVENTIONAL, but the intervention is the phenotyping protocol, not a therapy; status UNKNOWN) and NCT06500260 (CNKSR2 natural-history study, observational). Both were verified against the registry. Listing either as a treatment would misrepresent them, so the negative result is recorded here instead. Two DR-surfaced phenotypes are deliberately not modelled. Hypotonia (HP:0001252) and muscle weakness (HP:0001324) are reported in the SLC9A7 families, but only in that paper's full text - the cached record for PMID:30335141 is abstract-only, so no snippet can support them and the claim would be unverifiable. They should be added if an abstract-level source is found. Autistic features and seizures, by contrast, WERE added, because the Basque cohort paper (PMID:31906484) quantifies both at group level in text that is present in the cached record. Two of Edison's citation keys resolve to distinct papers by the same Basque group, and are cited here under their separately verified identities: "tejada2020non-syndromicxlinked" is the dedicated NS-XLID review (Tejada & Ibarluzea 2020, Clin Genet, PMID:31898314), and "ibarluzea2020targetednextgenerationsequencing" is the 82-gene panel cohort study (Ibarluzea et al. 2020, Genes, PMID:31906484). The DOI-to-PMID converter returns no PMID for the review's DOI (10.1111/cge.13698), so it was recovered by title search; a first pass of this curation conflated the two keys, and the review is the source of the class definition, the not-clear-cut boundary statement, and the 141-gene count recorded here.

Address PR review suggestions: Non-Syndromic X-Linked Intellectual Disability · 2026-08-12T13:42:29Z · View source

Addressed the seven non-blocking SUGGESTIONs from the automated review on PR #8367 (the PR was already APPROVED with no CRITICAL or IMPORTANT findings; these were optional improvements). Split fragile X (FMR1) repeat testing into its own diagnosis entry, since a repeat expansion is not reliably called by exome or panel sequencing so a normal sequencing result does not exclude fragile X. Three evidence items: the most-common-XLID-entity statement (PMID:22482801), the referral-level exclusion step and the normal-repeat entry criterion of the Basque cohort (PMID:31906484). Also added diagnosis_term bindings to all four diagnosis entries (NCIT:C19770 Molecular Analysis, NCIT:C15709 Genetic Testing, NCIT:C16809 Magnetic Resonance Imaging), which had none. Added the two mechanistic arms missing from the convergence node's machine-readable biological_processes: Golgi/post-Golgi pH regulation (GO:0051453) and glycosylation of exported cargo, plus the AFF2/FMR2 transcriptional-activation arm (GO:0045893). The reviewer suggested GO:0006486 for glycosylation; that term is OBSOLETE (reason for obsoletion: it represents a molecular function) and was replaced with its declared successor GO:0009101 glycoprotein biosynthetic process. GO:0045893 was chosen over the suggested GO:0006357 because the supporting assays are yeast and mammalian reporter transcription-activation experiments that do not resolve promoter class. The transcriptional arm is newly evidenced by Hillman and Gecz 2001 (PMID:11355014, fetched this session): one IN_VITRO item for the activation assays and one HUMAN_CLINICAL item connecting FRAXE methylation silencing of FMR2 to the cognitive endpoint. The node description now names the AFF2 arm. Added anatomical grounding via the locations slot: cerebral cortex (UBERON:0000956) and hippocampal formation (UBERON:0002421) on the TISSUE node, both already named in its description and in its cited expression snippets; brain (UBERON:0000955) on the ORGANISM node. Added two group-level phenotypes that the previous round had judged unsupportable. Both come from the Basque cohort paper (PMID:31906484), whose cached record is full text: autistic behavior (HP:0000729), frequency OCCASIONAL, from the sentence that quantifies autism spectrum disorders in nearly 30% of the cohort while confirming in the same sentence that the cohort is phenotypically unspecific; and the existing Seizure entry, which was unevidenced and scoped to the ARX subtype, broadened to class level with frequency OCCASIONAL on the almost-15%-epilepsy figure for the X-linked group. The ARX-designation reasoning and the refusal to attach the syndromic-ARX quote are preserved in the description. The OCCASIONAL band for autism is recorded as the conservative reading of "nearly 30%", which sits exactly on the OCCASIONAL/FREQUENT boundary; that judgement is stated in the evidence explanation. Split Speech and Language Therapy (NCIT:C159273) and Occupational Therapy (NCIT:C121351) out of the lumped Supportive Care entry as queryable NCIT-coded entries, each explicitly recorded as carrying no evidence block because the deep-research support for them is full-text-only and no cached abstract enumerates the individual modalities. A PubMed search for an abstract-level source enumerating these modalities returned only GeneReviews chapters for other disorders (MBD5, DDX11), which would have been wrong-disease evidence and were not used. The Supportive Care description was rewritten accordingly: it no longer claims the modalities are deliberately unsplit. Retagged the PMID:38424476 evidence_source from HUMAN_CLINICAL to OTHER on the hemizygous-expression node, as the reviewer noted the quoted sentence is a methodological statement rather than a clinical observation, and applied the same correction to the second PMID:38424476 item on Supportive Care, whose snippet states the scope of a review. Recorded the negative clinical-trials result in notes rather than adding a clinical_trials block. Independently verified against the ClinicalTrials.gov API v2 this session rather than relayed from the deep-research report: a condition search for X-linked intellectual disability returns only syndromic entities (Rett, fragile X, MPS), and the two studies naming this population - NCT02854956 and NCT06500260 - were fetched individually and are phenotyping and natural-history studies, not treatments. Also recorded in notes why hypotonia and muscle weakness remain unmodelled: they appear only in the full text of PMID:30335141, whose cached record is abstract-only, so no verifiable snippet exists. A stale claim in the speech-delay phenotype description, which attributed that same gap to the --no-full-text flag rather than to the cache being abstract-only, was corrected - this session established that CI does accept snippets from cached full text. A second, independent review was then run by an agent given no context on this work and instructed to distrust the commit message, the notes prose and this history record. It returned APPROVE WITH SUGGESTIONS, and its findings were acted on in the same session. Two were substantive. First, the second PMID:11355014 evidence item was tagged HUMAN_CLINICAL although that paper reports no human clinical data (MeSH: HeLa cells, Saccharomyces cerevisiae) and the quoted sentence is the abstract's opening background statement - retagged OTHER, which is also the standard this session applied to the two PMID:38424476 items. Second, the convergence node's closed list of arms lacking a cited synaptic endpoint was not updated when the AFF2 arm was added, so it implied AFF2 had one - AFF2 added to the caveat. Suggestions also acted on: PMID:22482801 retagged OTHER (historical review, field-summary sentence) and its explanation corrected from "most common XLID entity" to "most common of the XLID syndromes", matching the quote; the FMR1 entry's "precondition of the workup" explanation softened to what the cohort sentence actually supports, with the generalisation labelled as the entry's own inference; both new frequency bands annotated with their real denominators (the 61 males are a referral population of whom only 16 received a candidate variant, and the epilepsy figure covers the roughly 47-proband X-linked sub-arm, not all 61); the parent/child HPO overlap between Atypical behavior (HP:0000708) and the new Autistic behavior (HP:0000729) resolved by removing the autism claim from the parent entry and stating why both are retained; the lost subtype cross-reference restored as a phenotype_contexts entry scoped to ARX-related, so the subtype association survives structurally without mis-scoping the class-level claim; the stale "verified against the cached abstract" sentence in notes corrected, since four snippets quote cached body text; the therapy entries' rationale corrected - a grep of all cached references for this entry finds no mention of speech-language or occupational therapy at all, including in a full-text-cached source, so the DR report over-attributed the modality list; and the trials note softened from "returns only trials in syndromic entities" and now records that NCT02854956 is registered as INTERVENTIONAL even though its intervention is a phenotyping protocol. Validation: just validate (schema and terms) passes; just validate-disorders - the batched sweep CI runs, with --no-full-text - passes with exit 0 and reports 90/90 snippets verified, confirming the two new body-text snippets are acceptable to CI; just validate-history passes; just check-cache-order and just check-term-cache-integrity pass, and the only cache diff is two additive rows for the new GO terms; the full tests/test_data.py suite passes (32173 passed). Global compliance is 92.3 percent (191/207), weighted 92.2 percent - level with the pre-review entry rather than the 92.7 percent reached mid-session, because the ARX phenotype context added during the second review round is deliberately unevidenced (the subtype label establishes that seizures vary without quantifying them).

Create: Non-Syndromic X-Linked Intellectual Disability · 2026-08-12T09:40:51Z · View source

Created the umbrella entry for non-syndromic X-linked intellectual disability (MONDO:0019181), completing the non-syndromic intellectual-disability trio alongside the existing autosomal dominant and autosomal recessive entries. Modelled 8 gene-anchored has_subtypes (IL1RAPL1/MRX21, PAK3/MRX30, GDI1/MRX41, TSPAN7/MRX58, FTSJ1/MRX9, ACSL4/MRX63, AFF2/FRAXE, and the non-syndromic arm of the ARX allelic series), each bound to a MONDO descendant of the root term; SLC9A7 curated under genetic because no MONDO descendant was confirmed. Five-node pathophysiology chain from X-linked gene disruption through hemizygous expression and convergent synaptic disruption to static cognitive impairment without brain malformation. Three KNOWLEDGE_GAP discussions: the Piton 2013 questioned-gene reassessment (17 of 25 challenged genes still unresolved as of the 2017 update), the instability of the syndromic/non-syndromic boundary, and the absence of a group-level prevalence. Per the curation issue, syndromic entries were deliberately excluded: FGD1, ZDHHC9 and OPHN1 map to syndromic MONDO entities, RLIM placement is unresolved, and AGTR2 is excluded on evidence grounds. Deep research: Edison (falcon). NEC preflight returned SKIP because MONDO records no causal gene for this umbrella term; the manual fallback check was performed and passed - the report top genes are all genuine XLID genes and the report is unambiguously about this entity. Every PMID and snippet used from the report was independently fetched and verified against the cached abstract. A self-review round was run before opening the PR and materially changed the entry. Its blocking finding: a first pass conflated two distinct Edison citation keys by the same Basque group, and as a result the dedicated NS-XLID review (Tejada and Ibarluzea 2020, PMID:31898314) - the report's most-cited source - was omitted entirely, while a notes block asserted a citation-resolution that had not actually been verified. That review has been fetched and added, and now sources the class definition, the not-clear-cut syndromic/non-syndromic boundary statement, and the 141-gene count; the notes block has been corrected to record both keys under their separately verified identities and to state that the DOI-to-PMID converter returns no PMID for the review's DOI. Other review fixes: removed three evidence items whose snippets did not make the claim they were attached to (global developmental delay, speech delay, and ARX seizures - the last quoted the syndromic ARX entities this entry deliberately excludes), keeping the phenotypes as described clinical context; added the FRAXE founding paper (PMID:8673086) because the previous evidence quoted sequence variants rather than the defining CCG repeat expansion; renamed the convergence node from Synaptic to Neuronal Function and hedged its description, since the tRNA, fatty-acid and Golgi-pH arms have no cited synaptic endpoint; hedged the IL1RAPL1 and TSPAN7 mechanism prose, which restated authors' speculation as fact; hedged the static/non-progressive claim, which no cited source evidences; retagged six evidence_source values (PAK3 and IL1RAPL1 expression work to MODEL_ORGANISM per their MeSH species terms, TSPAN7 in situ hybridisation to IN_VITRO, three textbook background statements to OTHER); added Chaves 2023 (PMID:36943625) for the X-inactivation-skewing yield, marked PARTIAL because half its recovered variants were autosomal; dropped three unquantified OCCASIONAL frequency bands and an unevidenced COMPLETE penetrance; dropped a misleading HP:0001249 binding from the absence-of-features phenotype and unsupported pyramidal/glutamatergic cell-type specificity; and changed a case-fraction prevalence record from PERIOD_PREVALENCE to UNKNOWN. Validation after all fixes: just validate (schema and terms) passes; just validate-disorders - the batched schema, terms and reference sweep CI runs - passes with exit 0 and reports 83/83 snippets verified; just verify-datasets OK for geo:GSE179384; targeted pytest FK/uniqueness selection 6055 passed and the full tests/test_data.py suite passed. Global compliance 92.3 percent, weighted 92.2 percent - slightly below the pre-review 93.8 percent because unsupported evidence items were removed rather than retained for score.

Falcon ▸

Non-Syndromic X-Linked Intellectual Disability: Research Report

Edison Scientific Literature 44 citations 2026-08-12T10:19:53.706474

Non-Syndromic X-Linked Intellectual Disability: Research Report

Scope note. Non-syndromic X-linked intellectual disability (NS-XLID) is not one molecularly uniform disease. It is an umbrella category for numerous X-linked neurodevelopmental disorders in which intellectual disability (ID) is the only consistent shared feature. Additional neurologic, behavioral, or dysmorphic findings may occur, but do not form a reproducible syndrome. Consequently, prevalence, penetrance, natural history, biomarkers, and treatment should ideally be curated at the causal-gene/variant level rather than assigned uniformly to the umbrella term. The boundary with syndromic XLID is increasingly regarded as blurred or biologically arbitrary. (tejada2020non‐syndromicxlinked pages 1-5, neri2018x‐linkedintellectualdisability pages 3-4, tejada2020non‐syndromicxlinked pages 12-15)

Executive summary

Identifier: MONDO:0019181. Open Targets associates this record with 25 targets, including HCFC1, RPS6KA3, ARX, IQSEC2, OGT, BRWD3, IL1RAPL1, AFF2, TSPAN7, SLC9A7, CLCN4, DLG3, GDI1, SYP, HUWE1, and others. This database list is not equivalent to a fully validated contemporary clinical gene panel. (OpenTargets Search: non-syndromic X-linked intellectual disability)
Definition: ID begins during development and impairs intellectual and adaptive functioning. In NS-XLID, ID is the only common feature across affected individuals; variable speech delay, hypotonia, epilepsy, autistic traits, or minor dysmorphism may coexist. (tejada2020non‐syndromicxlinked pages 1-5)
Etiology: Rare germline X-chromosomal sequence variants, repeat expansions, copy-number/structural variants, or occasionally mosaic variants disrupt diverse but interconnected neuronal pathways. A 2020 review retained 44 NS-XLID genes after excluding questioned associations; 25 of those also caused syndromic presentations. It reported 56 implicated NS-XLID genes under a broader historical definition and 146 XLID genes overall. (tejada2020non‐syndromicxlinked pages 23-25, tejada2020non‐syndromicxlinked pages 1-5)
Epidemiology: XLID broadly is estimated to account for approximately 5–10% of ID in males; one 2023 paper cited a prevalence of 1 in 600–1,000 males. These are not reliable prevalence estimates for strict NS-XLID itself, for which no robust population prevalence or incidence was identified. (luca2020challengesinmolecular pages 1-2, mir2023wholeexomesequencing pages 1-2)
Diagnosis: Clinical assessment, three-generation pedigree, Fragile X testing where indicated, copy-number analysis, and preferably trio exome or genome sequencing with segregation and phenotype-aware reinterpretation. RNA or biochemical assays can resolve selected variants. (luca2020challengesinmolecular pages 1-2, ibarluzea2020targetednextgenerationsequencing pages 1-3)
Treatment: No disease-group-level disease-modifying treatment is established. Current implementation is genotype-informed surveillance plus developmental, educational, speech-language, occupational, physical, behavioral, psychiatric, and seizure care. Gene therapy, controlled X-reactivation, and synapse/circuit-directed interventions remain experimental. (martinez2024overcominggeneticand pages 7-8, martinez2024overcominggeneticand pages 8-10, martinez2024overcominggeneticand pages 6-7)

The following ontology-ready summary complements the narrative report.

Domain	Knowledge-base content	Suggested ontology terms/IDs	Evidence caveat
Disease identity	Non-syndromic X-linked intellectual disability (NS-XLID) is a genetically heterogeneous X-linked neurodevelopmental disease group in which intellectual disability is the only consistent shared feature; additional neurologic, behavioral, or dysmorphic findings may occur but are variable and gene-/family-specific. Exact disease-level knowledge is aggregated from literature/reviews and should not be overgeneralized to every gene-defined subtype. (OpenTargets Search: non-syndromic X-linked intellectual disability, tejada2020non‐syndromicxlinked pages 1-5, neri2018x‐linkedintellectualdisability pages 3-4)	MONDO:0019181; term label: non-syndromic X-linked intellectual disability	“Nonsyndromic” does not mean absence of all other findings; rather, no consistent syndromic pattern across cases. Scope overlaps with syndromic XLID for many genes.
Synonyms / scope	Non-specific X-linked intellectual disability; nonsyndromal X-linked intellectual disability; NS-XLID; historical: non-syndromic X-linked mental retardation. (tejada2020non‐syndromicxlinked pages 1-5, neri2018x‐linkedintellectualdisability pages 3-4)	term suggestions; verify release	Historical terminology in older papers may use outdated language.
Core phenotype	Intellectual disability is the defining phenotype, often mild to severe depending on gene/variant. (tejada2020non‐syndromicxlinked pages 1-5)	HP:0001249 Intellectual disability	Frequency at disease-group level cannot be meaningfully quantified because NS-XLID aggregates many disorders.
Core phenotype	Developmental delay / global developmental delay may precede formal ID diagnosis in childhood. (khayat2019arecurrentmissense pages 3-4, mir2023wholeexomesequencing pages 1-2, mir2023wholeexomesequencing pages 2-4)	HP:0001263 Global developmental delay; HP:0011344 Severe global developmental delay	More typical in pediatric case series; adult historical families may be described primarily as ID.
Core phenotype	Speech/language delay or poor/absent speech is common in several gene-specific forms. (khayat2019arecurrentmissense pages 3-4, mir2023wholeexomesequencing pages 1-2, mir2023fourfamilieswith pages 9-11, mir2023wholeexomesequencing pages 4-6)	HP:0000750 Delayed speech and language development; HP:0001344 Expressive language delay	Strongly gene-dependent; not universal across all NS-XLID genes.
Core phenotype	Hypotonia / muscle weakness reported in subsets, including SLC9A7-related cases. (khayat2019arecurrentmissense pages 3-4)	HP:0001252 Hypotonia; HP:0001324 Muscle weakness	Variable and not specific; may reflect particular gene mechanisms.
Core phenotype	Seizures/epilepsy occur in some NS-XLID genes (for example IQSEC2-, GLRA2-, ATP2B3-related cases) but are inconsistent at disease-group level. (tejada2020non‐syndromicxlinked pages 12-15, mir2023wholeexomesequencing pages 1-2, mir2023fourfamilieswith pages 9-11, mir2023wholeexomesequencing pages 4-6)	HP:0001250 Seizure; HP:0002123 Generalized myoclonic seizure (term suggestion; verify release if subtyped)	Presence of seizures can shift some cases toward broader neurodevelopmental syndromes; use gene-level assertion when possible.
Core phenotype	Autism spectrum features / autistic traits / behavioral abnormalities / psychiatric problems may occur in subsets. (tejada2020non‐syndromicxlinked pages 12-15, tejada2020non‐syndromicxlinked pages 19-23, mir2023wholeexomesequencing pages 1-2)	HP:0000729 Autism; HP:0000708 Behavioral abnormality	HPO choice should be tailored to reported feature (autism, aggression, hyperactivity, anxiety, etc.).
Anatomy	Primary organ/system affected: brain, especially forebrain/cerebral cortex and synaptic networks underlying cognition and behavior. (tejada2020non‐syndromicxlinked pages 5-8, tejada2020non‐syndromicxlinked pages 8-12, martinez2024overcominggeneticand pages 1-2)	UBERON:0000955 brain; UBERON:0000956 cerebral cortex	Disease-level anatomy is inferred from shared neurodevelopmental biology rather than uniform lesion localization.
Tissue / cell types	Principal affected tissue: nervous tissue; relevant cell types include excitatory neurons, inhibitory neurons, and broader cortical/hippocampal neuronal populations. (tejada2020non‐syndromicxlinked pages 8-12, martinez2024overcominggeneticand pages 7-8, martinez2024overcominggeneticand pages 11-12, martinez2024overcominggeneticand pages 1-2)	CL:0000540 neuron; term suggestions: excitatory neuron, inhibitory neuron, cortical neuron, hippocampal neuron; verify release	Exact CL subtype should match gene/mechanism-specific evidence; many papers infer rather than directly prove target cell types.
Subcellular compartments	Recurrently implicated compartments include synapse, presynaptic vesicle, postsynaptic density, dendritic spine, nucleus/chromatin, Golgi/TGN/post-Golgi vesicles, endosome, and mitochondrion for some genes. (tejada2020non‐syndromicxlinked pages 23-25, tejada2020non‐syndromicxlinked pages 5-8, tejada2020non‐syndromicxlinked pages 8-12, khayat2019arecurrentmissense pages 3-4, khayat2019arecurrentmissense pages 2-3, khayat2019arecurrentmissense pages 8-9)	GO:0045202 synapse; GO:0098793 presynapse; GO:0014069 postsynaptic density; GO:0043197 dendritic spine; GO:0005654 nucleoplasm; GO:0005794 Golgi apparatus; GO:0005802 trans-Golgi network; GO:0005768 endosome; GO:0005739 mitochondrion	Use gene-level annotation for highest confidence; not every compartment applies to every NS-XLID gene.
Major mechanism	Synaptic function/plasticity defects: vesicle trafficking, neurotransmitter release, postsynaptic signaling, receptor trafficking, dendritic spine regulation. Representative genes include GDI1, IL1RAPL1, SYN1, SYP, DLG3, GRIA3, IQSEC2, NLGN3, NLGN4, RAB39B, OPHN1, PAK3, TSPAN7. (tejada2020non‐syndromicxlinked pages 23-25, tejada2020non‐syndromicxlinked pages 12-15, tejada2020non‐syndromicxlinked pages 8-12)	GO:0007268 chemical synaptic transmission; GO:0016079 synaptic vesicle exocytosis; GO:0048167 regulation of synaptic plasticity	Shared pathway category is review-derived; representative genes vary in evidence strength.
Major mechanism	Cytoskeleton / Rho- and Arf-family GTPase signaling affecting dendrites and spines. Representative genes include IQSEC2, OPHN1, PAK3, FGD1. (tejada2020non‐syndromicxlinked pages 12-15, tejada2020non‐syndromicxlinked pages 8-12)	GO:0032956 regulation of actin cytoskeleton organization; GO:0007015 actin filament organization	Often downstream of synaptic signaling; phenotype correlations remain incomplete.
Major mechanism	Transcription, chromatin, RNA processing, translation regulation. Representative genes include HCFC1, KDM5C, MECP2, MED12, PQBP1, RPS6KA3, THOC2, UPF3B, ZNF711, AFF2, ATRX, DDX3X. (tejada2020non‐syndromicxlinked pages 23-25, tejada2020non‐syndromicxlinked pages 5-8, tejada2020non‐syndromicxlinked pages 19-23)	GO:0006357 regulation of transcription by RNA polymerase II; GO:0006338 chromatin remodeling; GO:0000398 mRNA splicing; GO:0000184 nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	Many of these genes also cause syndromic XLID; classify carefully at variant/disorder level.
Major mechanism	Ubiquitination / proteostasis dysregulation, including neuronal proliferation/differentiation and substrate turnover. Representative genes include HUWE1, MID2, RLIM, USP9X. (tejada2020non‐syndromicxlinked pages 23-25, tejada2020non‐syndromicxlinked pages 19-23)	GO:0016567 protein ubiquitination; GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process	Evidence is stronger for some genes than others; downstream neuronal effects remain incompletely resolved.
Major mechanism	Membrane transport / ion homeostasis / metabolism. Representative genes include SLC6A8, CLCN4, SLC16A2, SLC25A5, NDUFA1, ACSL4, ATP2B3, GLRA2. (tejada2020non‐syndromicxlinked pages 25-28, mir2023wholeexomesequencing pages 1-2, mir2023wholeexomesequencing pages 4-6)	GO term suggestions: transmembrane transport, ion homeostasis, creatine transmembrane transporter activity, mitochondrial ATP transport; verify release	Some genes produce broader syndromic/metabolic phenotypes outside strict NS-XLID.
Major mechanism	Golgi/TGN pH regulation and glycosylation defects. Best current gene-specific example: SLC9A7 p.Leu515Phe causing altered Golgi acidification and aberrant glycosylation with abnormal transferrin N-glycosylation. (khayat2019arecurrentmissense pages 3-4, khayat2019arecurrentmissense pages 2-3, khayat2019arecurrentmissense pages 8-9)	GO:0051453 regulation of intracellular pH; GO:0006486 protein glycosylation; GO:0005794 Golgi apparatus; GO:0005802 trans-Golgi network	Mechanism currently best established for SLC9A7-related NS-XLID, not the entire disease group.
Causal genes / heterogeneity	Highly heterogeneous disorder group. Review-level counts reported ~56 genes implicated in NS-XLID, with many overlapping syndromic genes; 146 total XLID genes reported by 2020 review, and disease-target databases list additional associated genes. (tejada2020non‐syndromicxlinked pages 1-5, tejada2020non‐syndromicxlinked pages 23-25, OpenTargets Search: non-syndromic X-linked intellectual disability)	Gene symbols only; disease-group curation should link to gene-specific disorder records where possible	Gene lists change with reclassification; some historical genes remain uncertain/questioned.
Inheritance	Usually X-linked inheritance affecting males more often; female carriers may be unaffected or mildly/variably affected, influenced by X-chromosome inactivation and gene escape status. (tejada2020non‐syndromicxlinked pages 1-5, luca2020challengesinmolecular pages 1-2, martinez2024overcominggeneticand pages 1-2, chaves2023skewedxchromosomeinactivation pages 1-5)	HP:0001417 X-linked inheritance; term suggestion: X-linked recessive inheritance; verify release	Some genes act through dominant, de novo, mosaic, or dosage-sensitive mechanisms in females.
Diagnostics	Recommended workup typically includes clinical evaluation/family history, FMR1 testing, chromosomal microarray, and next-generation sequencing (panel, exome, or genome) with segregation analysis and variant interpretation under ACMG/AMP. (luca2020challengesinmolecular pages 1-2, ibarluzea2020targetednextgenerationsequencing pages 1-3)	NCIT term suggestions: Genetic Testing, Chromosomal Microarray Analysis, Whole Exome Sequencing, Whole Genome Sequencing; verify release	No single disease-specific laboratory biomarker exists for NS-XLID as a group.
Diagnostics	Exome/genome sequencing now outperforms CMA/panels for unexplained GDD/ID broadly; targeted XLID panels may still help in suggestive pedigrees. In one XLID panel study, 17 candidate variants were identified in 16/61 unrelated males after negative karyotype/FMR1 testing. (ibarluzea2020targetednextgenerationsequencing pages 1-3)	NCIT term suggestions: Whole Exome Sequencing, Next-Generation Sequencing Panel; verify release	Yield figures vary by cohort design and inclusion criteria; many statistics are for GDD/ID broadly, not NS-XLID alone.
Diagnostics	Functional follow-up may include RNA studies, biochemical assays, and gene-specific tests; example: urine creatine/creatinine ratio and brain MRS for SLC6A8 deficiency; transferrin glycosylation for SLC9A7-related disease. (tejada2020non‐syndromicxlinked pages 12-15, ibarluzea2020targetednextgenerationsequencing pages 1-3, khayat2019arecurrentmissense pages 2-3)	LOINC/NCIT term suggestions; CHEBI: creatine (verify ontology mapping in KB)	These are gene-specific adjuncts, not universal NS-XLID diagnostics.
Diagnostics in females	Extreme skewing of X-inactivation in females with idiopathic ID can enrich for pathogenic findings; in one 2023 cohort, 11/136 informative women (8%) had >=90% skewing and WES found pathogenic variants in 8/11 (73%). (chaves2023skewedxchromosomeinactivation pages 1-5)	term suggestions: skewed X-chromosome inactivation; verify release	Evidence pertains to idiopathic ID in females, not a diagnostic criterion for all NS-XLID.
Treatment / management	No disease-modifying therapy is established for NS-XLID as a disease group. Current care is supportive and individualized: developmental therapies, speech-language therapy, special education, behavioral/psychiatric management, and antiseizure treatment when indicated. (luca2020challengesinmolecular pages 1-2, martinez2024overcominggeneticand pages 7-8, martinez2024overcominggeneticand pages 8-10)	NCIT term suggestions: Supportive Care, Speech Therapy, Occupational Therapy, Physical Therapy, Special Education, Anticonvulsant Therapy; verify release	Management is phenotype- and gene-specific; evidence base often extrapolated from broader neurodevelopmental care.
Advanced therapeutics	Research directions include gene therapy, selective X-reactivation, dosage-controlled transgene strategies, and circuit/synapse-targeted interventions; these remain experimental and are mostly not NS-XLID-specific. (martinez2024overcominggeneticand pages 7-8, martinez2024overcominggeneticand pages 8-10, martinez2024overcominggeneticand pages 6-7, martinez2024overcominggeneticand pages 11-12)	NCIT term suggestions: Gene Therapy, CRISPR-based Gene Editing, RNA Therapy; verify release	Most therapeutic development is for specific syndromic X-linked NDDs; translation to NS-XLID is unresolved.
Prevention / counseling	Genetic counseling, cascade testing, carrier testing, reproductive counseling, and when a familial pathogenic variant is known, options such as prenatal diagnosis or preimplantation genetic testing. (luca2020challengesinmolecular pages 1-2, mir2023wholeexomesequencing pages 1-2, mir2023wholeexomesequencing pages 4-6)	NCIT term suggestions: Genetic Counseling, Carrier Screening, Prenatal Genetic Testing, Preimplantation Genetic Testing; verify release	Prevention is primarily genetic/reproductive rather than environmental because NS-XLID is a monogenic/heterogeneous genetic disease group.
Epidemiology	Intellectual disability overall affects ~1% of the population; males are affected more often. XLID accounts for an estimated 5-10% of ID in males, but disease-specific prevalence for NS-XLID is not well established because it comprises many rare gene-defined disorders. (tejada2020non‐syndromicxlinked pages 1-5, luca2020challengesinmolecular pages 1-2, mir2023wholeexomesequencing pages 1-2)	No exact disease-level prevalence ID recommended	Avoid presenting a single prevalence for MONDO:0019181 as if it were a uniform entity.
Natural history / prognosis	Usually childhood-onset and lifelong. Course is generally chronic/stable in terms of core cognitive impairment, while associated features (seizures, behavior, speech limitations) depend on the causal gene and comorbidities. (tejada2020non‐syndromicxlinked pages 1-5, khayat2019arecurrentmissense pages 3-4, mir2023wholeexomesequencing pages 1-2)	term suggestions: childhood onset; chronic course; verify release	Prognosis cannot be generalized across all NS-XLID subtypes.
Models	Model systems include mouse models, human iPSCs, and cellular assays; current 2024 work emphasizes mosaic female models, reporter-based strategies, dual-eGRASP/synaptic assays, electrophysiology, imaging, and human iPSC approaches to resolve circuit heterogeneity. (martinez2024overcominggeneticand pages 7-8, martinez2024overcominggeneticand pages 8-10, martinez2024overcominggeneticand pages 11-12, martinez2024overcominggeneticand pages 1-2)	NCIT term suggestions: Disease Model, Induced Pluripotent Stem Cell, Mouse Model; CL:0000000 cell (generic, term suggestion for specific derived neurons); verify release	Much model literature is from broader XLID/X-linked NDDs, not exclusively strict NS-XLID.
Exemplary gene-specific subtype	SLC9A7-related NS-XLID: recurrent p.Leu515Phe reported in two unrelated families; associated with moderate-severe ID, speech delay, hypotonia/muscle weakness, reserved personality, clinodactyly; mechanism involves TGN/post-Golgi alkalinization and abnormal glycosylation. (khayat2019arecurrentmissense pages 3-4, khayat2019arecurrentmissense pages 2-3, khayat2019arecurrentmissense pages 8-9, khayat2019arecurrentmissense pages 45-45)	Gene: SLC9A7; GO/UBERON/HPO terms above as applicable	Useful exemplar of mechanistic depth, but not representative of all NS-XLID mechanisms.

Table: This table provides a compact, ontology-ready summary of nonsyndromic X-linked intellectual disability for knowledge-base use. It emphasizes heterogeneous gene-dependent biology and highlights that intellectual disability is the only consistent shared feature across the disease group.

1. Disease information

Definition and identifiers

NS-XLID—also called non-specific XLID, nonsyndromal XLID, or historically X-linked nonsyndromic mental retardation—is an early-onset genetic neurodevelopmental disease group. “Non-syndromic” does not mean that every patient has isolated ID; it means no additional feature is consistently shared across the relevant family or disorder definition. The dedicated review states: “Non-Specific or Non-Syndromic Intellectual Disability (NS-XLID) [is that] where the only common feature is ID.” (tejada2020non‐syndromicxlinked pages 1-5)

MONDO: MONDO:0019181.
OMIM: No single umbrella OMIM phenotype number was established in the retrieved evidence. Historically, pedigrees were assigned MRX/IDX locus numbers; the 2018 update described 105 nonsyndromal families with IDX numbers, 67 with cloned genes, 33 mapped but unresolved, and five reserved numbers. Individual causal genes and phenotypes have separate OMIM records. (neri2018x‐linkedintellectualdisability pages 3-4)
Orphanet, MeSH, ICD-10/ICD-11: No unique, validated NS-XLID-specific code was established from the retrieved literature. Clinical coding usually uses intellectual-developmental-disorder and/or genetic-etiology codes, while the molecular diagnosis is recorded separately. These mappings should be verified directly against the current releases before production use.
Data provenance: The report is principally aggregated disease-level evidence from reviews, databases, family studies, and experimental papers—not individual EHR data. Patient counts are stated where primary cohorts were available.

The historical syndromic/non-syndromic division is unstable: different variants in one gene—and sometimes the same familial variant—can produce either label because of variant location, dosage, genetic background, X-inactivation, and other modifiers. (tejada2020non‐syndromicxlinked pages 1-5, tejada2020non‐syndromicxlinked pages 12-15)

2. Etiology, risk, protection, and gene–environment interaction

Causal factors

The primary cause is a germline pathogenic or likely pathogenic X-chromosomal variant. Relevant classes include missense, nonsense, frameshift, splice-altering, repeat-expansion, exon/gene deletion or duplication, and larger structural variants. Pathogenic mechanisms include loss of function, altered dosage, impaired protein interactions, and occasional apparent gain of function. Most variants are constitutionally inherited or de novo; somatic/gonadal mosaicism is possible but not quantified for the umbrella disease.

Representative clinically supported genes include AFF2, ARX, ATRX, BRWD3, CLCN4, DLG3, FTSJ1, GDI1, HCFC1, HUWE1, IL1RAPL1, IQSEC2, KDM5C, MECP2, MED12, NLGN3, NLGN4X, OGT, OPHN1, PAK3, RAB39B, RPS6KA3, SLC6A8, SLC9A7, SYP, SYN1, TSPAN7, UPF3B, and ZNF711. Gene validity and the “non-syndromic” designation require periodic reassessment; older candidate lists contained associations later questioned by population sequencing. (OpenTargets Search: non-syndromic X-linked intellectual disability, tejada2020non‐syndromicxlinked pages 23-25, tejada2020non‐syndromicxlinked pages 1-5)

A recent human example is the October 2023 WES study of nine affected males from four Iranian families. It identified likely pathogenic ZDHHC9 c.566T>C (p.Leu189Pro), GLRA2 c.1048C>T (p.Arg350Cys), ATP2B3 c.2541C>G (p.Asp847Glu) and previously reported pathogenic L1CAM c.925G>A (p.Glu309Lys) variants. The three novel variants were classified under ACMG/AMP criteria and segregated in X-linked pedigrees. [BMC Medical Genomics, October 2023, DOI: https://doi.org/10.1186/s12920-023-01680-y]. (mir2023wholeexomesequencing pages 1-2, mir2023fourfamilieswith pages 9-11, mir2023wholeexomesequencing pages 4-6)

Risk factors

Genetic: male hemizygosity; a carrier mother; affected maternal male relatives; a known familial pathogenic variant; X-chromosome structural rearrangement; or de novo mutation.
Female expression: skewed X-chromosome inactivation (XCI), escape from XCI, dosage sensitivity, mosaicism, and variant mechanism influence risk and severity. Approximately 15–30% of X-linked genes can escape XCI, depending on tissue and cell type. (martinez2024overcominggeneticand pages 1-2)
Family history: absence of family history does not exclude XLID because de novo variants, small families, reduced female expression, and mosaicism are common diagnostic complications. (luca2020challengesinmolecular pages 1-2)
Environmental/lifestyle/infectious: no environmental exposure, lifestyle behavior, toxin, or pathogen is a primary cause of monogenic NS-XLID. General prenatal/perinatal insults remain differential causes of ID, not established causes of genetically confirmed NS-XLID.

Protective factors and gene–environment interaction

No reproducible protective allele, diet, lifestyle, medication, or environmental exposure has been established for NS-XLID as a group. Favorable XCI that preferentially silences the mutant allele may reduce expression in heterozygous females, but is tissue-specific and is better considered a modifier than a dependable protective factor. The literature suggests environmental or genetic background can modify phenotype even within a family, but no validated quantitative gene–environment interaction was identified. (tejada2020non‐syndromicxlinked pages 1-5)

3. Phenotypes

Defining phenotype: developmental-onset impairment of intellectual and adaptive functioning (HP:0001249 Intellectual disability), ranging from mild to profound. Developmental delay (HP:0001263) may be recognized before formal cognitive testing. Onset is congenital/developmental, generally becoming apparent in infancy or childhood; the cognitive disability is chronic and lifelong rather than episodic. (tejada2020non‐syndromicxlinked pages 1-5)

Common but non-universal, gene-dependent findings include:

speech/language delay (HP:0000750), poor or absent speech;
hypotonia (HP:0001252) and occasionally muscle weakness (HP:0001324);
seizures/epilepsy (HP:0001250);
autism (HP:0000729), behavioral abnormality (HP:0000708), or psychiatric symptoms;
motor delay, variable reflexes, minor dysmorphism, clinodactyly, micro- or macrocephaly, and occasional structural brain anomalies.

These features cannot be assigned meaningful umbrella-level percentages. For example, early IQSEC2 families showed moderate-to-severe ID, while seizures, autistic traits, and psychiatric problems were inconsistent. More than 70 IQSEC2 variants had been reported by 2020, with severe truncating variants often producing a broader encephalopathy. (tejada2020non‐syndromicxlinked pages 12-15)

In the 2023 Iranian series, severe ID, developmental and speech delay were prominent; seizures, behavioral problems, muscle weakness, dysmorphism, agenesis of the corpus callosum, and colpocephaly varied by family and gene. (mir2023wholeexomesequencing pages 2-4, mir2023fourfamilieswith pages 9-11, mir2023wholeexomesequencing pages 4-6)

Quality of life: impairment chiefly affects communication, education, independent living, employment, social participation, and lifelong caregiver needs. Epilepsy, behavioral disorders, and absent speech add substantial morbidity. No NS-XLID-specific EQ-5D, SF-36, PROMIS, or disease-specific quality-of-life estimate was found; quantitative quality-of-life claims should therefore not be imputed from general ID cohorts.

4. Genetic and molecular information

Variant interpretation

Pathogenic variants are generally rare or absent from population databases and evaluated with ACMG/AMP criteria, segregation, phenotype consistency, XCI/escape status, and functional evidence. Healthy carrier mothers do not automatically refute pathogenicity. Conversely, rarity and in-silico prediction alone do not establish causality. RNA sequencing, biochemical assays, deep mutational scanning, and cell models can reclassify variants of uncertain significance. (luca2020challengesinmolecular pages 1-2, ibarluzea2020targetednextgenerationsequencing pages 1-3)

The variant classes and consequences are gene-specific:

Loss of function: truncating/splice/deletion variants in numerous genes; disturbed synaptic, transcriptional, or transport functions.
Dosage change: duplications of XLID genes can produce variable phenotypes; excessive expression may be as harmful as deficiency. (tejada2020non‐syndromicxlinked pages 5-8, martinez2024overcominggeneticand pages 6-7)
Missense/domain effects: IQSEC2 variants in IQ or Sec7 domains can respectively impair calmodulin binding/increase GEF activity or reduce ARF6 GEF activity. (tejada2020non‐syndromicxlinked pages 12-15, tejada2020non‐syndromicxlinked pages 19-23)
Gain-of-function-like physiology: SLC9A7 p.Leu515Phe causes alkalinization of trans-Golgi/post-Golgi compartments with abnormal glycosylation, despite broadly preserved localization and trafficking. (khayat2019arecurrentmissense pages 2-3, khayat2019arecurrentmissense pages 8-9)

Allele frequency must be documented per exact HGVS allele and genome build in gnomAD; there is no meaningful group-level allele frequency. Germline inheritance predominates. Somatic origin is not a defining feature, although mosaicism should be considered. No consistently validated modifier gene or anticipation phenomenon was found. Founder effects and carrier frequencies are variant/population-specific and not established for the umbrella entity.

X-inactivation and epigenetics

Random XCI creates cellular mosaics in females; escape from XCI and tissue-specific skewing complicate penetrance and blood-to-brain inference. In a 2023 study of 194 women with idiopathic ID, 136 were informative for the androgen-receptor methylation assay; 11/136 (8%) had extreme/total skewing of at least 90%. WES diagnosed 8/11 (73%), including X-linked DDX3X, WDR45, PDHA1 and autosomal KCNB1, CTNNB1, YY1, ANKRD11 variants. Thus extreme XCI is an enrichment signal, not a standalone NS-XLID diagnostic criterion. [Molecular Neurobiology, March 2023, DOI: https://doi.org/10.1007/s12035-023-03311-0]. (chaves2023skewedxchromosomeinactivation pages 1-5)

5. Environmental information

No toxin, radiation exposure, pollutant, occupation, smoking, alcohol pattern, diet, exercise level, or infectious agent is known to cause genetically defined NS-XLID. These factors may influence general neurodevelopment, health, or seizure control, but evidence for a disease-specific causal interaction is absent. NS-XLID is neither infectious nor transmissible, and vaccination is not etiologic or preventive.

6. Mechanism and pathophysiology

The upstream event is a pathogenic X-linked variant. The downstream chain depends on the gene, but several convergent modules emerge:

Synaptic vesicle cycling and neurotransmitter release. GDI1 regulates Rab GTPases; IL1RAPL1 regulates calcium-dependent secretion; SYN1 and SYP control synaptic-vesicle trafficking/endocytosis. Defects impair presynaptic release and activity-dependent plasticity. Suggested GO terms: GO:0007268 chemical synaptic transmission, GO:0016079 synaptic vesicle exocytosis. (tejada2020non‐syndromicxlinked pages 8-12)
Postsynaptic organization and receptor trafficking. DLG3 organizes NMDA-receptor signaling; GRIA3 encodes an AMPA-receptor component; IQSEC2/ARF6 regulates AMPA trafficking and dendritic actin. Disrupted receptor localization and spine plasticity impair learning and memory. Suggested GO: GO:0048167 regulation of synaptic plasticity, GO:0032956 regulation of actin cytoskeleton organization. (tejada2020non‐syndromicxlinked pages 12-15, tejada2020non‐syndromicxlinked pages 8-12)
Chromatin/transcription/RNA regulation. ATRX, MECP2, KDM5C, HCFC1, MED12, UPF3B and related proteins alter chromatin organization, RNA-polymerase-II signaling, splicing, export, translation, or nonsense-mediated decay, disturbing developmental neuronal gene programs. MED12 defects can disrupt GLI3-dependent Sonic Hedgehog, REST-dependent epigenetic signaling, and immediate-early-gene expression. Suggested GO: GO:0006338 chromatin remodeling, GO:0006357 regulation of transcription by RNA polymerase II, GO:0000184 nonsense-mediated mRNA decay. (tejada2020non‐syndromicxlinked pages 5-8, tejada2020non‐syndromicxlinked pages 19-23)
Ubiquitin/proteostasis pathways. HUWE1 and other ubiquitin-system genes alter substrate turnover, neuronal proliferation, differentiation, and stress responses. Suggested GO: GO:0016567 protein ubiquitination. (tejada2020non‐syndromicxlinked pages 19-23)
Transport, metabolism, and organelles. SLC6A8 deficiency impairs brain creatine uptake and energy buffering; CLCN4 alters endosomal ion homeostasis; NDUFA1/SLC25A5 affect mitochondrial function; SLC9A7 alters Golgi pH and glycosylation. (tejada2020non‐syndromicxlinked pages 12-15, tejada2020non‐syndromicxlinked pages 25-28, khayat2019arecurrentmissense pages 3-4)

Mechanistic exemplar: SLC9A7-related NS-XLID

Khayat and colleagues reported the recurrent SLC9A7 c.1543C>T (p.Leu515Phe) allele in two unrelated families: four Australian males aged 65, 58, 56, and 27 years and two American males aged 36 and four years. Clinical findings included moderate-to-severe ID, speech delay, hypotonia/muscle weakness, reserved personality, variable reflexes, and bilateral clinodactyly; carrier females were clinically unaffected. [Human Molecular Genetics, October 2019; PMID 30335141; DOI: https://doi.org/10.1093/hmg/ddy371]. (khayat2019arecurrentmissense pages 3-4, khayat2019arecurrentmissense pages 45-45)

SLC9A7/NHE7 normally localizes predominantly to the trans-Golgi network (TGN) and post-Golgi vesicles. The mutant retained localization and had a nonsignificantly shorter half-life—2.2 ± 0.43 versus 2.92 ± 1.52 hours—but alkalinized TGN/post-Golgi compartments, impaired N-linked oligosaccharide maturation, and produced abnormal serum-transferrin N-glycosylation. The causal chain is therefore: missense variant → dysregulated organellar proton/cation exchange → Golgi alkalinization → abnormal cargo glycosylation → altered neuronal protein processing → neurodevelopmental impairment. Evidence is human genetic plus serum biochemical and transfected-cell functional evidence, not yet proof of every downstream brain step. (khayat2019arecurrentmissense pages 2-3, khayat2019arecurrentmissense pages 8-9)

Cells, anatomy, immune/tissue injury, and omics

Relevant cells are principally neurons—especially cortical and hippocampal excitatory and inhibitory populations—and their synapses; glia may participate in selected disorders. Suggested terms include CL:0000540 neuron, plus release-verified cortical, glutamatergic, GABAergic, and hippocampal neuronal subclasses. The primary organ is the brain (UBERON:0000955), particularly cerebral cortex (UBERON:0000956) and distributed cognitive circuits. (martinez2024overcominggeneticand pages 7-8, martinez2024overcominggeneticand pages 11-12, martinez2024overcominggeneticand pages 1-2)

There is no common autoimmune, immunodeficiency, inflammatory, ischemic, fibrotic, necrotic, or oxidative-tissue-injury mechanism for NS-XLID as a whole. Likewise, no validated umbrella-level transcriptomic, proteomic, metabolomic, or lipidomic diagnostic signature exists. Gene-specific data include transferrin glycosylation in SLC9A7 and creatine abnormalities in SLC6A8. Single-cell, spatial-transcriptomic, and integrated multi-omic findings remain research-stage and are not sufficiently uniform for disease-group annotation.

7. Anatomical structures affected

Primary system: central nervous system.
Organ/site: brain and distributed bilateral neural circuits; no characteristic lateralization.
Tissue: nervous tissue, especially cortical and hippocampal networks.
Cellular: neurons, dendrites, axons, synapses; gene-dependent involvement of glia is possible.
Subcellular: synaptic vesicle, presynapse, postsynaptic density, dendritic spine, nucleus/chromatin, Golgi/TGN, endosome, or mitochondrion according to gene. Suggested GO cellular-component terms include GO:0045202 synapse, GO:0014069 postsynaptic density, GO:0043197 dendritic spine, GO:0005794 Golgi apparatus, GO:0005802 TGN, GO:0005768 endosome, GO:0005739 mitochondrion. (tejada2020non‐syndromicxlinked pages 23-25, tejada2020non‐syndromicxlinked pages 25-28, tejada2020non‐syndromicxlinked pages 8-12, khayat2019arecurrentmissense pages 3-4)

Secondary organ involvement is not intrinsic to strict NS-XLID. Consistent extracerebral abnormalities should prompt reconsideration of a gene-specific syndromic diagnosis.

8. Temporal development

Onset is developmental, usually recognized through delayed milestones, language delay, learning difficulty, or adaptive impairment in infancy or childhood. ID is chronic and lifelong. The core cognitive deficit is usually relatively stable rather than relapsing-remitting, although developmental gains occur and comorbid epilepsy or behavior may fluctuate. There is no accepted staging system, remission pattern, or end stage for the umbrella disease.

Early childhood is the key period for diagnostic testing and developmental intervention because neuroplasticity and acquisition of communication/adaptive skills are greatest. Evidence does not support spontaneous cure. Gene-specific disorders may be progressive or epileptic-encephalopathic and should not be generalized to strict NS-XLID.

9. Inheritance and population

Inheritance is usually X-linked: hemizygous males are more frequently and often more severely affected, while heterozygous females range from unaffected to severely affected depending on XCI, escape, dosage, and variant mechanism. Some genes behave as X-linked dominant disorders with frequent de novo female cases rather than conventional recessive traits. (luca2020challengesinmolecular pages 1-2, martinez2024overcominggeneticand pages 1-2, chaves2023skewedxchromosomeinactivation pages 1-5)

ID overall is reported around 1%, with male prevalence approximately 30% higher than female prevalence in one meta-analytic summary. XLID mutations account for an estimated 5–10% of male ID, but strict NS-XLID prevalence, incidence, carrier frequency, geographic distribution, and male:female ratio are unavailable. (tejada2020non‐syndromicxlinked pages 1-5, luca2020challengesinmolecular pages 1-2)

Penetrance and expressivity are gene- and sex-dependent. Germline mosaicism is relevant for counseling after an apparently de novo result, but no umbrella recurrence percentage is available. Genetic anticipation is not characteristic, except that AFF2/FMR2- and FMR1-related repeat biology must be handled under their specific disease definitions. Consanguinity is not a primary risk factor for X-linked disease, although it can clarify or complicate pedigrees. Founder alleles and population differences must be assessed variant by variant; the 2023 Iranian family study illustrates the importance of studying underrepresented ancestries but does not establish a general regional excess. (mir2023wholeexomesequencing pages 1-2, mir2023wholeexomesequencing pages 4-6)

10. Diagnostics

Recommended workflow

Confirm developmental ID using standardized cognitive and adaptive-behavior assessment; document neurologic, behavioral, growth, dysmorphic, and systemic findings.
Obtain prenatal/perinatal history and a three-generation pedigree, specifically maternal male relatives and mildly affected females.
Perform hearing/vision assessment and phenotype-directed EEG, brain MRI, metabolic tests, or biochemical assays. EEG and MRI are not universal diagnostic biomarkers.
Test FMR1 CGG expansion when clinically/family-history indicated. Standard exome sequencing does not reliably exclude repeat expansion.
Use trio exome sequencing or genome sequencing early, with validated CNV calling. Chromosomal microarray remains useful where sequencing-based CNV detection is unavailable or structural variation is suspected.
Analyze a curated ID/XLID gene set but do not restrict interpretation to X-linked genes; apparent XLID pedigrees can have autosomal or de novo causes.
Confirm relevant variants orthogonally where required; perform parental/segregation testing, ACMG/AMP classification, and periodic reanalysis.
Add RNA studies, methylation/XCI studies, enzyme/transporter assays, metabolomics, or glycosylation testing when a candidate mechanism warrants it. (luca2020challengesinmolecular pages 1-2, ibarluzea2020targetednextgenerationsequencing pages 1-3, chaves2023skewedxchromosomeinactivation pages 1-5)

In a panel study of 61 unrelated males with suggestive NS-XLID after normal karyotype and FMR1 testing, sequencing 82 XLID genes found 17 candidate variants in 16 patients. The authors cited approximately 25% diagnostic yields for panel/X-exome strategies and stressed segregation, RNA, and biochemical follow-up. [Genes, January 2020, DOI: https://doi.org/10.3390/genes11010051]. (ibarluzea2020targetednextgenerationsequencing pages 1-3)

Gene-specific adjuncts include elevated urine creatine/creatinine and reduced brain creatine by proton MRS for SLC6A8 deficiency, and serum-transferrin N-glycosylation for SLC9A7. These are not universal NS-XLID biomarkers. (tejada2020non‐syndromicxlinked pages 12-15, khayat2019arecurrentmissense pages 2-3)

Differential diagnosis and screening

Differentials include Fragile X syndrome, syndromic XLID, autosomal dominant/recessive ID, chromosomal CNVs, mitochondrial disease, cerebral palsy, fetal alcohol exposure, congenital infection, endocrine/metabolic disorders, autism without ID, and acquired brain injury. There are no universal NS-XLID clinical criteria beyond developmental ID plus a confirmed causal X-linked diagnosis and absence of a consistent defining syndrome.

No population newborn screen exists. Appropriate screening comprises cascade testing after a familial diagnosis, targeted carrier testing, and variant-specific prenatal/preimplantation testing. Broad carrier screening may not capture all genes/variant classes.

11. Outcome and prognosis

No NS-XLID-specific survival curves, mortality rates, or life-expectancy estimates were identified. Isolated cognitive disability is not inherently life-limiting, but prognosis varies with epilepsy, aspiration, mobility, congenital anomalies, or gene-specific systemic disease. Functional morbidity is lifelong and may include dependence in communication, education, employment, finances, and daily living.

Recovery to typical cognition is not expected, although developmental, educational, and communication gains can be substantial. Prognostic factors are causal gene/variant, severity of early delay, epilepsy burden, speech acquisition, motor ability, behavior, and access to intervention. No validated molecular prognostic biomarker applies across NS-XLID.

12. Treatment and current applications

There is no FDA/EMA-approved pharmacotherapy, surgery, cell therapy, immunotherapy, RNA therapy, or gene therapy for NS-XLID as an umbrella disease. Current real-world management is multidisciplinary:

early intervention and individualized education;
speech-language therapy, including augmentative/alternative communication;
occupational and physical therapy;
behavioral and psychiatric assessment/intervention;
standard genotype- and seizure-type-appropriate antiseizure medication;
treatment of sleep, feeding, gastrointestinal, sensory, orthopedic, or other comorbidities;
social-work support, respite care, transition planning, and supported decision-making.

Suggested NCIT intervention concepts, with current-release verification, are Supportive Care, Speech Therapy, Occupational Therapy, Physical Therapy, Behavioral Therapy, Genetic Counseling, Anticonvulsant Therapy, Whole Exome Sequencing, and Gene Therapy.

A ClinicalTrials.gov search did not identify a disease-modifying interventional trial for strict NS-XLID. Relevant research infrastructure includes NCT02854956, a broad XLID clinical phenotyping/neural-network study, and NCT06500260, an observational CNKSR2 natural-history study. Trials for Fragile X, Rett, or CDKL5-related disease should not be represented as treatments for NS-XLID.

Experimental directions include AAV gene replacement, dosage-controlled transgenes, RNA destabilization/microRNA regulatory elements, and selective reactivation of the healthy inactive X chromosome. Experts emphasize that mosaic females create a central safety problem: indiscriminate expression may rescue mutant cells while overdosing cells already expressing the normal allele. CRISPR/pharmacologic X-reactivation currently lacks adequate cellular specificity. (martinez2024overcominggeneticand pages 7-8, martinez2024overcominggeneticand pages 8-10, martinez2024overcominggeneticand pages 6-7)

13. Prevention

Primary prevention through lifestyle modification, vaccination, or environmental avoidance is not applicable to a monogenic disease group. Actionable prevention is reproductive and family-based:

genetic counseling and precise variant interpretation;
cascade testing of at-risk relatives;
carrier testing with discussion of variable female expression;
prenatal diagnosis by chorionic-villus sampling or amniocentesis for a known familial variant;
preimplantation genetic testing for monogenic disease;
counseling about residual recurrence risk from gonadal mosaicism;
early developmental surveillance of at-risk or diagnosed children.

Secondary/tertiary prevention consists of early diagnosis, timely therapy, seizure recognition, safety planning, and prevention of avoidable complications. There is no prophylactic drug or immunization specific to NS-XLID. (luca2020challengesinmolecular pages 1-2, mir2023wholeexomesequencing pages 1-2)

14. Other species and natural disease

No naturally occurring veterinary disease corresponding to the aggregate human NS-XLID category was identified. The condition is not infectious, zoonotic, or cross-species transmissible. Orthologous genes are widely conserved in mammals and other vertebrates, but NCBI Gene/Taxonomy identifiers must be attached gene by gene rather than to the umbrella disease. Relevant experimental species include Homo sapiens (NCBI Taxon 9606) and Mus musculus (10090); zebrafish, Drosophila, and cultured mammalian cells are also plausible gene-specific systems. No VBO breed association is applicable at group level.

15. Model organisms and advanced technologies

Model choice is gene-specific. Available approaches include knockout, knock-in, conditional, reporter, and mosaic mice; transfected mammalian cells; patient-derived fibroblasts; human iPSCs and differentiated neurons; and, for selected genes, zebrafish or invertebrate models.

The 2024 expert review highlights a major limitation: conventional hemizygous knockout mice do not reproduce the cellular mosaicism of heterozygous human females. Proposed F1 crosses combine X-linked reporters with mutant alleles so wild-type and mutant cells can be distinguished while retaining random XCI. dual-eGRASP, split-biotin-ligase systems, electrophysiology, calcium/voltage imaging, optogenetics, and chemogenetics can then resolve cell-type-specific synaptic and circuit defects. [Journal of Neurodevelopmental Disorders, February 2024, DOI: https://doi.org/10.1186/s11689-024-09517-0]. (martinez2024overcominggeneticand pages 7-8, martinez2024overcominggeneticand pages 8-10)

Evidence from broader X-linked neurodevelopmental models includes abnormal allele-specific neuronal clustering and circuit development in mosaic PCDH19 models, altered callosal/hippocampal NMDA-receptor circuitry in CDKL5 models, patient-derived CDKL5 iPSCs, and experimental rescue of dendritic-spine instability with IGF-1. These are mechanistically informative but are not direct treatment evidence for strict NS-XLID. (martinez2024overcominggeneticand pages 6-7, martinez2024overcominggeneticand pages 11-12)

Key limitations and knowledge gaps

The nonsyndromic/syndromic dichotomy is unstable, and gene counts vary with curation criteria.
Most phenotype frequencies, prognoses, and biomarkers are gene-specific; aggregate percentages would be misleading.
Blood XCI may not represent brain XCI.
Many mechanistic conclusions rely on cells or animals rather than direct human neural tissue.
NS-XLID-specific natural-history cohorts, patient-reported outcomes, single-cell/spatial atlases, and therapeutic trials remain scarce.
OMIM, Orphanet, ICD, MeSH, HGNC, HPO, GO, CL, UBERON, LOINC, CHEBI, and NCIT mappings should be release-verified before database ingestion.

Selected authoritative sources

Tejada MI, Ibarluzea N. Non-syndromic X-linked intellectual disability: current knowledge in light of recent molecular and functional studies. Clinical Genetics. Published January 2020. DOI: https://doi.org/10.1111/cge.13698. Abstract statement: “the only common feature is ID,” while distinct variants in several genes can cause syndromic or nonsyndromic disease. (tejada2020non‐syndromicxlinked pages 1-5)
Neri G, Schwartz CE, Lubs HA, Stevenson RE. X-linked intellectual disability update 2017. American Journal of Medical Genetics A. Published June 2018. DOI: https://doi.org/10.1002/ajmg.a.38710. (neri2018x‐linkedintellectualdisability pages 3-4, neri2018x‐linkedintellectualdisability pages 1-3)
Mir A et al. Whole exome sequencing revealed variants in four genes underlying XLID in four Iranian families. BMC Medical Genomics. Published October 2023. DOI: https://doi.org/10.1186/s12920-023-01680-y. (mir2023wholeexomesequencing pages 1-2, mir2023wholeexomesequencing pages 4-6)
Chaves LD et al. Skewed X-chromosome inactivation in women with idiopathic ID is indicative of pathogenic variants. Molecular Neurobiology. Published March 2023. DOI: https://doi.org/10.1007/s12035-023-03311-0. (chaves2023skewedxchromosomeinactivation pages 1-5)
Martinez D, Jiang E, Zhou Z. Overcoming genetic and cellular complexity to study the pathophysiology of XLIDs. Journal of Neurodevelopmental Disorders. Published February 2024. DOI: https://doi.org/10.1186/s11689-024-09517-0. (martinez2024overcominggeneticand pages 7-8, martinez2024overcominggeneticand pages 1-2)
Khayat W et al. A recurrent missense variant in SLC9A7 causes nonsyndromic XLID with alteration of Golgi acidification and aberrant glycosylation. Human Molecular Genetics. Published October 2019; PMID: 30335141. DOI: https://doi.org/10.1093/hmg/ddy371. Abstract-supported statement: patient serum showed “an abnormal N-glycosylation profile for transferrin,” implicating TGN/post-Golgi pH homeostasis and cargo glycosylation. (khayat2019arecurrentmissense pages 2-3, khayat2019arecurrentmissense pages 45-45)
De Luca C et al. Challenges in molecular diagnosis of X-linked intellectual disability. British Medical Bulletin. Published February 2020. DOI: https://doi.org/10.1093/bmb/ldz039. (luca2020challengesinmolecular pages 1-2)
Ibarluzea N et al. Targeted next-generation sequencing in patients with suggestive XLID. Genes. Published January 2020. DOI: https://doi.org/10.3390/genes11010051. (ibarluzea2020targetednextgenerationsequencing pages 1-3)

References

(tejada2020non‐syndromicxlinked pages 1-5): María Isabel Tejada and Nekane Ibarluzea. Non‐syndromic x linked intellectual disability: current knowledge in light of the recent advances in molecular and functional studies. Jan 2020. URL: https://doi.org/10.1111/cge.13698, doi:10.1111/cge.13698. This article has 32 citations and is from a peer-reviewed journal.
(neri2018x‐linkedintellectualdisability pages 3-4): Giovanni Neri, Charles E. Schwartz, Herbert A. Lubs, and Roger E. Stevenson. X‐linked intellectual disability update 2017. American Journal of Medical Genetics Part A, 176:1375-1388, Jun 2018. URL: https://doi.org/10.1002/ajmg.a.38710, doi:10.1002/ajmg.a.38710. This article has 154 citations.
(tejada2020non‐syndromicxlinked pages 12-15): María Isabel Tejada and Nekane Ibarluzea. Non‐syndromic x linked intellectual disability: current knowledge in light of the recent advances in molecular and functional studies. Jan 2020. URL: https://doi.org/10.1111/cge.13698, doi:10.1111/cge.13698. This article has 32 citations and is from a peer-reviewed journal.
(OpenTargets Search: non-syndromic X-linked intellectual disability): Open Targets Query (non-syndromic X-linked intellectual disability, 10 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(tejada2020non‐syndromicxlinked pages 23-25): María Isabel Tejada and Nekane Ibarluzea. Non‐syndromic x linked intellectual disability: current knowledge in light of the recent advances in molecular and functional studies. Jan 2020. URL: https://doi.org/10.1111/cge.13698, doi:10.1111/cge.13698. This article has 32 citations and is from a peer-reviewed journal.
(luca2020challengesinmolecular pages 1-2): Chiara De Luca, Valérie Race, Liesbeth Keldermans, Marijke Bauters, and Hilde Van Esch. Challenges in molecular diagnosis of x-linked intellectual disability. British medical bulletin, Feb 2020. URL: https://doi.org/10.1093/bmb/ldz039, doi:10.1093/bmb/ldz039. This article has 36 citations and is from a peer-reviewed journal.
(mir2023wholeexomesequencing pages 1-2): Atefeh Mir, Yongjun Song, Hane Lee, Hossein Khanahmad, Erfan Khorram, Jafar Nasiri, and Mohammad Amin Tabatabaiefar. Whole exome sequencing revealed variants in four genes underlying x-linked intellectual disability in four iranian families: novel deleterious variants and clinical features with the review of literature. BMC Medical Genomics, Oct 2023. URL: https://doi.org/10.1186/s12920-023-01680-y, doi:10.1186/s12920-023-01680-y. This article has 10 citations and is from a peer-reviewed journal.
(ibarluzea2020targetednextgenerationsequencing pages 1-3): Nekane Ibarluzea, Ana Belén de la Hoz, Olatz Villate, Isabel Llano, Intzane Ocio, Itxaso Martí, Miriam Guitart, Elisabeth Gabau, Fernando Andrade, Blanca Gener, and María-Isabel Tejada. Targeted next-generation sequencing in patients with suggestive x-linked intellectual disability. Genes, 11:51, Jan 2020. URL: https://doi.org/10.3390/genes11010051, doi:10.3390/genes11010051. This article has 34 citations.
(martinez2024overcominggeneticand pages 7-8): Dayne Martinez, Evan Jiang, and Zhaolan Zhou. Overcoming genetic and cellular complexity to study the pathophysiology of x-linked intellectual disabilities. Journal of Neurodevelopmental Disorders, Feb 2024. URL: https://doi.org/10.1186/s11689-024-09517-0, doi:10.1186/s11689-024-09517-0. This article has 9 citations and is from a peer-reviewed journal.
(martinez2024overcominggeneticand pages 8-10): Dayne Martinez, Evan Jiang, and Zhaolan Zhou. Overcoming genetic and cellular complexity to study the pathophysiology of x-linked intellectual disabilities. Journal of Neurodevelopmental Disorders, Feb 2024. URL: https://doi.org/10.1186/s11689-024-09517-0, doi:10.1186/s11689-024-09517-0. This article has 9 citations and is from a peer-reviewed journal.
(martinez2024overcominggeneticand pages 6-7): Dayne Martinez, Evan Jiang, and Zhaolan Zhou. Overcoming genetic and cellular complexity to study the pathophysiology of x-linked intellectual disabilities. Journal of Neurodevelopmental Disorders, Feb 2024. URL: https://doi.org/10.1186/s11689-024-09517-0, doi:10.1186/s11689-024-09517-0. This article has 9 citations and is from a peer-reviewed journal.
(khayat2019arecurrentmissense pages 3-4): Wujood Khayat, Anna Hackett, Marie Shaw, Alina Ilie, Tracy Dudding-Byth, Vera M Kalscheuer, Louise Christie, Mark A Corbett, Jane Juusola, Kathryn L Friend, Brian M Kirmse, Jozef Gecz, Michael Field, and John Orlowski. A recurrent missense variant in slc9a7 causes nonsyndromic x-linked intellectual disability with alteration of golgi acidification and aberrant glycosylation. Human Molecular Genetics, 28:598–614, Oct 2019. URL: https://doi.org/10.1093/hmg/ddy371, doi:10.1093/hmg/ddy371. This article has 45 citations and is from a domain leading peer-reviewed journal.
(mir2023wholeexomesequencing pages 2-4): Atefeh Mir, Yongjun Song, Hane Lee, Hossein Khanahmad, Erfan Khorram, Jafar Nasiri, and Mohammad Amin Tabatabaiefar. Whole exome sequencing revealed variants in four genes underlying x-linked intellectual disability in four iranian families: novel deleterious variants and clinical features with the review of literature. BMC Medical Genomics, Oct 2023. URL: https://doi.org/10.1186/s12920-023-01680-y, doi:10.1186/s12920-023-01680-y. This article has 10 citations and is from a peer-reviewed journal.
(mir2023fourfamilieswith pages 9-11): Atefeh Mir, Yongjun Song, Hane Lee, Hossein Khanahmad, Erfan Khorram, Jafar Nasiri, and Mohammad-Amin Tabatabaiefar. Four families with x-linked intellectual disability affected males: novel deleterious variants and clinical features with the review of literature. Unknown journal, Apr 2023. URL: https://doi.org/10.21203/rs.3.rs-2833503/v1, doi:10.21203/rs.3.rs-2833503/v1.
(mir2023wholeexomesequencing pages 4-6): Atefeh Mir, Yongjun Song, Hane Lee, Hossein Khanahmad, Erfan Khorram, Jafar Nasiri, and Mohammad Amin Tabatabaiefar. Whole exome sequencing revealed variants in four genes underlying x-linked intellectual disability in four iranian families: novel deleterious variants and clinical features with the review of literature. BMC Medical Genomics, Oct 2023. URL: https://doi.org/10.1186/s12920-023-01680-y, doi:10.1186/s12920-023-01680-y. This article has 10 citations and is from a peer-reviewed journal.
(tejada2020non‐syndromicxlinked pages 19-23): María Isabel Tejada and Nekane Ibarluzea. Non‐syndromic x linked intellectual disability: current knowledge in light of the recent advances in molecular and functional studies. Jan 2020. URL: https://doi.org/10.1111/cge.13698, doi:10.1111/cge.13698. This article has 32 citations and is from a peer-reviewed journal.
(tejada2020non‐syndromicxlinked pages 5-8): María Isabel Tejada and Nekane Ibarluzea. Non‐syndromic x linked intellectual disability: current knowledge in light of the recent advances in molecular and functional studies. Jan 2020. URL: https://doi.org/10.1111/cge.13698, doi:10.1111/cge.13698. This article has 32 citations and is from a peer-reviewed journal.
(tejada2020non‐syndromicxlinked pages 8-12): María Isabel Tejada and Nekane Ibarluzea. Non‐syndromic x linked intellectual disability: current knowledge in light of the recent advances in molecular and functional studies. Jan 2020. URL: https://doi.org/10.1111/cge.13698, doi:10.1111/cge.13698. This article has 32 citations and is from a peer-reviewed journal.
(martinez2024overcominggeneticand pages 1-2): Dayne Martinez, Evan Jiang, and Zhaolan Zhou. Overcoming genetic and cellular complexity to study the pathophysiology of x-linked intellectual disabilities. Journal of Neurodevelopmental Disorders, Feb 2024. URL: https://doi.org/10.1186/s11689-024-09517-0, doi:10.1186/s11689-024-09517-0. This article has 9 citations and is from a peer-reviewed journal.
(martinez2024overcominggeneticand pages 11-12): Dayne Martinez, Evan Jiang, and Zhaolan Zhou. Overcoming genetic and cellular complexity to study the pathophysiology of x-linked intellectual disabilities. Journal of Neurodevelopmental Disorders, Feb 2024. URL: https://doi.org/10.1186/s11689-024-09517-0, doi:10.1186/s11689-024-09517-0. This article has 9 citations and is from a peer-reviewed journal.
(khayat2019arecurrentmissense pages 2-3): Wujood Khayat, Anna Hackett, Marie Shaw, Alina Ilie, Tracy Dudding-Byth, Vera M Kalscheuer, Louise Christie, Mark A Corbett, Jane Juusola, Kathryn L Friend, Brian M Kirmse, Jozef Gecz, Michael Field, and John Orlowski. A recurrent missense variant in slc9a7 causes nonsyndromic x-linked intellectual disability with alteration of golgi acidification and aberrant glycosylation. Human Molecular Genetics, 28:598–614, Oct 2019. URL: https://doi.org/10.1093/hmg/ddy371, doi:10.1093/hmg/ddy371. This article has 45 citations and is from a domain leading peer-reviewed journal.
(khayat2019arecurrentmissense pages 8-9): Wujood Khayat, Anna Hackett, Marie Shaw, Alina Ilie, Tracy Dudding-Byth, Vera M Kalscheuer, Louise Christie, Mark A Corbett, Jane Juusola, Kathryn L Friend, Brian M Kirmse, Jozef Gecz, Michael Field, and John Orlowski. A recurrent missense variant in slc9a7 causes nonsyndromic x-linked intellectual disability with alteration of golgi acidification and aberrant glycosylation. Human Molecular Genetics, 28:598–614, Oct 2019. URL: https://doi.org/10.1093/hmg/ddy371, doi:10.1093/hmg/ddy371. This article has 45 citations and is from a domain leading peer-reviewed journal.
(tejada2020non‐syndromicxlinked pages 25-28): María Isabel Tejada and Nekane Ibarluzea. Non‐syndromic x linked intellectual disability: current knowledge in light of the recent advances in molecular and functional studies. Jan 2020. URL: https://doi.org/10.1111/cge.13698, doi:10.1111/cge.13698. This article has 32 citations and is from a peer-reviewed journal.
(chaves2023skewedxchromosomeinactivation pages 1-5): Luiza D. Chaves, Laura M. L. Carvalho, Giovanna C. Tolezano, Sara F. Pires, Silvia S. Costa, Marília O. de Scliar, Liane de R. Giuliani, Debora R. Bertola, Cíntia B. Santos-Rebouças, Go Hun Seo, Paulo A. Otto, Carla Rosenberg, Angela M. Vianna-Morgante, and Ana C. V. Krepischi. Skewed x-chromosome inactivation in women with idiopathic intellectual disability is indicative of pathogenic variants. Molecular Neurobiology, 60:3758-3769, Mar 2023. URL: https://doi.org/10.1007/s12035-023-03311-0, doi:10.1007/s12035-023-03311-0. This article has 11 citations and is from a peer-reviewed journal.
(khayat2019arecurrentmissense pages 45-45): Wujood Khayat, Anna Hackett, Marie Shaw, Alina Ilie, Tracy Dudding-Byth, Vera M Kalscheuer, Louise Christie, Mark A Corbett, Jane Juusola, Kathryn L Friend, Brian M Kirmse, Jozef Gecz, Michael Field, and John Orlowski. A recurrent missense variant in slc9a7 causes nonsyndromic x-linked intellectual disability with alteration of golgi acidification and aberrant glycosylation. Human Molecular Genetics, 28:598–614, Oct 2019. URL: https://doi.org/10.1093/hmg/ddy371, doi:10.1093/hmg/ddy371. This article has 45 citations and is from a domain leading peer-reviewed journal.
(neri2018x‐linkedintellectualdisability pages 1-3): Giovanni Neri, Charles E. Schwartz, Herbert A. Lubs, and Roger E. Stevenson. X‐linked intellectual disability update 2017. American Journal of Medical Genetics Part A, 176:1375-1388, Jun 2018. URL: https://doi.org/10.1002/ajmg.a.38710, doi:10.1002/ajmg.a.38710. This article has 154 citations.

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Non-Syndromic X-Linked Intellectual Disability: Research Report

Executive summary

1. Disease information

Definition and identifiers

2. Etiology, risk, protection, and gene–environment interaction

Causal factors

Risk factors

Protective factors and gene–environment interaction

3. Phenotypes

4. Genetic and molecular information

Variant interpretation

X-inactivation and epigenetics

5. Environmental information

6. Mechanism and pathophysiology

Mechanistic exemplar: SLC9A7-related NS-XLID

Cells, anatomy, immune/tissue injury, and omics

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Recommended workflow

Differential diagnosis and screening

11. Outcome and prognosis

12. Treatment and current applications

13. Prevention

14. Other species and natural disease

15. Model organisms and advanced technologies

Key limitations and knowledge gaps

Selected authoritative sources

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