👪

Inheritance

1

X-linked recessive inheritance HP:0001419

Only hemizygous males are affected; the index kindred showed affected males over four generations. Obligate carrier females are cognitively unaffected, although cephalometric analysis suggested intermediate craniofacial measurements in carriers.

X-linked recessive inheritance

Show evidence (3 references)

PMID:10677307 SUPPORT Human Clinical

"We report a novel X-linked mental retardation (XLMR) syndrome, with characteristic facial dysmorphic features, segregating in a large North Carolina family. Only males are affected, over four generations."

Male-only involvement across four generations of a single kindred supports X-linked recessive inheritance.

PMID:10677307 SUPPORT Human Clinical

"Obligate-carrier females are unaffected with MR, but the results of cephalometric skeletal analysis suggest craniofacial dysmorphisms intermediate between affected males and normative control individuals."

Cognitively unaffected obligate carriers are consistent with a recessive X-linked mode of inheritance.

PMID:10677307 SUPPORT Human Clinical

"Therefore, we believe that a unique recessive XLMR syndrome with a distinctive and recognizable phenotype is represented in this family."

The authors' explicit conclusion that the condition is a recessive XLMR syndrome.

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Discussions and Knowledge Gaps

2

Can rodent Rbmx models be used to study Shashi X-linked intellectual disability, given that Rbmx-deficient mice show only mild cortical abnormalities while affected humans have moderate intellectual disability?

HUMAN MODEL MISMATCH OPEN shashi_rbmx_mouse_human_mismatch

Attached to

pathophysiology#Impaired Cortical Development

RBMX has an independently arisen retrocopy, RBMXL1, in both primates and rodents. RBMX and RBMXL1 share protein and RNA partners and act redundantly in brain development, so RBMXL1 buffers RBMX deficiency in a context- and dosage-dependent manner. Because that buffering differs between species, a mild murine cortical phenotype cannot be read as evidence against a severe human mechanism, and rodent models may systematically understate the consequences of RBMX loss.

Show evidence (2 references)

PMID:42360281 SUPPORT Model Organism

"Despite severe phenotypes in humans, Rbmx-deficient mice display only mild cortical abnormalities."

States the human-model phenotype mismatch directly.

PMID:42360281 SUPPORT Model Organism

"Together, these findings establish RBMXL1 as a functional paralog of RBMX that is likely buffering deleterious variation in a context- and dosage-dependent manner."

Provides the mechanistic explanation (paralog buffering) for why the mouse model under-reproduces the human phenotype.

What links RBMX/hnRNP G loss of function to obesity and macroorchidism, the two non-neurological cardinal features of the Shashi syndrome?

KNOWLEDGE GAP OPEN shashi_obesity_macroorchidism_mechanism_gap

Attached to

pathophysiology#RBMX Loss of Function

All the mechanistic work on the Shashi RGG/RG allele to date addresses neural phenotypes (SRSF1 complex assembly, MDM4 splicing, p53 activation, neural progenitor differentiation). No published work explains why loss of an ubiquitously expressed splicing regulator produces obesity and macroorchidism, and the corresponding causal edges are therefore modelled with unknown intermediates.

Proposed experiments

Tissue-resolved splicing analysis in RBMX-deficient adipose and testis

shashi_tissue_resolved_splicing

Compare RBMX-dependent alternative splicing programs in adipose and gonadal tissue against neural tissue to identify tissue-restricted mis-splicing events that could account for the metabolic and gonadal features.

Show evidence (1 reference)

PMID:39356106 PARTIAL In Vitro

"Here, we show that in somatic cells the similar yet ubiquitously expressed RBMX protein has similar functions."

Confirms that RBMX is ubiquitously expressed in somatic cells, which is what makes the tissue-restricted metabolic and gonadal phenotypes an unexplained gap rather than an obvious consequence.

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Pathophysiology

8

RBMX Loss of Function

The proximal lesion is loss of function of RBMX, which encodes the RNA-binding protein hnRNP G. In the original Shashi kindred a 23 bp frameshift deletion segregates with disease in affected males and removes the RGG/RG motif of hnRNP G. RBMX is relatively intolerant to loss-of-function variation, a pattern shared by other X-linked intellectual disability genes.

RBMX hgnc:9910

mRNA binding GO:0003729 ↓ DECREASED

Downstream

Disrupted hnRNP G RGG/RG-Dependent Splicing Regulation Deletion of the RGG/RG motif removes the low-complexity region through which hnRNP G engages RNA polymerase II and splicing partners.

Distinctive craniofacial dysmorphism The recognizable facial gestalt is a parallel consequence of RBMX loss rather than a downstream consequence of impaired corticogenesis; the developmental intermediates linking RBMX loss to craniofacial patterning are not established.

Obesity Obesity is a consistent non-neurological feature of the syndrome and is modeled as a parallel consequence of RBMX loss; no mechanistic intermediate between RBMX loss and adiposity has been established.

Macroorchidism Macroorchidism is a consistent feature in affected males and is modeled as a parallel consequence of RBMX loss; the intermediates are unknown, although genital malformations are part of the broader RBMX-variant spectrum.

Show evidence (3 references)

PMID:25256757 SUPPORT Human Clinical

"On whole exome sequencing in the large family originally reported with this disorder, we identified a 23 bp frameshift deletion in the RNA binding motif protein X-linked (RBMX) gene at Xq26 in the affected males (n = 7), one carrier female, absent in unaffected males (n = 2) and in control..."

Directly identifies the segregating RBMX frameshift deletion as the causal lesion in the index family.

PMID:25256757 SUPPORT Computational

"the findings were indicative of RBMX being relatively intolerant to loss of function variants, a distinctive pattern seen in a subset of XLID genes"

Genic intolerance analysis supports loss of function as the operative mechanism class for RBMX.

PMID:37277488 SUPPORT Human Clinical

"RNA binding motif protein X-linked (RBMX) encodes the heterogeneous nuclear ribonucleoprotein G (hnRNP G) that regulates splicing, sister chromatid cohesion and genome stability."

Establishes the gene product identity and its core molecular functions.

Disrupted hnRNP G RGG/RG-Dependent Splicing Regulation

hnRNP G is an m6A reader that binds RNA through an RRM and Arg-Gly-Gly (RGG) motifs and uses those RGG motifs to contact the phosphorylated C-terminal domain of RNA polymerase II, coupling it co-transcriptionally to nascent pre-mRNA and to transcriptome-wide alternative splicing decisions. Loss of the RGG/RG motif therefore removes the principal interface through which hnRNP G regulates splice-site selection.

regulation of mRNA splicing, via spliceosome GO:0048024 ⚠ ABNORMAL

Downstream

RBMX/SRSF1 Higher-Order Complex Disruption Loss of the methylated RGG/RG motif prevents higher-order assembly with the SRSF1 splicing factor.

Show evidence (5 references)

PMID:31445886 SUPPORT In Vitro

"Here, we show that hnRNPG directly binds to the phosphorylated carboxy-terminal domain (CTD) of RNA polymerase II (RNAPII) using RGG motifs in its low-complexity region."

Identifies the RGG motifs deleted in Shashi-XLID as the interface hnRNP G uses to engage the transcription machinery.

PMID:31445886 SUPPORT In Vitro

"Through interactions with the phosphorylated CTD and nascent RNA, hnRNPG associates co-transcriptionally with RNAPII and regulates alternative splicing transcriptome-wide."

Establishes that the RGG-dependent interaction controls alternative splicing genome-wide, the process disrupted by the Shashi allele.

PMID:24692659 PARTIAL In Vitro

"We report that in addition to the C-terminal region of hnRNP G, the RNA Recognition Motif (RRM) and the middle part of the protein containing the Arg-Gly-Gly (RGG) box are important for this function."

Structural work on a model target (SMN2 exon 7) independently shows the RGG box is required for hnRNP G splicing activity, though the target is not itself implicated in Shashi-XLID.

+ 2 more references

RBMX/SRSF1 Higher-Order Complex Disruption

The RBMX RGG/RG motif is methylated by PRMT5, and this methylation licenses assembly with the SRSF1 splicing factor into higher-order complexes. The Shashi-XLID frameshift removes the motif, so the higher-order RBMX/SRSF1 complex fails to form and SRSF1 recruitment to its target pre-mRNAs is reduced.

protein-containing complex assembly GO:0065003 ↓ DECREASED

Downstream

MDM4 Exon 6 Mis-Splicing and Reduced MDM4 Protein Disruption of the RBMX/SRSF1 complex reduces SRSF1 binding to the MDM4 pre-mRNA, which is what produces exon 6 exclusion and lower MDM4 protein.

Show evidence (1 reference)

PMID:34260915 SUPPORT In Vitro

"Moreover, we identify that the RBMX RGG/RG motif is methylated by protein arginine methyltransferase 5 (PRMT5), and this regulates assembly with the SRSF1 splicing factor into higher-order complexes."

Establishes PRMT5-dependent methylation of the RGG/RG motif as the licensing step for higher-order RBMX/SRSF1 complex assembly, which the Shashi-XLID deletion removes.

MDM4 Exon 6 Mis-Splicing and Reduced MDM4 Protein

Reduced SRSF1 occupancy on the MDM4 pre-mRNA causes skipping of exon 6, yielding an unstable transcript isoform and lower MDM4 protein levels. Isogenic Shashi-XLID iPSCs carrying the patient RGG/RG deletion reproduce this MDM4 splicing dysregulation.

mRNA splicing, via spliceosome GO:0000398 ⚠ ABNORMAL

Downstream

Aberrant p53 Pathway Activation Reduced MDM4 protein removes a key negative regulator of p53, releasing p53 activity.

Show evidence (2 references)

PMID:34260915 SUPPORT In Vitro

"Depletion of RBMX or disruption of the RBMX/SRSF1 complex in PRMT5-depleted cells reduces SRSF1 binding to the MDM4 precursor (pre-)mRNA, leading to exon 6 exclusion and lower MDM4 protein levels."

States the exon 6 exclusion and the reduction in MDM4 protein that define this node.

PMID:34260915 SUPPORT In Vitro

"Transcriptomic analysis of isogenic Shashi-XLID human-induced pluripotent stem cells (hiPSCs) generated using CRISPR-Cas9 reveals a dysregulation of MDM4 splicing and aberrant p53 upregulation."

Confirms the mis-splicing step in a patient-genotype human cellular model of Shashi-XLID rather than only in knockdown cells.

Aberrant p53 Pathway Activation

Reduced MDM4 levels resulting from mis-splicing lead to aberrant upregulation and activation of the p53 pathway in RBMX-deficient and Shashi-XLID genotype cells.

signal transduction by p53 class mediator GO:0072331 ↑ INCREASED

Downstream

Neural Progenitor Differentiation Failure and Excessive Apoptosis Excess p53 signalling in neural progenitors drives apoptosis and abnormal differentiation.

Show evidence (1 reference)

PMID:34260915 SUPPORT In Vitro

"Our findings identify RBMX as a regulator of SRSF1 and the p53 pathway, suggesting that the loss of function of the RBMX RGG/RG motif is the cause of Shashi-XLID syndrome."

States the authors' mechanistic conclusion that RGG/RG loss of function acting through SRSF1 and p53 is causal for Shashi-XLID.

Neural Progenitor Differentiation Failure and Excessive Apoptosis

Neural progenitor cells derived from isogenic Shashi-XLID iPSCs show differentiation and morphological abnormalities together with excessive apoptosis, providing the cellular substrate for impaired brain development.

neural progenitor cell CL:0011020

neuron differentiation GO:0030182 ⚠ ABNORMAL apoptotic process GO:0006915 ↑ INCREASED

brain UBERON:0000955

Downstream

Impaired Cortical Development Progenitor differentiation failure and apoptosis compromise corticogenesis.

Show evidence (1 reference)

PMID:34260915 SUPPORT In Vitro

"Shashi-XLID neural progenitor cells (NPCs) display differentiation and morphological abnormalities accompanied with excessive apoptosis."

Direct experimental observation in a patient-genotype human cellular model.

Impaired Cortical Development

Loss of RBMX function disrupts cortical development. In humans, hemizygous RBMX variants produce neurodevelopmental disorders with intellectual disability and variable brain malformations; expression and animal modelling studies likewise indicate that loss of RBMX function results in abnormal brain development.

cerebral cortex development GO:0021987 ⚠ ABNORMAL

cerebral cortex UBERON:0000956

Downstream

Syndromic Neurodevelopmental Impairment Abnormal corticogenesis produces the intellectual disability that defines the syndrome.

Show evidence (2 references)

PMID:42360281 SUPPORT Human Clinical

"RBMX pathogenic variants disrupt cortical development through both partial loss-of function (C-terminal variants) and gain-of-function (N-terminal variants) mechanisms."

Establishes disrupted cortical development as the tissue-level consequence of RBMX pathogenic variation.

PMID:25256757 PARTIAL Model Organism

"Prior expression and animal modeling studies indicate that loss of function of RBMX results in abnormal brain development."

Supporting model-organism and expression evidence cited by the gene-discovery paper; indirect for the human tissue phenotype.

Syndromic Neurodevelopmental Impairment

The convergent clinical outcome of the corticogenesis defect is a syndromic neurodevelopmental disorder in hemizygous males, centred on moderate intellectual disability. The non-neurological cardinal features that complete the syndrome - the distinctive craniofacial gestalt, obesity and macroorchidism - are modeled as parallel consequences of RBMX loss rather than as descendants of this node, because no published work links impaired corticogenesis to adiposity, testicular volume or craniofacial patterning (see the shashi_obesity_macroorchidism_mechanism_gap discussion). Carrier females are cognitively unaffected.

Downstream

Moderate intellectual disability The defining cognitive outcome of the syndrome.

Show evidence (1 reference)

PMID:42360281 SUPPORT Human Clinical

"Hemizygous RBMX variants lead to neurodevelopmental disorders characterized by intellectual disability and variable brain, ocular, and genital malformations."

Establishes the organism-level neurodevelopmental outcome of hemizygous RBMX variants.

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Pathograph

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

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Phenotypes

10

Ear 1

Large ears Macrotia HP:0000400

Show evidence (1 reference)

PMID:10677307 SUPPORT Human Clinical

"Clinical findings in the seven living affected males include a moderate degree of mental retardation (MR), coarse facies, puffy eyelids, narrow palpebral fissures, prominent supraorbital ridges, a bulbous nose, a prominent lower lip, large ears, obesity, and large testicles."

Large ears are listed among the clinical findings in the affected males.

Genitourinary 1

Macroorchidism VERY_FREQUENT Macroorchidism HP:0000053

Show evidence (2 references)

PMID:10677307 SUPPORT Human Clinical

"Clinical findings in the seven living affected males include a moderate degree of mental retardation (MR), coarse facies, puffy eyelids, narrow palpebral fissures, prominent supraorbital ridges, a bulbous nose, a prominent lower lip, large ears, obesity, and large testicles."

Large testicles are listed among the defining clinical findings of the syndrome in the index kindred. The VERY_FREQUENT band is assigned under the DisMech qualitative mapping for a highly characteristic feature; the abstract summarises findings across the seven living affected males as a group and does not tabulate per-patient counts.

PMID:12605440 SUPPORT Human Clinical

"The clinical features consist of coarse face, prominent lower lip, large testes, and obesity."

Large testes were also present in the second reported family.

Head and Neck 2

Distinctive craniofacial dysmorphism VERY_FREQUENT Coarse facial features HP:0000280

Show evidence (2 references)

PMID:10677307 SUPPORT Human Clinical

"Cephalometric measurements suggest that the affected males have a distinctive craniofacial skeletal structure, when compared with normative measures."

Objectively documents the distinctive craniofacial structure in affected males. The VERY_FREQUENT band is assigned under the DisMech qualitative mapping for a highly characteristic feature; neither report tabulates per-patient counts, so an exact percentage cannot be derived.

PMID:12605440 SUPPORT Human Clinical

"The clinical features consist of coarse face, prominent lower lip, large testes, and obesity."

Coarse facies was also present in both affected brothers of the second reported family.

Bulbous nose Bulbous nose HP:0000414

Show evidence (1 reference)

PMID:10677307 SUPPORT Human Clinical

"Clinical findings in the seven living affected males include a moderate degree of mental retardation (MR), coarse facies, puffy eyelids, narrow palpebral fissures, prominent supraorbital ridges, a bulbous nose, a prominent lower lip, large ears, obesity, and large testicles."

A bulbous nose is explicitly listed among the clinical findings.

Growth 1

Obesity VERY_FREQUENT Obesity HP:0001513

Show evidence (2 references)

PMID:10677307 SUPPORT Human Clinical

"Clinical findings in the seven living affected males include a moderate degree of mental retardation (MR), coarse facies, puffy eyelids, narrow palpebral fissures, prominent supraorbital ridges, a bulbous nose, a prominent lower lip, large ears, obesity, and large testicles."

Obesity is listed among the defining clinical findings of the syndrome in the index kindred. The VERY_FREQUENT band is assigned under the DisMech qualitative mapping for a highly characteristic feature; the abstract summarises findings across the seven living affected males as a group and does not tabulate per-patient counts.

PMID:12605440 SUPPORT Human Clinical

"The clinical features consist of coarse face, prominent lower lip, large testes, and obesity."

Obesity was also present in the second reported family.

Other 5

Moderate intellectual disability VERY_FREQUENT Moderate intellectual disability HP:0002342

Show evidence (2 references)

PMID:10677307 SUPPORT Human Clinical

"Clinical findings in the seven living affected males include a moderate degree of mental retardation (MR), coarse facies, puffy eyelids, narrow palpebral fissures, prominent supraorbital ridges, a bulbous nose, a prominent lower lip, large ears, obesity, and large testicles."

Moderate intellectual disability is listed among the defining clinical findings of the syndrome in the index kindred. The VERY_FREQUENT band is assigned under the DisMech qualitative mapping for a highly characteristic feature; the abstract summarises findings across the seven living affected males as a group and does not tabulate per-patient counts, so an exact percentage cannot be derived.

PMID:25256757 SUPPORT Human Clinical

"A novel X-linked intellectual disability (XLID) syndrome with moderate intellectual disability and distinguishing craniofacial dysmorphisms had been previously mapped to the Xq26-q27 interval."

Independently characterizes the syndrome as one of moderate intellectual disability.

Prominent lower lip Thick lower lip vermilion HP:0000179

Show evidence (2 references)

PMID:10677307 SUPPORT Human Clinical

"Clinical findings in the seven living affected males include a moderate degree of mental retardation (MR), coarse facies, puffy eyelids, narrow palpebral fissures, prominent supraorbital ridges, a bulbous nose, a prominent lower lip, large ears, obesity, and large testicles."

A prominent lower lip is listed among the clinical findings in the index family.

PMID:12605440 SUPPORT Human Clinical

"The clinical features consist of coarse face, prominent lower lip, large testes, and obesity."

A prominent lower lip was also present in the second reported family.

Puffy eyelids Periorbital fullness HP:0000629

Show evidence (1 reference)

PMID:10677307 SUPPORT Human Clinical

"Clinical findings in the seven living affected males include a moderate degree of mental retardation (MR), coarse facies, puffy eyelids, narrow palpebral fissures, prominent supraorbital ridges, a bulbous nose, a prominent lower lip, large ears, obesity, and large testicles."

Puffy eyelids are explicitly listed among the clinical findings.

Narrow palpebral fissures Narrow palpebral fissure HP:0045025

Show evidence (1 reference)

PMID:10677307 SUPPORT Human Clinical

"Clinical findings in the seven living affected males include a moderate degree of mental retardation (MR), coarse facies, puffy eyelids, narrow palpebral fissures, prominent supraorbital ridges, a bulbous nose, a prominent lower lip, large ears, obesity, and large testicles."

Narrow palpebral fissures are explicitly listed among the clinical findings.

Prominent supraorbital ridges Prominent supraorbital ridges HP:0000336

Show evidence (1 reference)

PMID:10677307 SUPPORT Human Clinical

"Clinical findings in the seven living affected males include a moderate degree of mental retardation (MR), coarse facies, puffy eyelids, narrow palpebral fissures, prominent supraorbital ridges, a bulbous nose, a prominent lower lip, large ears, obesity, and large testicles."

Prominent supraorbital ridges are explicitly listed among the clinical findings.

🧬

Genetic Associations

2

RBMX (Causal X-linked gene; a 23 bp frameshift deletion removing the hnRNP G RGG/RG motif segregates with disease in the index family.)

Gene: RBMX hgnc:9910 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:25256757 SUPPORT Human Clinical

"On whole exome sequencing in the large family originally reported with this disorder, we identified a 23 bp frameshift deletion in the RNA binding motif protein X-linked (RBMX) gene at Xq26 in the affected males (n = 7), one carrier female, absent in unaffected males (n = 2) and in control..."

Segregation in seven affected males with absence in unaffected males and in 7800 control exomes supports RBMX as the causal gene.

PMID:25256757 PARTIAL Human Clinical

"The RBMX gene has not been previously causal of human disease."

At the time of discovery this was a novel gene-disease relationship, which is why the original report framed RBMX as a candidate; subsequent functional and cohort work has strengthened the assertion.

PMID:34260915 SUPPORT In Vitro

"Our findings identify RBMX as a regulator of SRSF1 and the p53 pathway, suggesting that the loss of function of the RBMX RGG/RG motif is the cause of Shashi-XLID syndrome."

Functional modelling of the patient allele in isogenic iPSCs supports causality of the RGG/RG loss-of-function lesion.

RBMXL1 (Autosomal retrocopy of RBMX that shares protein and RNA partners and acts redundantly with RBMX in brain development, buffering the impact of RBMX deficiency in a context- and dosage-dependent manner.)

Gene: RBMXL1 hgnc:25073 relationship_type: MODIFIER

Show evidence (1 reference)

PMID:42360281 SUPPORT Model Organism

"We demonstrate that RBMX and RBMXL1 share protein and RNA partners and act redundantly in brain development, with RBMXL1 buffering the impact of RBMX deficiency."

Establishes RBMXL1 as a functional paralog capable of modifying the consequences of RBMX loss.

💊

Medical Actions

1

Genetic counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Management is supportive; no disease-modifying therapy exists. Because the disorder is X-linked recessive and carrier females can be identified molecularly, genetic counseling and carrier testing for at-risk female relatives are central to family management.

Show evidence (1 reference)

PMID:25256757 PARTIAL Human Clinical

"On whole exome sequencing in the large family originally reported with this disorder, we identified a 23 bp frameshift deletion in the RNA binding motif protein X-linked (RBMX) gene at Xq26 in the affected males (n = 7), one carrier female, absent in unaffected males (n = 2) and in control..."

Molecular identification of a carrier female in the index family demonstrates that carrier testing is feasible and underpins genetic counseling; the paper does not itself evaluate counseling as an intervention.

🔀

Differential Diagnoses

2

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

Fragile X syndrome MONDO:0010383

Overlapping Features Fragile X syndrome shares X-linked inheritance, intellectual disability, large ears and macroorchidism with the Shashi syndrome and was explicitly excluded in the index family.

Distinguishing Features

Fragile X is caused by an FMR1 CGG repeat expansion and is excluded by normal FMR1 DNA analysis, which was performed and normal in the index family.
The Shashi syndrome maps to Xq26-q27 and is caused by RBMX, a different locus from FMR1 at Xq27.3.
Puffy eyelids, narrow palpebral fissures and prominent supraorbital ridges are part of the Shashi facial gestalt and are not typical of fragile X syndrome.

Show evidence (1 reference)

PMID:10677307 SUPPORT Human Clinical

"The blood-lymphocyte karyotype and the results of DNA analysis for fragile-X syndrome and of other routine investigations are normal."

Fragile X syndrome was formally excluded by molecular testing in the index family.

Gustavson syndrome Not Yet Curated MONDO:0010661

Overlapping Features Gustavson syndrome is the other RBMX-related X-linked intellectual disability, caused by an in-frame deletion (p.Pro162del) rather than RGG/RG-motif loss.

Distinguishing Features

Gustavson syndrome presents with profound X-linked intellectual disability and early death, whereas the Shashi type has moderate intellectual disability with obesity and macroorchidism.
The Gustavson allele is an in-frame deletion, NM_002139.4; c.484_486del, p.(Pro162del), affecting a putative SH3-binding motif, rather than the C-terminal RGG/RG motif deleted in the Shashi type.
The two disorders show only minor phenotypic overlap, consistent with distinct domain-specific disease-causing mechanisms.

Show evidence (2 references)

PMID:37277488 SUPPORT Human Clinical

"Affected individuals presented minor phenotypic overlap with Shashi syndrome, indicating a different disease-causing mechanism."

Explicitly separates the two RBMX-related disorders on both phenotypic and mechanistic grounds.

PMID:37277488 SUPPORT Human Clinical

"The results indicate that disruption of different protein domains affects the severity of RBMX-associated intellectual disabilities."

Supports domain-specific genotype-phenotype correlation across the RBMX-related disorders.

{ }

Source YAML

click to show

name: Shashi X-Linked Intellectual Disability Syndrome
creation_date: '2026-07-31T00:00:00Z'
category: Mendelian
description: >-
  Shashi X-linked intellectual disability syndrome (MRXS11, SMRXS) is an
  ultra-rare X-linked recessive syndromic intellectual disability originally
  delineated in a large North Carolina family and subsequently confirmed in a
  second Brazilian family. Affected males have moderate intellectual
  disability together with a distinctive craniofacial gestalt (coarse facies,
  puffy eyelids, narrow palpebral fissures, prominent supraorbital ridges,
  bulbous nose, prominent lower lip, large ears), obesity and macroorchidism.
  The locus was mapped to Xq26-q27 and the causal gene identified as RBMX,
  which encodes heterogeneous nuclear ribonucleoprotein G (hnRNP G), an
  RNA-binding regulator of pre-mRNA splicing. The disease-associated allele in
  the original family is a 23 bp frameshift deletion removing the hnRNP G
  RGG/RG motif; loss of this motif disrupts PRMT5-dependent assembly with the
  SRSF1 splicing factor, causes MDM4 mis-splicing and aberrant p53 activation,
  and impairs neural progenitor differentiation.
disease_term:
  preferred_term: syndromic X-linked intellectual disability Shashi type
  term:
    id: MONDO:0010277
    label: syndromic X-linked intellectual disability Shashi type
synonyms:
- MRXS11
- SMRXS
- Shashi X-linked intellectual disability syndrome
- Shashi XLMR syndrome
- syndromic X-linked intellectual disability type 11
- intellectual disability, X-linked, syndromic 11, Shashi type
parents:
- hereditary disease
- neurodevelopmental disorder
- X-linked syndromic intellectual disability
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Only two families have been reported: the original four-generation North
    Carolina kindred with seven living affected males, and a Brazilian family
    with two affected brothers.
  evidence:
  - reference: PMID:10677307
    reference_title: >-
      A unique form of mental retardation with a distinctive phenotype maps to
      Xq26-q27.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a novel X-linked mental retardation (XLMR) syndrome, with
      characteristic facial dysmorphic features, segregating in a large North
      Carolina family. Only males are affected, over four generations.
    explanation: >-
      Establishes the size and structure of the index kindred, the primary
      source of reported cases.
  - reference: PMID:12605440
    reference_title: 'Shashi XLMR syndrome: report of a second family.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This report describes a family with mental retardation in two brothers.
    explanation: >-
      The only additional reported family contributes two further affected
      males, supporting an ultra-rare literature case count.
pathophysiology:
- name: RBMX Loss of Function
  biological_scale: MOLECULAR
  description: >-
    The proximal lesion is loss of function of RBMX, which encodes the
    RNA-binding protein hnRNP G. In the original Shashi kindred a 23 bp
    frameshift deletion segregates with disease in affected males and removes
    the RGG/RG motif of hnRNP G. RBMX is relatively intolerant to
    loss-of-function variation, a pattern shared by other X-linked
    intellectual disability genes.
  genes:
  - preferred_term: RBMX
    term:
      id: hgnc:9910
      label: RBMX
  molecular_functions:
  - preferred_term: mRNA binding
    term:
      id: GO:0003729
      label: mRNA binding
    modifier: DECREASED
  evidence:
  - reference: PMID:25256757
    reference_title: >-
      The RBMX gene as a candidate for the Shashi X-linked intellectual
      disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On whole exome sequencing in the large family originally reported with
      this disorder, we identified a 23 bp frameshift deletion in the RNA
      binding motif protein X-linked (RBMX) gene at Xq26 in the affected males
      (n = 7), one carrier female, absent in unaffected males (n = 2) and in
      control databases (7800 exomes).
    explanation: >-
      Directly identifies the segregating RBMX frameshift deletion as the
      causal lesion in the index family.
  - reference: PMID:25256757
    reference_title: >-
      The RBMX gene as a candidate for the Shashi X-linked intellectual
      disability syndrome.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      the findings were indicative of RBMX being relatively intolerant to loss
      of function variants, a distinctive pattern seen in a subset of XLID
      genes
    explanation: >-
      Genic intolerance analysis supports loss of function as the operative
      mechanism class for RBMX.
  - reference: PMID:37277488
    reference_title: >-
      Gustavson syndrome is caused by an in-frame deletion in RBMX associated
      with potentially disturbed SH3 domain interactions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RNA binding motif protein X-linked (RBMX) encodes the heterogeneous
      nuclear ribonucleoprotein G (hnRNP G) that regulates splicing, sister
      chromatid cohesion and genome stability.
    explanation: >-
      Establishes the gene product identity and its core molecular functions.
  downstream:
  - target: Disrupted hnRNP G RGG/RG-Dependent Splicing Regulation
    description: >-
      Deletion of the RGG/RG motif removes the low-complexity region through
      which hnRNP G engages RNA polymerase II and splicing partners.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37277488
      reference_title: >-
        Gustavson syndrome is caused by an in-frame deletion in RBMX associated
        with potentially disturbed SH3 domain interactions.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Deletion of the RGG/RG motif in hnRNP G has previously been associated
        with Shashi syndrome, however involvement of other hnRNP G domains in
        intellectual disability remain unknown.
      explanation: >-
        Assigns the Shashi-associated lesion specifically to the RGG/RG motif
        of hnRNP G.
  - target: Distinctive craniofacial dysmorphism
    description: >-
      The recognizable facial gestalt is a parallel consequence of RBMX loss
      rather than a downstream consequence of impaired corticogenesis; the
      developmental intermediates linking RBMX loss to craniofacial patterning
      are not established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10677307
      reference_title: >-
        A unique form of mental retardation with a distinctive phenotype maps to
        Xq26-q27.
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Cephalometric measurements suggest that the affected males have a
        distinctive craniofacial skeletal structure, when compared with normative
        measures.
      explanation: >-
        Documents that the craniofacial phenotype co-occurs with the syndrome in
        affected males. It does not establish the developmental intermediates
        between RBMX loss and craniofacial patterning, hence PARTIAL.
  - target: Obesity
    description: >-
      Obesity is a consistent non-neurological feature of the syndrome and is
      modeled as a parallel consequence of RBMX loss; no mechanistic
      intermediate between RBMX loss and adiposity has been established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:12605440
      reference_title: 'Shashi XLMR syndrome: report of a second family.'
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The clinical features consist of coarse face, prominent lower lip, large
        testes, and obesity.
      explanation: >-
        Establishes obesity as a feature of the syndrome in a second independent
        family. No mechanistic intermediate between RBMX loss and adiposity is
        demonstrated, hence PARTIAL.
  - target: Macroorchidism
    description: >-
      Macroorchidism is a consistent feature in affected males and is modeled as
      a parallel consequence of RBMX loss; the intermediates are unknown,
      although genital malformations are part of the broader RBMX-variant
      spectrum.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42360281
      reference_title: >-
        RBMX functional retrocopy safeguards brain development in a
        species-dependent context.
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hemizygous RBMX variants lead to neurodevelopmental disorders
        characterized by intellectual disability and variable brain, ocular, and
        genital malformations.
      explanation: >-
        Places genital phenotypes within the hemizygous RBMX-variant spectrum,
        consistent with the macroorchidism of the Shashi type. The causal
        intermediates are not established, hence PARTIAL.
- name: Disrupted hnRNP G RGG/RG-Dependent Splicing Regulation
  biological_scale: MOLECULAR
  description: >-
    hnRNP G is an m6A reader that binds RNA through an RRM and Arg-Gly-Gly
    (RGG) motifs and uses those RGG motifs to contact the phosphorylated
    C-terminal domain of RNA polymerase II, coupling it co-transcriptionally to
    nascent pre-mRNA and to transcriptome-wide alternative splicing decisions.
    Loss of the RGG/RG motif therefore removes the principal interface through
    which hnRNP G regulates splice-site selection.
  biological_processes:
  - preferred_term: regulation of mRNA splicing, via spliceosome
    term:
      id: GO:0048024
      label: regulation of mRNA splicing, via spliceosome
    modifier: ABNORMAL
  evidence:
  - reference: PMID:31445886
    reference_title: >-
      Regulation of Co-transcriptional Pre-mRNA Splicing by m(6)A through the
      Low-Complexity Protein hnRNPG.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we show that hnRNPG directly binds to the phosphorylated
      carboxy-terminal domain (CTD) of RNA polymerase II (RNAPII) using RGG
      motifs in its low-complexity region.
    explanation: >-
      Identifies the RGG motifs deleted in Shashi-XLID as the interface hnRNP G
      uses to engage the transcription machinery.
  - reference: PMID:31445886
    reference_title: >-
      Regulation of Co-transcriptional Pre-mRNA Splicing by m(6)A through the
      Low-Complexity Protein hnRNPG.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Through interactions with the phosphorylated CTD and nascent RNA, hnRNPG
      associates co-transcriptionally with RNAPII and regulates alternative
      splicing transcriptome-wide.
    explanation: >-
      Establishes that the RGG-dependent interaction controls alternative
      splicing genome-wide, the process disrupted by the Shashi allele.
  - reference: PMID:24692659
    reference_title: >-
      Characterization of the RNA recognition mode of hnRNP G extends its role
      in SMN2 splicing regulation.
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: >-
      We report that in addition to the C-terminal region of hnRNP G, the RNA
      Recognition Motif (RRM) and the middle part of the protein containing the
      Arg-Gly-Gly (RGG) box are important for this function.
    explanation: >-
      Structural work on a model target (SMN2 exon 7) independently shows the
      RGG box is required for hnRNP G splicing activity, though the target is
      not itself implicated in Shashi-XLID.
  - reference: PMID:39356106
    reference_title: >-
      An anciently diverged family of RNA binding proteins maintain correct
      splicing of a class of ultra-long exons through cryptic splice site
      repression.
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: >-
      RBMX protein-RNA interactions are enriched within ultra-long exons,
      particularly within genes involved in genome stability, and repress the
      selection of cryptic splice sites that would compromise gene function.
    explanation: >-
      Defines a second, Shashi-independent arm of RBMX splicing control
      (cryptic splice-site repression in ultra-long exons) that is plausibly
      perturbed by loss of function but has not been demonstrated for the
      Shashi allele specifically.
  - reference: PMID:39356106
    reference_title: >-
      An anciently diverged family of RNA binding proteins maintain correct
      splicing of a class of ultra-long exons through cryptic splice site
      repression.
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: >-
      The C-terminal disordered domain of RBMXL2 is sufficient to rescue proper
      splicing control after RBMX depletion.
    explanation: >-
      Implicates the C-terminal disordered region — the part of hnRNP G removed
      by the Shashi frameshift deletion — as the functional module for splicing
      control, in a paralog rescue experiment rather than in Shashi cells.
  downstream:
  - target: RBMX/SRSF1 Higher-Order Complex Disruption
    description: >-
      Loss of the methylated RGG/RG motif prevents higher-order assembly with
      the SRSF1 splicing factor.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34260915
      reference_title: >-
        Deletion of RBMX RGG/RG motif in Shashi-XLID syndrome leads to aberrant
        p53 activation and neuronal differentiation defects.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Moreover, we identify that the RBMX RGG/RG motif is methylated by
        protein arginine methyltransferase 5 (PRMT5), and this regulates
        assembly with the SRSF1 splicing factor into higher-order complexes.
      explanation: >-
        Links the RGG/RG motif directly to SRSF1 complex assembly.
- name: RBMX/SRSF1 Higher-Order Complex Disruption
  biological_scale: MOLECULAR
  description: >-
    The RBMX RGG/RG motif is methylated by PRMT5, and this methylation licenses
    assembly with the SRSF1 splicing factor into higher-order complexes. The
    Shashi-XLID frameshift removes the motif, so the higher-order RBMX/SRSF1
    complex fails to form and SRSF1 recruitment to its target pre-mRNAs is
    reduced.
  biological_processes:
  - preferred_term: protein-containing complex assembly
    term:
      id: GO:0065003
      label: protein-containing complex assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:34260915
    reference_title: >-
      Deletion of RBMX RGG/RG motif in Shashi-XLID syndrome leads to aberrant
      p53 activation and neuronal differentiation defects.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Moreover, we identify that the RBMX RGG/RG motif is methylated by
      protein arginine methyltransferase 5 (PRMT5), and this regulates
      assembly with the SRSF1 splicing factor into higher-order complexes.
    explanation: >-
      Establishes PRMT5-dependent methylation of the RGG/RG motif as the
      licensing step for higher-order RBMX/SRSF1 complex assembly, which the
      Shashi-XLID deletion removes.
  downstream:
  - target: MDM4 Exon 6 Mis-Splicing and Reduced MDM4 Protein
    description: >-
      Disruption of the RBMX/SRSF1 complex reduces SRSF1 binding to the MDM4
      pre-mRNA, which is what produces exon 6 exclusion and lower MDM4 protein.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34260915
      reference_title: >-
        Deletion of RBMX RGG/RG motif in Shashi-XLID syndrome leads to aberrant
        p53 activation and neuronal differentiation defects.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Depletion of RBMX or disruption of the RBMX/SRSF1 complex in
        PRMT5-depleted cells reduces SRSF1 binding to the MDM4 precursor
        (pre-)mRNA, leading to exon 6 exclusion and lower MDM4 protein levels.
      explanation: >-
        The "leading to" in the source sentence is this causal step: reduced
        SRSF1 binding is the cause, exon 6 exclusion and reduced MDM4 protein
        the consequence.
- name: MDM4 Exon 6 Mis-Splicing and Reduced MDM4 Protein
  biological_scale: MOLECULAR
  description: >-
    Reduced SRSF1 occupancy on the MDM4 pre-mRNA causes skipping of exon 6,
    yielding an unstable transcript isoform and lower MDM4 protein levels.
    Isogenic Shashi-XLID iPSCs carrying the patient RGG/RG deletion reproduce
    this MDM4 splicing dysregulation.
  biological_processes:
  - preferred_term: mRNA splicing, via spliceosome
    term:
      id: GO:0000398
      label: mRNA splicing, via spliceosome
    modifier: ABNORMAL
  evidence:
  - reference: PMID:34260915
    reference_title: >-
      Deletion of RBMX RGG/RG motif in Shashi-XLID syndrome leads to aberrant
      p53 activation and neuronal differentiation defects.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Depletion of RBMX or disruption of the RBMX/SRSF1 complex in
      PRMT5-depleted cells reduces SRSF1 binding to the MDM4 precursor
      (pre-)mRNA, leading to exon 6 exclusion and lower MDM4 protein levels.
    explanation: >-
      States the exon 6 exclusion and the reduction in MDM4 protein that define
      this node.
  - reference: PMID:34260915
    reference_title: >-
      Deletion of RBMX RGG/RG motif in Shashi-XLID syndrome leads to aberrant
      p53 activation and neuronal differentiation defects.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Transcriptomic analysis of isogenic Shashi-XLID human-induced pluripotent
      stem cells (hiPSCs) generated using CRISPR-Cas9 reveals a dysregulation
      of MDM4 splicing and aberrant p53 upregulation.
    explanation: >-
      Confirms the mis-splicing step in a patient-genotype human cellular model
      of Shashi-XLID rather than only in knockdown cells.
  downstream:
  - target: Aberrant p53 Pathway Activation
    description: >-
      Reduced MDM4 protein removes a key negative regulator of p53, releasing
      p53 activity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34260915
      reference_title: >-
        Deletion of RBMX RGG/RG motif in Shashi-XLID syndrome leads to aberrant
        p53 activation and neuronal differentiation defects.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We show that RBMX-depleted cells exhibit aberrant activation of the p53
        pathway.
      explanation: >-
        Connects loss of RBMX function to p53 pathway activation.
- name: Aberrant p53 Pathway Activation
  biological_scale: CELLULAR
  description: >-
    Reduced MDM4 levels resulting from mis-splicing lead to aberrant
    upregulation and activation of the p53 pathway in RBMX-deficient and
    Shashi-XLID genotype cells.
  biological_processes:
  - preferred_term: signal transduction by p53 class mediator
    term:
      id: GO:0072331
      label: signal transduction by p53 class mediator
    modifier: INCREASED
  evidence:
  - reference: PMID:34260915
    reference_title: >-
      Deletion of RBMX RGG/RG motif in Shashi-XLID syndrome leads to aberrant
      p53 activation and neuronal differentiation defects.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our findings identify RBMX as a regulator of SRSF1 and the p53 pathway,
      suggesting that the loss of function of the RBMX RGG/RG motif is the
      cause of Shashi-XLID syndrome.
    explanation: >-
      States the authors' mechanistic conclusion that RGG/RG loss of function
      acting through SRSF1 and p53 is causal for Shashi-XLID.
  downstream:
  - target: Neural Progenitor Differentiation Failure and Excessive Apoptosis
    description: >-
      Excess p53 signalling in neural progenitors drives apoptosis and
      abnormal differentiation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34260915
      reference_title: >-
        Deletion of RBMX RGG/RG motif in Shashi-XLID syndrome leads to aberrant
        p53 activation and neuronal differentiation defects.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Shashi-XLID neural progenitor cells (NPCs) display differentiation and
        morphological abnormalities accompanied with excessive apoptosis.
      explanation: >-
        Directly links the Shashi-XLID genotype to neural progenitor
        differentiation failure and apoptosis.
- name: Neural Progenitor Differentiation Failure and Excessive Apoptosis
  biological_scale: CELLULAR
  description: >-
    Neural progenitor cells derived from isogenic Shashi-XLID iPSCs show
    differentiation and morphological abnormalities together with excessive
    apoptosis, providing the cellular substrate for impaired brain
    development.
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: neuron differentiation
    term:
      id: GO:0030182
      label: neuron differentiation
    modifier: ABNORMAL
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:34260915
    reference_title: >-
      Deletion of RBMX RGG/RG motif in Shashi-XLID syndrome leads to aberrant
      p53 activation and neuronal differentiation defects.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Shashi-XLID neural progenitor cells (NPCs) display differentiation and
      morphological abnormalities accompanied with excessive apoptosis.
    explanation: >-
      Direct experimental observation in a patient-genotype human cellular
      model.
  downstream:
  - target: Impaired Cortical Development
    description: >-
      Progenitor differentiation failure and apoptosis compromise
      corticogenesis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25256757
      reference_title: >-
        The RBMX gene as a candidate for the Shashi X-linked intellectual
        disability syndrome.
      supports: PARTIAL
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Prior expression and animal modeling studies indicate that loss of
        function of RBMX results in abnormal brain development.
      explanation: >-
        Supports the link from cellular RBMX loss of function to abnormal brain
        development, though via model systems rather than human tissue.
- name: Impaired Cortical Development
  biological_scale: TISSUE
  description: >-
    Loss of RBMX function disrupts cortical development. In humans, hemizygous
    RBMX variants produce neurodevelopmental disorders with intellectual
    disability and variable brain malformations; expression and animal
    modelling studies likewise indicate that loss of RBMX function results in
    abnormal brain development.
  biological_processes:
  - preferred_term: cerebral cortex development
    term:
      id: GO:0021987
      label: cerebral cortex development
    modifier: ABNORMAL
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:42360281
    reference_title: >-
      RBMX functional retrocopy safeguards brain development in a
      species-dependent context.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RBMX pathogenic variants disrupt cortical development through both
      partial loss-of function (C-terminal variants) and gain-of-function
      (N-terminal variants) mechanisms.
    explanation: >-
      Establishes disrupted cortical development as the tissue-level
      consequence of RBMX pathogenic variation.
  - reference: PMID:25256757
    reference_title: >-
      The RBMX gene as a candidate for the Shashi X-linked intellectual
      disability syndrome.
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Prior expression and animal modeling studies indicate that loss of
      function of RBMX results in abnormal brain development.
    explanation: >-
      Supporting model-organism and expression evidence cited by the
      gene-discovery paper; indirect for the human tissue phenotype.
  downstream:
  - target: Syndromic Neurodevelopmental Impairment
    description: >-
      Abnormal corticogenesis produces the intellectual disability that
      defines the syndrome.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42360281
      reference_title: >-
        RBMX functional retrocopy safeguards brain development in a
        species-dependent context.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hemizygous RBMX variants lead to neurodevelopmental disorders
        characterized by intellectual disability and variable brain, ocular, and
        genital malformations.
      explanation: >-
        Connects disrupted RBMX-dependent brain development to the clinical
        neurodevelopmental outcome in hemizygous males.
- name: Syndromic Neurodevelopmental Impairment
  biological_scale: ORGANISM
  description: >-
    The convergent clinical outcome of the corticogenesis defect is a syndromic
    neurodevelopmental disorder in hemizygous males, centred on moderate
    intellectual disability. The non-neurological cardinal features that
    complete the syndrome - the distinctive craniofacial gestalt, obesity and
    macroorchidism - are modeled as parallel consequences of RBMX loss rather
    than as descendants of this node, because no published work links impaired
    corticogenesis to adiposity, testicular volume or craniofacial patterning
    (see the shashi_obesity_macroorchidism_mechanism_gap discussion). Carrier
    females are cognitively unaffected.
  evidence:
  - reference: PMID:42360281
    reference_title: >-
      RBMX functional retrocopy safeguards brain development in a
      species-dependent context.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hemizygous RBMX variants lead to neurodevelopmental disorders
      characterized by intellectual disability and variable brain, ocular, and
      genital malformations.
    explanation: >-
      Establishes the organism-level neurodevelopmental outcome of hemizygous
      RBMX variants.
  downstream:
  - target: Moderate intellectual disability
    description: The defining cognitive outcome of the syndrome.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10677307
      reference_title: >-
        A unique form of mental retardation with a distinctive phenotype maps to
        Xq26-q27.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinical findings in the seven living affected males include a moderate
        degree of mental retardation (MR), coarse facies, puffy eyelids, narrow
        palpebral fissures, prominent supraorbital ridges, a bulbous nose, a
        prominent lower lip, large ears, obesity, and large testicles.
      explanation: >-
        Moderate intellectual disability is the cognitive outcome observed in
        affected males, the clinical endpoint of the neurodevelopmental
        mechanism.
phenotypes:
- name: Moderate intellectual disability
  category: Neurologic
  diagnostic: true
  description: >-
    Affected males have a moderate degree of intellectual disability, the core
    and defining manifestation of the syndrome.
  phenotype_term:
    preferred_term: Moderate intellectual disability
    term:
      id: HP:0002342
      label: Moderate intellectual disability
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:10677307
    reference_title: >-
      A unique form of mental retardation with a distinctive phenotype maps to
      Xq26-q27.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical findings in the seven living affected males include a moderate
      degree of mental retardation (MR), coarse facies, puffy eyelids, narrow
      palpebral fissures, prominent supraorbital ridges, a bulbous nose, a
      prominent lower lip, large ears, obesity, and large testicles.
    explanation: >-
      Moderate intellectual disability is listed among the defining clinical
      findings of the syndrome in the index kindred. The VERY_FREQUENT band is
      assigned under the DisMech qualitative mapping for a highly
      characteristic feature; the abstract summarises findings across the seven
      living affected males as a group and does not tabulate per-patient
      counts, so an exact percentage cannot be derived.
  - reference: PMID:25256757
    reference_title: >-
      The RBMX gene as a candidate for the Shashi X-linked intellectual
      disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A novel X-linked intellectual disability (XLID) syndrome with moderate
      intellectual disability and distinguishing craniofacial dysmorphisms had
      been previously mapped to the Xq26-q27 interval.
    explanation: >-
      Independently characterizes the syndrome as one of moderate intellectual
      disability.
- name: Distinctive craniofacial dysmorphism
  category: Craniofacial
  diagnostic: true
  description: >-
    Affected males share a recognizable coarse facial gestalt. Cephalometric
    analysis showed a distinctive craniofacial skeletal structure relative to
    normative measures, and obligate carrier females showed intermediate
    craniofacial measurements.
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:10677307
    reference_title: >-
      A unique form of mental retardation with a distinctive phenotype maps to
      Xq26-q27.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cephalometric measurements suggest that the affected males have a
      distinctive craniofacial skeletal structure, when compared with normative
      measures.
    explanation: >-
      Objectively documents the distinctive craniofacial structure in affected
      males. The VERY_FREQUENT band is assigned under the DisMech qualitative
      mapping for a highly characteristic feature; neither report tabulates
      per-patient counts, so an exact percentage cannot be derived.
  - reference: PMID:12605440
    reference_title: 'Shashi XLMR syndrome: report of a second family.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical features consist of coarse face, prominent lower lip, large
      testes, and obesity.
    explanation: >-
      Coarse facies was also present in both affected brothers of the second
      reported family.
- name: Large ears
  category: Craniofacial
  description: Large ears are part of the characteristic facial gestalt.
  phenotype_term:
    preferred_term: Large ears
    term:
      id: HP:0000400
      label: Macrotia
  evidence:
  - reference: PMID:10677307
    reference_title: >-
      A unique form of mental retardation with a distinctive phenotype maps to
      Xq26-q27.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical findings in the seven living affected males include a moderate
      degree of mental retardation (MR), coarse facies, puffy eyelids, narrow
      palpebral fissures, prominent supraorbital ridges, a bulbous nose, a
      prominent lower lip, large ears, obesity, and large testicles.
    explanation: >-
      Large ears are listed among the clinical findings in the affected males.
- name: Prominent lower lip
  category: Craniofacial
  description: >-
    A prominent (thick-vermilion) lower lip is one of the most consistent
    facial features, present in both reported families.
  phenotype_term:
    preferred_term: Prominent lower lip
    term:
      id: HP:0000179
      label: Thick lower lip vermilion
  evidence:
  - reference: PMID:10677307
    reference_title: >-
      A unique form of mental retardation with a distinctive phenotype maps to
      Xq26-q27.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical findings in the seven living affected males include a moderate
      degree of mental retardation (MR), coarse facies, puffy eyelids, narrow
      palpebral fissures, prominent supraorbital ridges, a bulbous nose, a
      prominent lower lip, large ears, obesity, and large testicles.
    explanation: >-
      A prominent lower lip is listed among the clinical findings in the index
      family.
  - reference: PMID:12605440
    reference_title: 'Shashi XLMR syndrome: report of a second family.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical features consist of coarse face, prominent lower lip, large
      testes, and obesity.
    explanation: >-
      A prominent lower lip was also present in the second reported family.
- name: Puffy eyelids
  category: Craniofacial
  description: >-
    Puffy eyelids (periorbital fullness) contribute to the characteristic
    facial appearance.
  phenotype_term:
    preferred_term: Puffy eyelids
    term:
      id: HP:0000629
      label: Periorbital fullness
  evidence:
  - reference: PMID:10677307
    reference_title: >-
      A unique form of mental retardation with a distinctive phenotype maps to
      Xq26-q27.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical findings in the seven living affected males include a moderate
      degree of mental retardation (MR), coarse facies, puffy eyelids, narrow
      palpebral fissures, prominent supraorbital ridges, a bulbous nose, a
      prominent lower lip, large ears, obesity, and large testicles.
    explanation: >-
      Puffy eyelids are explicitly listed among the clinical findings.
- name: Narrow palpebral fissures
  category: Craniofacial
  description: Narrow palpebral fissures are part of the periorbital gestalt.
  phenotype_term:
    preferred_term: Narrow palpebral fissure
    term:
      id: HP:0045025
      label: Narrow palpebral fissure
  evidence:
  - reference: PMID:10677307
    reference_title: >-
      A unique form of mental retardation with a distinctive phenotype maps to
      Xq26-q27.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical findings in the seven living affected males include a moderate
      degree of mental retardation (MR), coarse facies, puffy eyelids, narrow
      palpebral fissures, prominent supraorbital ridges, a bulbous nose, a
      prominent lower lip, large ears, obesity, and large testicles.
    explanation: >-
      Narrow palpebral fissures are explicitly listed among the clinical
      findings.
- name: Prominent supraorbital ridges
  category: Craniofacial
  description: >-
    Prominent supraorbital ridges are a component of the coarse facial
    appearance.
  phenotype_term:
    preferred_term: Prominent supraorbital ridges
    term:
      id: HP:0000336
      label: Prominent supraorbital ridges
  evidence:
  - reference: PMID:10677307
    reference_title: >-
      A unique form of mental retardation with a distinctive phenotype maps to
      Xq26-q27.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical findings in the seven living affected males include a moderate
      degree of mental retardation (MR), coarse facies, puffy eyelids, narrow
      palpebral fissures, prominent supraorbital ridges, a bulbous nose, a
      prominent lower lip, large ears, obesity, and large testicles.
    explanation: >-
      Prominent supraorbital ridges are explicitly listed among the clinical
      findings.
- name: Bulbous nose
  category: Craniofacial
  description: A bulbous nose is part of the characteristic facial gestalt.
  phenotype_term:
    preferred_term: Bulbous nose
    term:
      id: HP:0000414
      label: Bulbous nose
  evidence:
  - reference: PMID:10677307
    reference_title: >-
      A unique form of mental retardation with a distinctive phenotype maps to
      Xq26-q27.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical findings in the seven living affected males include a moderate
      degree of mental retardation (MR), coarse facies, puffy eyelids, narrow
      palpebral fissures, prominent supraorbital ridges, a bulbous nose, a
      prominent lower lip, large ears, obesity, and large testicles.
    explanation: >-
      A bulbous nose is explicitly listed among the clinical findings.
- name: Obesity
  category: Metabolic
  description: >-
    Obesity is a consistent non-neurological feature reported in affected males
    in both families.
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:10677307
    reference_title: >-
      A unique form of mental retardation with a distinctive phenotype maps to
      Xq26-q27.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical findings in the seven living affected males include a moderate
      degree of mental retardation (MR), coarse facies, puffy eyelids, narrow
      palpebral fissures, prominent supraorbital ridges, a bulbous nose, a
      prominent lower lip, large ears, obesity, and large testicles.
    explanation: >-
      Obesity is listed among the defining clinical findings of the syndrome in
      the index kindred. The VERY_FREQUENT band is assigned under the DisMech
      qualitative mapping for a highly characteristic feature; the abstract
      summarises findings across the seven living affected males as a group and
      does not tabulate per-patient counts.
  - reference: PMID:12605440
    reference_title: 'Shashi XLMR syndrome: report of a second family.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical features consist of coarse face, prominent lower lip, large
      testes, and obesity.
    explanation: >-
      Obesity was also present in the second reported family.
- name: Macroorchidism
  category: Genitourinary
  description: >-
    Large testes are a consistent feature in affected males and overlap with
    the fragile X phenotype, making fragile X testing a required exclusion.
  phenotype_term:
    preferred_term: Macroorchidism
    term:
      id: HP:0000053
      label: Macroorchidism
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:10677307
    reference_title: >-
      A unique form of mental retardation with a distinctive phenotype maps to
      Xq26-q27.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical findings in the seven living affected males include a moderate
      degree of mental retardation (MR), coarse facies, puffy eyelids, narrow
      palpebral fissures, prominent supraorbital ridges, a bulbous nose, a
      prominent lower lip, large ears, obesity, and large testicles.
    explanation: >-
      Large testicles are listed among the defining clinical findings of the
      syndrome in the index kindred. The VERY_FREQUENT band is assigned under
      the DisMech qualitative mapping for a highly characteristic feature; the
      abstract summarises findings across the seven living affected males as a
      group and does not tabulate per-patient counts.
  - reference: PMID:12605440
    reference_title: 'Shashi XLMR syndrome: report of a second family.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical features consist of coarse face, prominent lower lip, large
      testes, and obesity.
    explanation: >-
      Large testes were also present in the second reported family.
genetic:
- name: RBMX
  gene_term:
    preferred_term: RBMX
    term:
      id: hgnc:9910
      label: RBMX
  association: >-
    Causal X-linked gene; a 23 bp frameshift deletion removing the hnRNP G
    RGG/RG motif segregates with disease in the index family.
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:25256757
    reference_title: >-
      The RBMX gene as a candidate for the Shashi X-linked intellectual
      disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On whole exome sequencing in the large family originally reported with
      this disorder, we identified a 23 bp frameshift deletion in the RNA
      binding motif protein X-linked (RBMX) gene at Xq26 in the affected males
      (n = 7), one carrier female, absent in unaffected males (n = 2) and in
      control databases (7800 exomes).
    explanation: >-
      Segregation in seven affected males with absence in unaffected males and
      in 7800 control exomes supports RBMX as the causal gene.
  - reference: PMID:25256757
    reference_title: >-
      The RBMX gene as a candidate for the Shashi X-linked intellectual
      disability syndrome.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The RBMX gene has not been previously causal of human disease.
    explanation: >-
      At the time of discovery this was a novel gene-disease relationship,
      which is why the original report framed RBMX as a candidate; subsequent
      functional and cohort work has strengthened the assertion.
  - reference: PMID:34260915
    reference_title: >-
      Deletion of RBMX RGG/RG motif in Shashi-XLID syndrome leads to aberrant
      p53 activation and neuronal differentiation defects.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our findings identify RBMX as a regulator of SRSF1 and the p53 pathway,
      suggesting that the loss of function of the RBMX RGG/RG motif is the
      cause of Shashi-XLID syndrome.
    explanation: >-
      Functional modelling of the patient allele in isogenic iPSCs supports
      causality of the RGG/RG loss-of-function lesion.
- name: RBMXL1
  gene_term:
    preferred_term: RBMXL1
    term:
      id: hgnc:25073
      label: RBMXL1
  association: >-
    Autosomal retrocopy of RBMX that shares protein and RNA partners and acts
    redundantly with RBMX in brain development, buffering the impact of RBMX
    deficiency in a context- and dosage-dependent manner.
  relationship_type: MODIFIER
  evidence:
  - reference: PMID:42360281
    reference_title: >-
      RBMX functional retrocopy safeguards brain development in a
      species-dependent context.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We demonstrate that RBMX and RBMXL1 share protein and RNA partners and
      act redundantly in brain development, with RBMXL1 buffering the impact of
      RBMX deficiency.
    explanation: >-
      Establishes RBMXL1 as a functional paralog capable of modifying the
      consequences of RBMX loss.
inheritance:
- name: X-linked recessive inheritance
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: >-
    Only hemizygous males are affected; the index kindred showed affected males
    over four generations. Obligate carrier females are cognitively unaffected,
    although cephalometric analysis suggested intermediate craniofacial
    measurements in carriers.
  evidence:
  - reference: PMID:10677307
    reference_title: >-
      A unique form of mental retardation with a distinctive phenotype maps to
      Xq26-q27.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a novel X-linked mental retardation (XLMR) syndrome, with
      characteristic facial dysmorphic features, segregating in a large North
      Carolina family. Only males are affected, over four generations.
    explanation: >-
      Male-only involvement across four generations of a single kindred
      supports X-linked recessive inheritance.
  - reference: PMID:10677307
    reference_title: >-
      A unique form of mental retardation with a distinctive phenotype maps to
      Xq26-q27.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Obligate-carrier females are unaffected with MR, but the results of
      cephalometric skeletal analysis suggest craniofacial dysmorphisms
      intermediate between affected males and normative control individuals.
    explanation: >-
      Cognitively unaffected obligate carriers are consistent with a recessive
      X-linked mode of inheritance.
  - reference: PMID:10677307
    reference_title: >-
      A unique form of mental retardation with a distinctive phenotype maps to
      Xq26-q27.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, we believe that a unique recessive XLMR syndrome with a
      distinctive and recognizable phenotype is represented in this family.
    explanation: >-
      The authors' explicit conclusion that the condition is a recessive XLMR
      syndrome.
diagnosis:
- name: Molecular genetic testing for RBMX
  description: >-
    Identification of a pathogenic RBMX variant in a hemizygous male with the
    characteristic phenotype confirms the diagnosis. The causal gene was
    identified by whole exome sequencing in the index family after linkage
    mapping to Xq26-q27.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:25256757
    reference_title: >-
      The RBMX gene as a candidate for the Shashi X-linked intellectual
      disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On whole exome sequencing in the large family originally reported with
      this disorder, we identified a 23 bp frameshift deletion in the RNA
      binding motif protein X-linked (RBMX) gene at Xq26 in the affected males
      (n = 7), one carrier female, absent in unaffected males (n = 2) and in
      control databases (7800 exomes).
    explanation: >-
      Exome sequencing establishing the RBMX variant is the definitive
      diagnostic step.
- name: Exclusion of fragile X syndrome and chromosomal abnormality
  description: >-
    Because the phenotype overlaps fragile X syndrome (intellectual
    disability, large ears, macroorchidism), karyotype and FMR1 testing were
    normal in the index family and remain a necessary exclusion before this
    diagnosis is considered.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:10677307
    reference_title: >-
      A unique form of mental retardation with a distinctive phenotype maps to
      Xq26-q27.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The blood-lymphocyte karyotype and the results of DNA analysis for
      fragile-X syndrome and of other routine investigations are normal.
    explanation: >-
      Documents that normal karyotype and normal fragile X testing were part of
      establishing this as a distinct entity.
differential_diagnoses:
- name: Fragile X syndrome
  disease_term:
    preferred_term: fragile X syndrome
    term:
      id: MONDO:0010383
      label: fragile X syndrome
  description: >-
    Fragile X syndrome shares X-linked inheritance, intellectual disability,
    large ears and macroorchidism with the Shashi syndrome and was explicitly
    excluded in the index family.
  distinguishing_features:
  - >-
    Fragile X is caused by an FMR1 CGG repeat expansion and is excluded by
    normal FMR1 DNA analysis, which was performed and normal in the index
    family.
  - >-
    The Shashi syndrome maps to Xq26-q27 and is caused by RBMX, a different
    locus from FMR1 at Xq27.3.
  - >-
    Puffy eyelids, narrow palpebral fissures and prominent supraorbital ridges
    are part of the Shashi facial gestalt and are not typical of fragile X
    syndrome.
  evidence:
  - reference: PMID:10677307
    reference_title: >-
      A unique form of mental retardation with a distinctive phenotype maps to
      Xq26-q27.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The blood-lymphocyte karyotype and the results of DNA analysis for
      fragile-X syndrome and of other routine investigations are normal.
    explanation: >-
      Fragile X syndrome was formally excluded by molecular testing in the
      index family.
- name: Gustavson syndrome
  disease_term:
    preferred_term: severe X-linked intellectual disability, Gustavson type
    term:
      id: MONDO:0010661
      label: severe X-linked intellectual disability, Gustavson type
  description: >-
    Gustavson syndrome is the other RBMX-related X-linked intellectual
    disability, caused by an in-frame deletion (p.Pro162del) rather than
    RGG/RG-motif loss.
  distinguishing_features:
  - >-
    Gustavson syndrome presents with profound X-linked intellectual disability
    and early death, whereas the Shashi type has moderate intellectual
    disability with obesity and macroorchidism.
  - >-
    The Gustavson allele is an in-frame deletion, NM_002139.4;
    c.484_486del, p.(Pro162del), affecting a putative SH3-binding motif, rather
    than the C-terminal RGG/RG motif deleted in the Shashi type.
  - >-
    The two disorders show only minor phenotypic overlap, consistent with
    distinct domain-specific disease-causing mechanisms.
  evidence:
  - reference: PMID:37277488
    reference_title: >-
      Gustavson syndrome is caused by an in-frame deletion in RBMX associated
      with potentially disturbed SH3 domain interactions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals presented minor phenotypic overlap with Shashi
      syndrome, indicating a different disease-causing mechanism.
    explanation: >-
      Explicitly separates the two RBMX-related disorders on both phenotypic
      and mechanistic grounds.
  - reference: PMID:37277488
    reference_title: >-
      Gustavson syndrome is caused by an in-frame deletion in RBMX associated
      with potentially disturbed SH3 domain interactions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The results indicate that disruption of different protein domains affects
      the severity of RBMX-associated intellectual disabilities.
    explanation: >-
      Supports domain-specific genotype-phenotype correlation across the
      RBMX-related disorders.
treatments:
- name: Genetic counseling
  description: >-
    Management is supportive; no disease-modifying therapy exists. Because the
    disorder is X-linked recessive and carrier females can be identified
    molecularly, genetic counseling and carrier testing for at-risk female
    relatives are central to family management.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:25256757
    reference_title: >-
      The RBMX gene as a candidate for the Shashi X-linked intellectual
      disability syndrome.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On whole exome sequencing in the large family originally reported with
      this disorder, we identified a 23 bp frameshift deletion in the RNA
      binding motif protein X-linked (RBMX) gene at Xq26 in the affected males
      (n = 7), one carrier female, absent in unaffected males (n = 2) and in
      control databases (7800 exomes).
    explanation: >-
      Molecular identification of a carrier female in the index family
      demonstrates that carrier testing is feasible and underpins genetic
      counseling; the paper does not itself evaluate counseling as an
      intervention.
discussions:
- discussion_id: shashi_rbmx_mouse_human_mismatch
  prompt: >-
    Can rodent Rbmx models be used to study Shashi X-linked intellectual
    disability, given that Rbmx-deficient mice show only mild cortical
    abnormalities while affected humans have moderate intellectual disability?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Cortical Development
  rationale: >-
    RBMX has an independently arisen retrocopy, RBMXL1, in both primates and
    rodents. RBMX and RBMXL1 share protein and RNA partners and act redundantly
    in brain development, so RBMXL1 buffers RBMX deficiency in a context- and
    dosage-dependent manner. Because that buffering differs between species,
    a mild murine cortical phenotype cannot be read as evidence against a
    severe human mechanism, and rodent models may systematically understate
    the consequences of RBMX loss.
  evidence:
  - reference: PMID:42360281
    reference_title: >-
      RBMX functional retrocopy safeguards brain development in a
      species-dependent context.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Despite severe phenotypes in humans, Rbmx-deficient mice display only
      mild cortical abnormalities.
    explanation: >-
      States the human-model phenotype mismatch directly.
  - reference: PMID:42360281
    reference_title: >-
      RBMX functional retrocopy safeguards brain development in a
      species-dependent context.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Together, these findings establish RBMXL1 as a functional paralog of RBMX
      that is likely buffering deleterious variation in a context- and
      dosage-dependent manner.
    explanation: >-
      Provides the mechanistic explanation (paralog buffering) for why the
      mouse model under-reproduces the human phenotype.
- discussion_id: shashi_obesity_macroorchidism_mechanism_gap
  prompt: >-
    What links RBMX/hnRNP G loss of function to obesity and macroorchidism, the
    two non-neurological cardinal features of the Shashi syndrome?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#RBMX Loss of Function
  rationale: >-
    All the mechanistic work on the Shashi RGG/RG allele to date addresses
    neural phenotypes (SRSF1 complex assembly, MDM4 splicing, p53 activation,
    neural progenitor differentiation). No published work explains why loss of
    an ubiquitously expressed splicing regulator produces obesity and
    macroorchidism, and the corresponding causal edges are therefore modelled
    with unknown intermediates.
  evidence:
  - reference: PMID:39356106
    reference_title: >-
      An anciently diverged family of RNA binding proteins maintain correct
      splicing of a class of ultra-long exons through cryptic splice site
      repression.
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: >-
      Here, we show that in somatic cells the similar yet ubiquitously
      expressed RBMX protein has similar functions.
    explanation: >-
      Confirms that RBMX is ubiquitously expressed in somatic cells, which is
      what makes the tissue-restricted metabolic and gonadal phenotypes an
      unexplained gap rather than an obvious consequence.
  proposed_experiments:
  - experiment_id: shashi_tissue_resolved_splicing
    name: Tissue-resolved splicing analysis in RBMX-deficient adipose and testis
    description: >-
      Compare RBMX-dependent alternative splicing programs in adipose and
      gonadal tissue against neural tissue to identify tissue-restricted
      mis-splicing events that could account for the metabolic and gonadal
      features.
notes: >-
  This is a small-literature disorder: the clinical description rests on two
  families (nine affected males in total) reported in 2000 and 2003, with the
  causal RBMX allele identified in 2015 and functionally characterized in
  isogenic patient-genotype iPSCs in 2021. No GeneReviews chapter exists for
  RBMX-related or Shashi X-linked intellectual disability (the only Shashi
  GeneReviews chapter, PMID:39527683, covers the unrelated ASXL2-associated
  Shashi-Pena syndrome). The entry is deliberately kept thin rather than padded
  with unsourced claims; prevalence, natural history, and management are not
  quantitatively described in the primary literature.

  Deep-research caveat: the Edison/falcon report generated for this entry
  summarized the historical phenotype as "intellectual disability, short
  stature, obesity, and hypogonadism", apparently from an aggregated
  secondary source. That is not what the primary reports say. PMID:10677307
  and PMID:12605440 describe macroorchidism (large testicles / large testes),
  which is the opposite of hypogonadism, and neither abstract mentions short
  stature. The phenotype list here is taken directly from the primary
  abstracts; short stature and hypogonadism were deliberately not curated.
  Similarly, features such as microcephaly, corpus callosum abnormalities,
  seizures and early death belong to the wider RBMX-related spectrum
  (especially Gustavson syndrome) and are not assigned to the Shashi type.

  Frequency-band convention in this entry. The single PMID:10677307 sentence
  "Clinical findings in the seven living affected males include a moderate
  degree of mental retardation (MR), coarse facies, puffy eyelids, narrow
  palpebral fissures, prominent supraorbital ridges, a bulbous nose, a
  prominent lower lip, large ears, obesity, and large testicles" is the source
  for ten phenotypes, but only four of them carry a VERY_FREQUENT band:
  moderate intellectual disability, coarse facial features, obesity and
  macroorchidism. These are the cardinal features of the syndrome and are the
  ones re-observed in the independent second family (PMID:12605440), so a
  Pattern C qualitative band for a highly characteristic feature is defensible
  and is declared as such in each explanation. The remaining six entries -
  puffy eyelids, narrow palpebral fissures, prominent supraorbital ridges,
  bulbous nose, prominent lower lip and large ears - are the constituent
  sub-features of the coarse facial gestalt that "coarse facies" already
  captures. Banding each of them separately would re-assert the same single
  observation six more times at a granularity the source does not support (the
  sentence gives no per-feature count within the seven males), so they are
  deliberately left without a band per
  docs/frequency-evidence-guidelines.md ("when in doubt, omit the frequency").

  Pathograph shape. The distinctive craniofacial gestalt, obesity and
  macroorchidism hang off "RBMX Loss of Function" as parallel
  INDIRECT_UNKNOWN_INTERMEDIATES consequences, not off "Syndromic
  Neurodevelopmental Impairment". No published work links impaired
  corticogenesis to adiposity, testicular volume or craniofacial patterning,
  and asserting such edges would contradict the
  shashi_obesity_macroorchidism_mechanism_gap knowledge gap recorded below.
  Only "Moderate intellectual disability" descends from the corticogenesis
  branch.

📚

References & Deep Research

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 19 citations 2026-07-31T01:32:24.507734

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Shashi X-Linked Intellectual Disability Syndrome
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Shashi X-Linked Intellectual Disability Syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Shashi X-Linked Intellectual Disability Syndrome

Executive summary

Shashi X-linked intellectual disability syndrome (Shashi-XLID) is an ultra-rare Mendelian neurodevelopmental disorder associated with a hemizygous, 23-base-pair coding deletion in RBMX, which encodes the nuclear RNA-binding protein hnRNP G. The defining family contained seven affected males. The historical clinical phenotype comprises intellectual disability, short stature, obesity, and hypogonadism, but patient-level frequencies, standardized developmental assessments, longitudinal outcomes, and population prevalence have not been published adequately in the retrievable literature. Open Targets maps the disorder to MONDO:0010277 and links it to RBMX using evidence citing PMIDs 10677307 and 25256757. (OpenTargets Search: Shashi X-linked intellectual disability syndrome, cai2021deletionofrbmx pages 1-4)

The strongest disease-specific mechanistic evidence comes from a 2021 human isogenic iPSC study. The RBMX deletion removes the C-terminal RGG/RG motif, disrupting PRMT5-dependent arginine methylation, RBMX–SRSF1 complex formation, and MDM4 exon-6 splicing. Reduced MDM4 protein releases p53 activity, increases apoptosis, and impairs glutamatergic neuronal differentiation. No disease-modifying treatment, validated biomarker, natural-history registry, or Shashi-specific clinical trial was identified. (cai2021deletionofrbmx pages 1-4, cai2021deletionofrbmx pages 9-11)

A central caveat is nomenclature: Shashi-XLID is not Shashi–Pena syndrome, an unrelated ASXL2 disorder, and should not be conflated with Gustavson syndrome, another RBMX-associated XLID caused by a different in-frame deletion and apparently distinct domain-specific mechanism. (johansson2024gustavsonsyndromeis pages 7-8)

1. Disease information

Definition and identifiers

Preferred name: syndromic X-linked intellectual disability, Shashi type.
Synonyms: Shashi syndrome; Shashi-XLID; Shashi X-linked intellectual disability syndrome; Shashi X-linked mental retardation syndrome; MRXSS.
MONDO: MONDO:0010277.
Causal gene: RBMX, RNA binding motif protein X-linked; Ensembl ENSG00000147274.
Foundational literature: original clinical report, PMID 10677307; genetic association report, PMID 25256757; mechanistic study, Cai et al., published 13 July 2021, DOI 10.1016/j.celrep.2021.109337.
OMIM/Orphanet: an exact disease-entry number was not securely recoverable from the available evidence and should be verified directly before database ingestion.
ICD-10/ICD-11 and MeSH: no syndrome-specific code or descriptor was identified. Coding would ordinarily use broader intellectual-disability, developmental-disorder, obesity, short-stature, or hypogonadism categories as clinically appropriate. (OpenTargets Search: Shashi X-linked intellectual disability syndrome, cai2021deletionofrbmx pages 15-16, cai2021deletionofrbmx pages 1-4)

The knowledge base is derived principally from an individual pedigree and experimental disease models, subsequently summarized in aggregated disease resources. It is not based on EHR-scale cohorts, claims databases, surveillance registries, or population studies. The initial pedigree comprised seven affected males. (cai2021deletionofrbmx pages 1-4)

Key abstract quotation

Cai et al. state: “Transcriptomic analysis of isogenic Shashi-XLID human-induced pluripotent stem cells (hiPSCs) generated using CRISPR-Cas9 reveals a dysregulation of MDM4 splicing and aberrant p53 upregulation.” They conclude that their findings suggest “the loss of function of the RBMX RGG/RG motif is the cause of Shashi-XLID syndrome.” (cai2021deletionofrbmx pages 1-4)

2. Etiology

Causal and genetic risk factors

The established cause is a germline X-chromosomal RBMX lesion. The reported 23-bp deletion lies in the last coding exon, causes a frameshift and predicted premature termination codon, and removes the terminal 38 amino acids, including the C-terminal RGG/RG motif. It is therefore best interpreted mechanistically as a domain-specific partial loss-of-function allele rather than assuming complete absence of RBMX. The precise HGVS expression was not available in the retrieved full text and should be copied from the original variant report or ClinVar rather than reconstructed. (cai2021deletionofrbmx pages 4-6, cai2021deletionofrbmx pages 1-4)

The disorder follows X-linked inheritance: hemizygous males are expected to be at greatest risk, while the phenotype in heterozygous females may depend on X-chromosome inactivation. However, penetrance, carrier manifestations, X-inactivation measurements, germline-mosaicism risk, and recurrence estimates specific to this family were not available in the retrieved evidence.

No susceptibility loci, confirmed modifier genes, founder allele, anticipation, or consanguinity effect has been established. RBMXL1, a functional RBMX retrocopy, is a plausible biological modifier because it shares RNA/protein partners and can compensate experimentally for RBMX deficiency, but this has not been clinically validated for the original Shashi family. Later mouse and cellular work found that RBMXL1 can rescue RBMX-dependent neurogenesis and splicing defects. (tilliole2025rbmxfunctionalretrocopy pages 11-14, tilliole2025rbmxfunctionalretrocopy pages 8-11)

Environmental, infectious, lifestyle, and protective factors

No toxin, infection, diet, activity pattern, substance exposure, parental age effect, or other environmental factor is known to cause Shashi-XLID. Smoking, alcohol, occupational exposure, pollution, and infectious agents are not etiologic categories for this monogenic syndrome. No genetic or environmental protective factor has been demonstrated clinically. Supportive developmental environments may improve function but do not prevent inheritance of the causal allele.

A disease-specific gene–environment interaction has not been reported. General prenatal or postnatal insults could modify neurodevelopment independently, but that proposition should not be entered as a Shashi-specific association.

3. Phenotypes

The human clinical evidence is too small and incompletely quantified to support reliable prevalence percentages. The original phenotype is generally summarized as intellectual disability, short stature, obesity, and hypogonadism. Accordingly, frequency labels should be recorded as reported/characteristic, exact frequency unknown, rather than “frequent” or “obligate.” (OpenTargets Search: Shashi X-linked intellectual disability syndrome, cai2021deletionofrbmx pages 1-4)

Phenotype	Type and likely timing	Severity/course	Suggested HPO term	Evidence limitation
Intellectual disability/developmental impairment	Neurodevelopmental symptom; childhood onset	Lifelong; severity insufficiently quantified for the original family	HP:0001249 Intellectual disability; consider HP:0012758 Neurodevelopmental delay	Defining feature, but standardized scores unavailable
Short stature	Growth sign emerging in childhood	Degree and progression unknown	HP:0004322 Short stature	Frequency and endocrine work-up unavailable
Obesity	Metabolic/physical manifestation	Timing and trajectory unknown	HP:0001513 Obesity	No BMI distribution, hyperphagia, or metabolic data found
Hypogonadism	Endocrine/reproductive sign, often apparent around puberty	Type and severity unknown	HP:0000135 Hypogonadism	No hormonal, fertility, or genital measurements found

The primary quality-of-life burden is expected to arise from cognitive/developmental disability, educational dependence, communication limitations, and possible endocrine or metabolic complications. No EQ-5D, SF-36, PROMIS, caregiver-burden, adaptive-behavior, or disease-specific quality-of-life study exists in the retrieved evidence.

Microcephaly, corpus-callosum abnormalities, seizures, progressive spasticity, arthrogryposis, eye anomalies, and early mortality occur in the wider spectrum of recently described RBMX-related disorders, but should not automatically be assigned to classic Shashi syndrome. These features were prominent in other RBMX genotypes and particularly in Gustavson syndrome or later expanded cohorts. (tilliole2025rbmxfunctionalretrocopy pages 11-14, johansson2024gustavsonsyndromeis pages 7-8, tilliole2025rbmxfunctionalretrocopy pages 14-17)

4. Genetic and molecular information

Gene and protein

RBMX encodes hnRNP G, a predominantly nuclear RNA-binding and splicing-regulatory protein. Its N-terminal RNA-recognition motif binds RNA, while low-complexity C-terminal regions mediate interactions and higher-order assemblies. RBMX participates in pre-mRNA splicing, maintenance of genome stability, DNA-damage responses, and repression of cryptic splice sites. The Shashi deletion specifically removes the C-terminal RGG/RG region. (cai2021deletionofrbmx pages 1-4, tilliole2025rbmxfunctionalretrocopy pages 1-4)

Variant interpretation

Gene: RBMX.
Origin: germline, inherited in an X-linked pedigree.
Class: 23-bp deletion; frameshift with premature stop; C-terminal truncation.
Functional consequence: loss of the last 38 amino acids and RGG/RG motif; defective arginine methylation-dependent splicing complex formation.
Clinical classification: the family segregation and functional evidence strongly support pathogenicity, but the exact current ClinVar assertion and ACMG evidence codes should be confirmed against the live record before ingestion.
Population frequency: not reported in the retrieved evidence. Because the disorder is ultra-rare and the allele segregated with a severe X-linked phenotype, absence or extreme rarity in population databases is expected but should not be asserted without a current gnomAD query.
Somatic status: not a somatic cancer mutation in this disease.

RBMX’s C-terminal residues R369 and R373 were identified as methylated in cells, and the minimal PRMT5-methylated region was mapped to residues 366–391. This directly overlaps the region removed by the Shashi-associated truncation. (cai2021deletionofrbmx pages 4-6)

Epigenetics and chromosomal abnormalities

The relevant regulatory event is post-translational arginine methylation, not a proven syndrome-specific DNA-methylation episignature. No Shashi-specific blood DNA methylation signature, histone profile, chromatin-accessibility assay, or epigenomic diagnostic test has been validated.

The causal lesion is a small coding deletion rather than an aneuploidy, translocation, inversion, or large copy-number variant. No recurrent gross chromosomal abnormality is established.

5. Environmental information

Environmental toxicants, radiation, pollution, lifestyle behavior, and infectious agents have no established causal role. There is no zoonotic, contagious, inflammatory-trigger, or exposure-mediated component. Environmental surveillance and infectious-disease prevention are therefore not disease-specific interventions, although ordinary preventive health care remains important.

6. Mechanism and pathophysiology

Disease-specific causal chain

Upstream genetic lesion: the terminal RBMX deletion removes its C-terminal RGG/RG motif.
Post-translational defect: the deleted region normally contains PRMT5-methylated arginines, notably R369 and R373.
Nuclear-complex defect: methylated RBMX normally assembles with the splicing factor SRSF1 in higher-order nuclear structures. Deletion of the motif or PRMT5 depletion disrupts these assemblies.
Splicing defect: SRSF1 association with MDM4 pre-mRNA decreases, promoting MDM4 exon-6 exclusion and lowering full-length MDM4 protein.
Signaling defect: MDM4 ordinarily restrains p53. Reduced MDM4 therefore causes inappropriate p53 stabilization and activation.
Cellular outcome: p53 targets such as CDKN1A, BBC3, BAX, and other cell-cycle/apoptosis genes rise, producing excessive apoptosis and altered neurodevelopmental transcription.
Tissue outcome: neural progenitors and differentiating cortical neurons exhibit abnormal morphology, altered splicing, and markedly impaired maturation into VGLUT1-positive glutamatergic neurons.
Clinical outcome: disrupted cortical neurogenesis provides a biologically coherent explanation for developmental impairment and intellectual disability. (cai2021deletionofrbmx pages 4-6, cai2021deletionofrbmx pages 9-11, cai2021deletionofrbmx pages 1-4)

Quantitatively, nuclear p53-positive cells rose from 8.67% in control iPSCs to 19.74% and 19.93% in two edited RBMX-DRGG lines. Cleaved-caspase-3-positive area increased from 2.9% to 4.8% and 6.06%. RNA sequencing identified 847 upregulated and 1,067 downregulated genes in mutant iPSCs at an absolute fold-change threshold above 1.5. (cai2021deletionofrbmx pages 4-6)

In NPCs, more than 90% of cells expressed SOX1, SOX2, or PAX6 after induction, demonstrating that early NPC specification remained possible. Nevertheless, mutant NPCs had 258 downregulated genes, 15 upregulated genes, and 111 significant alternative-splicing changes. Downregulated neurodevelopmental genes included FOXG1, TBR1, EMX1, and SLC17A7. After cortical differentiation, only approximately 3% of mutant neurons were VGLUT1-positive versus 15% of controls; the GABAergic fraction was not significantly different. (cai2021deletionofrbmx pages 9-11)

Physical disruption of nuclear assemblies reduced RBMX-foci size by 43.8%, intensity by 62.48%, RBMX–SRSF1 colocalization by 25%, and SRSF1 association with MDM4 RNA by 50%. These experiments support a mechanistic role for methylation-regulated higher-order assembly, although the exact biophysical classification of these puncta in vivo remains an active question. (cai2021deletionofrbmx pages 9-11)

Other RBMX biology and recent research

A 2024 eLife study showed that RBMX-family proteins repress cryptic splice sites within unusually long exons, particularly in genome-stability genes. This broadens the mechanistic framework but is not direct proof that ultra-long-exon missplicing causes classic Shashi syndrome. DOI 10.7554/eLife.89705, published May 2024.

A 2024 review emphasized that hnRNP proteins, although widely expressed, are increasingly implicated in intellectual disability, epilepsy, microcephaly, ALS, and dementia because of their crucial CNS functions. DOI 10.3389/fnmol.2024.1411639, published July 2024. These sources support authoritative expert consensus that tissue-selective neurodevelopmental vulnerability can arise from ubiquitous RNA-processing proteins.

A 2025 preprint—outside the requested 2023–2024 priority window and not yet equivalent to peer-reviewed evidence—proposed domain-dependent loss- and gain-of-function mechanisms across nine RBMX-associated families and showed functional compensation by RBMXL1. It also implicated abnormal ATRX exitron splicing. These findings are important emerging evidence but should not overwrite the established Shashi-specific PRMT5–MDM4–p53 mechanism until peer reviewed. (tilliole2025rbmxfunctionalretrocopy pages 11-14, tilliole2025rbmxfunctionalretrocopy pages 14-17, tilliole2025rbmxfunctionalretrocopy pages 1-4)

Suggested GO and CL annotations

GO biological process: mRNA splicing via spliceosome (GO:0000398); regulation of mRNA splicing (GO:0048024); neuron differentiation (GO:0030182); CNS development (GO:0007417); forebrain development (GO:0030900); apoptotic process (GO:0006915); intrinsic apoptotic signaling by p53 (GO:0072332); protein arginine methylation (GO:0018216).
GO molecular function: RNA binding (GO:0003723).
GO cellular component: nucleus (GO:0005634); nuclear speck (GO:0016607), with the caveat that RBMX puncta were experimentally described as membraneless nuclear structures.
Cell Ontology: neural progenitor cell (CL:0011115); glutamatergic neuron (CL:0000679); cortical neuron, where a locally validated exact descendant term should be selected.

No disease-specific metabolomics, lipidomics, proteomics biomarker, spatial-transcriptomic atlas, or clinical single-cell dataset was found. Transcriptomics and splicing analysis are the principal available molecular profiles.

7. Anatomical structures affected

The primary system is the central nervous system, especially developing forebrain/cerebral cortex. Experimental effects occur in neural progenitors and differentiating cortical glutamatergic neurons. Suggested anatomy terms are brain (UBERON:0000955), cerebral cortex (UBERON:0000956), forebrain, and central nervous system. At the subcellular level, the nucleus and splicing-associated nuclear puncta are implicated. (cai2021deletionofrbmx pages 9-11, cai2021deletionofrbmx pages 1-4)

Secondary endocrine/metabolic involvement is suggested clinically by short stature, obesity, and hypogonadism, but specific hypothalamic, pituitary, gonadal, adipose, or skeletal pathology has not been demonstrated. No lateralization is expected or reported.

8. Temporal development

The syndrome is congenital in genetic origin and developmental in expression. Intellectual/developmental manifestations would ordinarily become evident in infancy or childhood, while short stature and obesity may evolve during growth and hypogonadism may become clearer around puberty. Exact onset ages are unavailable.

The course is presumed chronic and lifelong rather than episodic or relapsing. No formal disease stages, remission pattern, progression rate, or critical therapeutic window has been defined. Mechanistically, prenatal and early postnatal corticogenesis are plausible periods of greatest vulnerability because RBMX dysfunction alters NPC differentiation and cortical-neuron maturation, but this inference has not been tested clinically.

9. Inheritance and population

Shashi-XLID is X-linked and was delineated in a family with seven affected males. Hemizygous males are therefore the principal recognized affected group. Female penetrance, skewed X-inactivation, carrier phenotype, male-to-female ratio in an independent cohort, and age distribution cannot be calculated. (cai2021deletionofrbmx pages 1-4)

No prevalence, incidence, carrier frequency, founder effect, ethnic enrichment, or geographic distribution has been established. It should be represented as ultra-rare; prevalence unknown, not assigned a numerical rate. Genetic anticipation is not expected for a small deletion and has not been reported. Germline mosaicism remains a general counseling possibility but has not been documented specifically.

10. Diagnostics

Clinical recognition and testing strategy

The phenotype is not sufficiently specific for diagnosis without molecular confirmation. Evaluation should include developmental history and examination, growth trajectory, BMI, pubertal/genital assessment, and a three-generation pedigree emphasizing affected males and maternal-line transmission.

A reasonable genetic workflow is:

Neurodevelopmental/XLID multigene panel or WES, ensuring adequate RBMX coverage and indel calling.
Trio or family segregation testing whenever possible.
WGS when exome/panel testing is negative but suspicion remains, particularly to detect noncoding or structural lesions.
RBMX single-gene sequencing for targeted familial testing or a highly suggestive pedigree.
Deletion/duplication analysis or CMA if a larger X-chromosome copy-number lesion is suspected; conventional CMA may not detect a 23-bp deletion.
Sanger confirmation of a candidate small indel and testing of at-risk relatives.

Karyotyping and FISH are low-yield for a small coding deletion. Mitochondrial sequencing and repeat-expansion assays are not disease-specific tests. RNA sequencing could demonstrate abnormal splicing in research settings, but no validated clinical MDM4-splicing assay exists. There is no diagnostic blood protein, metabolite, imaging, EEG, biopsy, or epigenetic biomarker. (cai2021deletionofrbmx pages 4-6, cai2021deletionofrbmx pages 1-4)

Differential diagnosis

Other monogenic syndromic XLID conditions.
Prader–Willi and other syndromic-obesity disorders when obesity and hypogonadism dominate.
Endocrine causes of short stature/hypogonadism.
Gustavson syndrome, caused by RBMX c.484_486del, p.(Pro162del), which has profound ID, brain abnormalities, epilepsy, sensory deficits, and early death and is mechanistically distinct.
Other recently recognized RBMX-related neurodevelopmental disorders.
Shashi–Pena syndrome (ASXL2) must be excluded as a nomenclaturally similar but genetically unrelated condition. (johansson2024gustavsonsyndromeis pages 7-8)

No newborn or population screening program exists. Cascade testing is appropriate after a molecular diagnosis.

11. Outcome and prognosis

No survival curve, life-expectancy estimate, disease-specific mortality rate, hospitalization rate, or validated prognostic biomarker is available. Classic Shashi syndrome should not be assigned the early mortality reported in Gustavson syndrome. (johansson2024gustavsonsyndromeis pages 7-8)

Long-term morbidity likely centers on intellectual/developmental disability and possible growth, weight, and reproductive-endocrine complications. Recovery of the underlying neurodevelopmental disorder is not expected, although developmental skills and adaptive function may improve with individualized intervention. Neither genotype–phenotype predictors nor treatment-response predictors are validated.

12. Treatment

There is no approved disease-modifying pharmacotherapy, gene therapy, RNA therapy, cell therapy, or genotype-specific drug. No relevant Shashi-specific interventional clinical trial was identified.

Current care should be individualized and supportive:

developmental and neuropsychological assessment;
early-intervention services and special education;
speech/language, occupational, and physical therapy as indicated;
behavioral and communication support;
nutritional and weight-management services;
pediatric endocrinology for growth, pubertal development, and hypogonadism;
symptom-directed seizure, sleep, gastrointestinal, orthopedic, or psychiatric treatment if such problems occur in an individual;
social-work and caregiver support.

Suggested MAXO mappings include molecular genetic testing, genetic counseling, developmental assessment, speech therapy, occupational therapy, physical therapy, nutritional management, and endocrine evaluation; exact MAXO identifiers should be validated against the current ontology release.

The PRMT5 inhibitor EPZ015666 reproduced mutant phenotypes—p53 activation, apoptosis, and reduced FOXG1/TBR1—in control neuronal cultures. It is therefore a mechanistic probe and potential hazard, not a proposed treatment. Conversely, suppressing p53 or correcting MDM4 splicing may be experimentally testable rescue strategies, but neither has clinical efficacy or safety evidence in Shashi syndrome. (cai2021deletionofrbmx pages 9-11)

13. Prevention

Primary prevention by lifestyle modification, vaccine, or medication is not applicable to the inherited molecular lesion. Relevant reproductive options after identifying the familial variant include genetic counseling, carrier testing, prenatal diagnosis, and preimplantation genetic testing where legally and ethically available.

Secondary prevention consists of early molecular diagnosis and prompt developmental/endocrine assessment. Tertiary prevention includes therapies and surveillance intended to limit disability, obesity-related complications, contractures, communication barriers, and psychosocial burden. There is no disease-specific immunization, chemoprophylaxis, or public-health environmental intervention.

14. Other species and natural disease

No naturally occurring veterinary counterpart, breed predisposition, animal-to-human transmission, or zoonotic potential was identified. RBMX orthologs are evolutionarily conserved across vertebrates, supporting comparative developmental studies but not establishing naturally occurring animal disease.

Experimental depletion of RBMX orthologs impairs brain and somite development in zebrafish and neural/muscle development in Xenopus laevis. RBMX knockdown in rat hippocampal neurons reduces dendritic-spine density. These are induced functional models rather than spontaneous Shashi syndrome. (cai2021deletionofrbmx pages 15-16, cai2021deletionofrbmx pages 1-4, tilliole2025rbmxfunctionalretrocopy pages 1-4)

15. Model organisms and experimental systems

Human cellular disease model

The strongest model uses CRISPR-Cas9-engineered male human iPSCs with C-terminal RBMX truncations designed to recapitulate the Shashi deletion. These cells were differentiated into SOX1/SOX2/PAX6-positive NPCs and cortical neurons. The system reproduces MDM4 missplicing, p53 activation, excessive apoptosis, altered neurodevelopmental transcription, and impaired glutamatergic maturation. Its principal limitation is that the edited lines were isogenic models rather than multiple independent patient-derived lines; they also cannot model whole-organism endocrine manifestations or long-term cognition. (cai2021deletionofrbmx pages 4-6, cai2021deletionofrbmx pages 9-11, cai2021deletionofrbmx pages 1-4)

Vertebrate models

Zebrafish: rbmx depletion causes brain, eye, muscle, and somite developmental abnormalities; useful for embryonic development and rescue studies, but not shown to reproduce the human metabolic/endocrine syndrome.
Xenopus: Rbmx is necessary for neural and muscle development.
Rat primary hippocampal neurons: knockdown reduces dendritic-spine density, providing a synaptic model.
Mouse: later Rbmx-knockout work found only mild neuroanatomical changes—approximately 9.3% lower total brain area and 15.1% smaller corpus-callosum genu—probably because mouse Rbmxl1 retrocopies compensate. Combined Rbmx/Rbmxl1 knockdown increased abnormal cortical-cell delamination by 38–44%, and human RBMX or RBMXL1 rescued the phenotype. This work is valuable but was reported in a 2025 preprint and is not classic Shashi-allele knock-in evidence. (tilliole2025rbmxfunctionalretrocopy pages 11-14, tilliole2025rbmxfunctionalretrocopy pages 8-11, tilliole2025rbmxfunctionalretrocopy pages 49-52, tilliole2025rbmxfunctionalretrocopy pages 1-4)

No validated Shashi-specific organoid, conditional knock-in, adult behavioral, or therapeutic-rescue model was identified.

Evidence-and-ontology summary

domain	disease-specific finding	quantitative evidence / frequency	suggested ontology terms	evidence level and source date
Nosology	Syndromic X-linked intellectual disability, Shashi type; causal gene RBMX	MONDO MONDO:0010277; disease-target association to RBMX supported by literature and ClinVar-linked evidence	MONDO:0010277; Gene: RBMX	Curated disease ontology and genetics evidence; Open Targets context citing PMIDs 10677307 and 25256757; accessed in current tool session (OpenTargets Search: Shashi X-linked intellectual disability syndrome)
Disease definition	RBMX-associated X-linked intellectual disability syndrome originally described in a pedigree with affected males	Original pedigree reported 7 affected males; aggregated disease-level knowledge remains sparse	MONDO:0010277; HPO: Intellectual disability HP:0001249	Human clinical genetics and pedigree-level evidence; 2015 genetic association summarized in 2021 Cell Reports intro (cai2021deletionofrbmx pages 1-4)
Inheritance	X-linked inheritance	Male-limited affected pedigree; exact penetrance not reported	MONDO:0010277; inheritance ontology not specified here	Human pedigree evidence; original family summarized 2021 (cai2021deletionofrbmx pages 1-4)
Core phenotype	Intellectual disability is the defining clinical feature	Frequency in original pedigree not fully enumerated in retrieved text; syndrome-level feature established	HPO: HP:0001249	Human clinical and pedigree evidence; 2000 and 2015 source lineage via curated association and 2021 summary (OpenTargets Search: Shashi X-linked intellectual disability syndrome, cai2021deletionofrbmx pages 1-4)
Core phenotype	Short stature reported in original syndrome descriptions	Frequency not reported in retrieved evidence	HPO: Short stature HP:0004322	Human clinical report lineage; evidence indirect in retrieved corpus and sparsely quantified (OpenTargets Search: Shashi X-linked intellectual disability syndrome)
Core phenotype	Obesity reported in original syndrome descriptions	Frequency not reported in retrieved evidence	HPO: Obesity HP:0001513	Human clinical report lineage; evidence indirect in retrieved corpus and sparsely quantified (OpenTargets Search: Shashi X-linked intellectual disability syndrome)
Core phenotype	Hypogonadism or genital phenotype reported in original syndrome descriptions	Frequency not reported in retrieved evidence	HPO: Hypogonadism HP:0000135; genital abnormality term uncertain or not specified from retrieved text	Human clinical report lineage; evidence indirect in retrieved corpus and sparsely quantified (OpenTargets Search: Shashi X-linked intellectual disability syndrome)
Molecular lesion	23-bp deletion in the last exon of RBMX predicted to cause frameshift and premature stop, deleting the C-terminal RGG or RG motif	Size 23 bp; truncates last 38 aa encompassing RGG or RG motif	Gene: RBMX; GO: RNA binding GO:0003723; protein region: C-terminal RGG or RG motif	Human genetic evidence and disease-model recapitulation; 2021 peer-reviewed mechanistic study summarizing 2015 family variant (cai2021deletionofrbmx pages 4-6, cai2021deletionofrbmx pages 1-4)
Protein and mechanism	RBMX C-terminal RGG or RG motif is methylated by PRMT5	In vivo methylated arginines identified at R369 and R373; minimal PRMT5-methylated region aa 366-391	GO: protein arginine methylation GO:0018216; GO: mRNA splicing via spliceosome GO:0000398	In vitro and cellular mechanistic evidence; 2021 (cai2021deletionofrbmx pages 4-6)
Mechanism	PRMT5-RBMX methylation promotes RBMX-SRSF1 higher-order complexes that support MDM4 exon 6 inclusion	1,6-hexanediol reduced RBMX foci size by 43.8 percent, intensity by 62.48 percent, RBMX-SRSF1 colocalization by 25 percent, and SRSF1 binding to MDM4 RNA by 50 percent	GO: regulation of mRNA splicing GO:0048024; GO: nuclear speck GO:0016607; CL: neural progenitor cell CL:0011115	Cellular mechanistic evidence in U2OS and neuronal systems; 2021 (cai2021deletionofrbmx pages 9-11)
Mechanism	Loss of RBMX RGG or RG function causes MDM4 missplicing, reduced MDM4 protein, p53 pathway activation, and apoptosis	In patient-modeled iPSCs, nuclear p53-positive cells: 8.67 percent control vs 19.74 percent DRGG1 vs 19.93 percent DRGG2; cleaved caspase-3 area: 2.9 percent control vs 4.8 percent DRGG1 vs 6.06 percent DRGG2	GO: apoptotic process GO:0006915; GO: regulation of transcription by p53 class mediator GO:1901796; GO: alternative mRNA splicing via spliceosome GO:0000380	Human iPSC disease model; 2021 (cai2021deletionofrbmx pages 4-6, cai2021deletionofrbmx pages 1-4)
Transcriptomics	Shashi-XLID iPSCs show broad transcriptional dysregulation with p53 signature enrichment	847 upregulated and 1067 downregulated genes in DRGG1 iPSCs with fold change threshold greater than 1.5	GO: intrinsic apoptotic signaling pathway by p53 class mediator GO:0072332; GO: neuron differentiation GO:0030182	Human CRISPR-engineered iPSC model; 2021 (cai2021deletionofrbmx pages 4-6)
NPC phenotype	Neural progenitor cells differentiate efficiently but show developmental transcriptional defects	NPC induction efficiency greater than 90 percent SOX1 positive, SOX2 positive, and PAX6 positive; 258 downregulated and 15 upregulated genes in DRGG1 NPCs; 111 significant splicing events in DRGG NPCs	CL: neural progenitor cell CL:0011115; GO: central nervous system development GO:0007417; GO: neuron differentiation GO:0030182	Human iPSC-derived NPC model; 2021 (cai2021deletionofrbmx pages 9-11)
Neuronal phenotype	Impaired glutamatergic neurogenesis in cortical-neuron differentiation	3 percent VGLUT1 positive neurons in RBMX-DRGG cultures vs 15 percent in controls; GABAergic difference not significant in reported experiment	GO: glutamatergic synaptic transmission GO:0035249; CL: glutamatergic neuron CL:0000679; UBERON: cerebral cortex UBERON:0000956; HPO neurodevelopmental term broad or unspecified	Human iPSC-derived cortical neuron model; 2021 (cai2021deletionofrbmx pages 9-11)
Additional neuronal readouts	Neurogenesis regulators are reduced and apoptosis rises after neuronal differentiation	Downregulated FOXG1, TBR1, and SLC17A7; increased CDKN1A and BAX in 14-day neurons; increased cleaved caspase-3 or 7 activity	GO: forebrain development GO:0030900; GO: neuron fate commitment GO:0048663; CL: cortical neuron term uncertain or not specified	Human iPSC-derived neuronal model; 2021 (cai2021deletionofrbmx pages 9-11)
Affected anatomy	Primary system is central nervous system and cerebral cortex; subcellular involvement includes nucleus and splicing-related compartments	Quantitative anatomy not available for Shashi patients in retrieved evidence	UBERON: brain UBERON:0000955; UBERON: cerebral cortex UBERON:0000956; GO cellular component nucleus GO:0005634; GO cellular component nuclear speck GO:0016607	Mechanistic and model-based inference anchored to disease models; 2021 (cai2021deletionofrbmx pages 9-11, cai2021deletionofrbmx pages 1-4)
Comparative RBMX disorders	Gustavson syndrome is also RBMX-related but clinically more severe and mechanistically distinct, so it should not be conflated with Shashi syndrome	Comparative statement only; not a Shashi frequency estimate	Differential diagnosis note; MONDO term not specified here	Human comparative genetics; 2024 peer-reviewed study (johansson2024gustavsonsyndromeis pages 7-8)
Diagnostics	Most direct diagnostic approach is molecular testing of RBMX, especially sequencing methods capable of detecting small coding deletions; phenotype alone is insufficiently specific	No validated biomarker beyond genetic diagnosis found; no disease-specific biochemical assay found	MAXO: genetic testing term uncertain or not specified; HPO-guided neurodevelopmental gene panel or exome sequencing concept	Clinical genetics practice inference from causal variant architecture and mechanistic confirmation (OpenTargets Search: Shashi X-linked intellectual disability syndrome, cai2021deletionofrbmx pages 1-4)
Genetic testing modalities	Single-gene RBMX analysis, XLID or neurodevelopmental gene panels, WES, and WGS are reasonable; CMA and karyotype may miss small exon-level indels unless rearrangement is suspected	No performance statistics reported for Shashi specifically in retrieved evidence	MAXO: molecular genetic testing term uncertain or not specified	Evidence-informed inference based on lesion type and published disease-model recapitulation; no disease-specific guideline located (cai2021deletionofrbmx pages 4-6, cai2021deletionofrbmx pages 1-4)
Treatment and management	No disease-specific molecular therapy established; management is supportive and multidisciplinary	No disease-specific response-rate data found	MAXO: supportive care term uncertain or not specified; speech therapy, occupational therapy, and physical therapy terms uncertain or not specified	Evidence gap plus standard rare neurodevelopmental care inference; no relevant disease-specific trials found in tool search (OpenTargets Search: Shashi X-linked intellectual disability syndrome)
Prevention and counseling	Genetic counseling, cascade testing in families, and reproductive counseling are relevant because of X-linked inheritance	No carrier-frequency or founder-effect data found	MAXO: genetic counseling term uncertain or not specified	Human genetics implication from pedigree structure; disease-specific epidemiology sparse (OpenTargets Search: Shashi X-linked intellectual disability syndrome, cai2021deletionofrbmx pages 1-4)
Clinical trials	No Shashi syndrome-specific interventional trials identified	0 relevant disease-specific trials found in current search	MAXO not applicable	Clinical trials search in current session; no relevant registered study returned (OpenTargets Search: Shashi X-linked intellectual disability syndrome)
Epidemiology	Ultra-rare Mendelian disorder with evidence based on a small number of reported families and patients	Prevalence, incidence, sex ratio beyond X-linked expectation, and life expectancy not reported in retrieved evidence	MONDO:0010277	Evidence gap; current knowledge largely from individual patients, pedigrees, and disease-level curation (OpenTargets Search: Shashi X-linked intellectual disability syndrome, cai2021deletionofrbmx pages 1-4)

Table: This table compacts the key disease-specific evidence and ontology suggestions for RBMX-related Shashi X-linked intellectual disability syndrome. It highlights what is directly supported by available evidence, where quantitative model data exist, and where frequencies or ontology IDs remain uncertain.

Major evidence gaps and curation recommendations

Verify the exact OMIM/Orphanet entries and syndrome-specific HGVS nomenclature directly from live primary databases.
Do not calculate phenotype frequencies from the seven-male family unless patient-level tables are recovered.
Record prevalence, incidence, penetrance, female expressivity, life expectancy, and carrier frequency as unknown.
Keep classic Shashi syndrome separate from Shashi–Pena syndrome, Gustavson syndrome, and the broader emerging RBMX-related neurodevelopmental spectrum.
Mark mechanistic evidence as primarily human in vitro disease-model evidence; mark zebrafish, Xenopus, rat, and mouse observations separately.
Treat RBMXL1 compensation and ATRX-splicing mechanisms as emerging later evidence, not yet a replacement for the peer-reviewed Shashi-specific MDM4–p53 model.
Do not present PRMT5 inhibition as therapy: experimentally, it phenocopies the disease-associated defect. (cai2021deletionofrbmx pages 9-11, johansson2024gustavsonsyndromeis pages 7-8, tilliole2025rbmxfunctionalretrocopy pages 11-14)

Overall, current understanding supports Shashi-XLID as an RBMX domain-specific spliceopathy in which disruption of methylation-dependent RNA-processing complexes activates p53 during neuronal differentiation. Clinical knowledge remains substantially less mature than molecular knowledge, making natural-history collection, standardized phenotyping, female-carrier assessment, and variant-resolved functional studies the highest priorities.

References

(OpenTargets Search: Shashi X-linked intellectual disability syndrome): Open Targets Query (Shashi X-linked intellectual disability syndrome, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(cai2021deletionofrbmx pages 1-4): Ting Cai, Jessica K. Cinkornpumin, Zhenbao Yu, Oscar D. Villarreal, William A. Pastor, and Stéphane Richard. Deletion of rbmx rgg/rg motif in shashi-xlid syndrome leads to aberrant p53 activation and neuronal differentiation defects. Cell reports, 36 2:109337, Jul 2021. URL: https://doi.org/10.1016/j.celrep.2021.109337, doi:10.1016/j.celrep.2021.109337. This article has 42 citations and is from a highest quality peer-reviewed journal.
(cai2021deletionofrbmx pages 9-11): Ting Cai, Jessica K. Cinkornpumin, Zhenbao Yu, Oscar D. Villarreal, William A. Pastor, and Stéphane Richard. Deletion of rbmx rgg/rg motif in shashi-xlid syndrome leads to aberrant p53 activation and neuronal differentiation defects. Cell reports, 36 2:109337, Jul 2021. URL: https://doi.org/10.1016/j.celrep.2021.109337, doi:10.1016/j.celrep.2021.109337. This article has 42 citations and is from a highest quality peer-reviewed journal.
(johansson2024gustavsonsyndromeis pages 7-8): Josefin Johansson, Sarah Lidéus, Carina Frykholm, Cecilia Gunnarsson, Filip Mihalic, Sanna Gudmundsson, Sara Ekvall, Anna-Maja Molin, Mai Pham, Mauno Vihinen, Kristina Lagerstedt-Robinson, Ann Nordgren, Per Jemth, Adam Ameur, Göran Annerén, Maria Wilbe, and Marie-Louise Bondeson. Gustavson syndrome is caused by an in-frame deletion in rbmx associated with potentially disturbed sh3 domain interactions. European Journal of Human Genetics, 32:333-341, Jun 2024. URL: https://doi.org/10.1038/s41431-023-01392-y, doi:10.1038/s41431-023-01392-y. This article has 17 citations and is from a domain leading peer-reviewed journal.
(cai2021deletionofrbmx pages 15-16): Ting Cai, Jessica K. Cinkornpumin, Zhenbao Yu, Oscar D. Villarreal, William A. Pastor, and Stéphane Richard. Deletion of rbmx rgg/rg motif in shashi-xlid syndrome leads to aberrant p53 activation and neuronal differentiation defects. Cell reports, 36 2:109337, Jul 2021. URL: https://doi.org/10.1016/j.celrep.2021.109337, doi:10.1016/j.celrep.2021.109337. This article has 42 citations and is from a highest quality peer-reviewed journal.
(cai2021deletionofrbmx pages 4-6): Ting Cai, Jessica K. Cinkornpumin, Zhenbao Yu, Oscar D. Villarreal, William A. Pastor, and Stéphane Richard. Deletion of rbmx rgg/rg motif in shashi-xlid syndrome leads to aberrant p53 activation and neuronal differentiation defects. Cell reports, 36 2:109337, Jul 2021. URL: https://doi.org/10.1016/j.celrep.2021.109337, doi:10.1016/j.celrep.2021.109337. This article has 42 citations and is from a highest quality peer-reviewed journal.
(tilliole2025rbmxfunctionalretrocopy pages 11-14): Pierre Tilliole, Carolin Mattausch, Peggy Tilly, Elsa Leitão, Lucile Boutaud, Daphné Lehalle, Isabelle An, Emanuela Argilli, Sharon Aufox, Bert Callewaert, Perrine Charles, Jessica K. Cinkornpumin, Thomas Courtin, Marco Dalla Vecchia, Erica E. Davis, Boyan Ivanov Dimitrov, William Dobyns, Ekaterina Epifanova, Erwan Grandgirard, Matthieu Jung, Sarah Jurgensmeyer Langas, Sabine Kaya, Boris Keren, Tahir N. Khan, Elodie Lejeune, Mingfeng Li, Yannick Marie, Bastien Morlet, Caroline Nava, William A. Pastor, Damien Plassard, Carlos E. Prada, Agnès Rastetter, Noémie Schwaller, Nenad Sestan, Elliott Sherr, Suzanna L. Temple, Jude-Felix Tenywa, Sylvia Tielens, Arie van Haeringen, Helen Whitley, Laurent Nguyen, Laura Steenpaß, Muriel Rhinn, Stephan C. Collins, Delphine Héron, Valerie Cormier-Daire, Tania Attie-Bitach, Binnaz Yalcin, Christel Depienne, and Juliette D. Godin. Rbmx functional retrocopy safeguards brain development. MedRxiv, Oct 2025. URL: https://doi.org/10.1101/2025.10.17.25337589, doi:10.1101/2025.10.17.25337589. This article has 1 citations.
(tilliole2025rbmxfunctionalretrocopy pages 8-11): Pierre Tilliole, Carolin Mattausch, Peggy Tilly, Elsa Leitão, Lucile Boutaud, Daphné Lehalle, Isabelle An, Emanuela Argilli, Sharon Aufox, Bert Callewaert, Perrine Charles, Jessica K. Cinkornpumin, Thomas Courtin, Marco Dalla Vecchia, Erica E. Davis, Boyan Ivanov Dimitrov, William Dobyns, Ekaterina Epifanova, Erwan Grandgirard, Matthieu Jung, Sarah Jurgensmeyer Langas, Sabine Kaya, Boris Keren, Tahir N. Khan, Elodie Lejeune, Mingfeng Li, Yannick Marie, Bastien Morlet, Caroline Nava, William A. Pastor, Damien Plassard, Carlos E. Prada, Agnès Rastetter, Noémie Schwaller, Nenad Sestan, Elliott Sherr, Suzanna L. Temple, Jude-Felix Tenywa, Sylvia Tielens, Arie van Haeringen, Helen Whitley, Laurent Nguyen, Laura Steenpaß, Muriel Rhinn, Stephan C. Collins, Delphine Héron, Valerie Cormier-Daire, Tania Attie-Bitach, Binnaz Yalcin, Christel Depienne, and Juliette D. Godin. Rbmx functional retrocopy safeguards brain development. MedRxiv, Oct 2025. URL: https://doi.org/10.1101/2025.10.17.25337589, doi:10.1101/2025.10.17.25337589. This article has 1 citations.
(tilliole2025rbmxfunctionalretrocopy pages 14-17): Pierre Tilliole, Carolin Mattausch, Peggy Tilly, Elsa Leitão, Lucile Boutaud, Daphné Lehalle, Isabelle An, Emanuela Argilli, Sharon Aufox, Bert Callewaert, Perrine Charles, Jessica K. Cinkornpumin, Thomas Courtin, Marco Dalla Vecchia, Erica E. Davis, Boyan Ivanov Dimitrov, William Dobyns, Ekaterina Epifanova, Erwan Grandgirard, Matthieu Jung, Sarah Jurgensmeyer Langas, Sabine Kaya, Boris Keren, Tahir N. Khan, Elodie Lejeune, Mingfeng Li, Yannick Marie, Bastien Morlet, Caroline Nava, William A. Pastor, Damien Plassard, Carlos E. Prada, Agnès Rastetter, Noémie Schwaller, Nenad Sestan, Elliott Sherr, Suzanna L. Temple, Jude-Felix Tenywa, Sylvia Tielens, Arie van Haeringen, Helen Whitley, Laurent Nguyen, Laura Steenpaß, Muriel Rhinn, Stephan C. Collins, Delphine Héron, Valerie Cormier-Daire, Tania Attie-Bitach, Binnaz Yalcin, Christel Depienne, and Juliette D. Godin. Rbmx functional retrocopy safeguards brain development. MedRxiv, Oct 2025. URL: https://doi.org/10.1101/2025.10.17.25337589, doi:10.1101/2025.10.17.25337589. This article has 1 citations.
(tilliole2025rbmxfunctionalretrocopy pages 1-4): Pierre Tilliole, Carolin Mattausch, Peggy Tilly, Elsa Leitão, Lucile Boutaud, Daphné Lehalle, Isabelle An, Emanuela Argilli, Sharon Aufox, Bert Callewaert, Perrine Charles, Jessica K. Cinkornpumin, Thomas Courtin, Marco Dalla Vecchia, Erica E. Davis, Boyan Ivanov Dimitrov, William Dobyns, Ekaterina Epifanova, Erwan Grandgirard, Matthieu Jung, Sarah Jurgensmeyer Langas, Sabine Kaya, Boris Keren, Tahir N. Khan, Elodie Lejeune, Mingfeng Li, Yannick Marie, Bastien Morlet, Caroline Nava, William A. Pastor, Damien Plassard, Carlos E. Prada, Agnès Rastetter, Noémie Schwaller, Nenad Sestan, Elliott Sherr, Suzanna L. Temple, Jude-Felix Tenywa, Sylvia Tielens, Arie van Haeringen, Helen Whitley, Laurent Nguyen, Laura Steenpaß, Muriel Rhinn, Stephan C. Collins, Delphine Héron, Valerie Cormier-Daire, Tania Attie-Bitach, Binnaz Yalcin, Christel Depienne, and Juliette D. Godin. Rbmx functional retrocopy safeguards brain development. MedRxiv, Oct 2025. URL: https://doi.org/10.1101/2025.10.17.25337589, doi:10.1101/2025.10.17.25337589. This article has 1 citations.
(tilliole2025rbmxfunctionalretrocopy pages 49-52): Pierre Tilliole, Carolin Mattausch, Peggy Tilly, Elsa Leitão, Lucile Boutaud, Daphné Lehalle, Isabelle An, Emanuela Argilli, Sharon Aufox, Bert Callewaert, Perrine Charles, Jessica K. Cinkornpumin, Thomas Courtin, Marco Dalla Vecchia, Erica E. Davis, Boyan Ivanov Dimitrov, William Dobyns, Ekaterina Epifanova, Erwan Grandgirard, Matthieu Jung, Sarah Jurgensmeyer Langas, Sabine Kaya, Boris Keren, Tahir N. Khan, Elodie Lejeune, Mingfeng Li, Yannick Marie, Bastien Morlet, Caroline Nava, William A. Pastor, Damien Plassard, Carlos E. Prada, Agnès Rastetter, Noémie Schwaller, Nenad Sestan, Elliott Sherr, Suzanna L. Temple, Jude-Felix Tenywa, Sylvia Tielens, Arie van Haeringen, Helen Whitley, Laurent Nguyen, Laura Steenpaß, Muriel Rhinn, Stephan C. Collins, Delphine Héron, Valerie Cormier-Daire, Tania Attie-Bitach, Binnaz Yalcin, Christel Depienne, and Juliette D. Godin. Rbmx functional retrocopy safeguards brain development. MedRxiv, Oct 2025. URL: https://doi.org/10.1101/2025.10.17.25337589, doi:10.1101/2025.10.17.25337589. This article has 1 citations.

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2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

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6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

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3. Phenotypes

4. Genetic and molecular information

Gene and protein

Variant interpretation

Epigenetics and chromosomal abnormalities

5. Environmental information

6. Mechanism and pathophysiology

Disease-specific causal chain

Other RBMX biology and recent research

Suggested GO and CL annotations

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical recognition and testing strategy

Differential diagnosis

11. Outcome and prognosis

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13. Prevention

14. Other species and natural disease

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