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Classifications

Harrison's Part

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Inheritance

1

Autosomal dominant inheritance HP:0000006

MRD72 is inherited in an autosomal dominant manner, but nearly all molecularly confirmed probands carry a de novo heterozygous loss-of-function SRRM2 variant or a de novo 16p13.3 deletion spanning the gene. A single multigenerational Chinese pedigree with a transmitted nonsense variant has been reported, establishing that vertical transmission does occur.

Autosomal dominant inheritance Expressivity: VARIABLE

Show evidence (2 references)

PMID:35567594 SUPPORT Human Clinical

"Among the 1000 probands studied with developmental delay and intellectual disability in our database, we found 2 patients with de novo LoF variants in SRRM2."

Establishes the de novo heterozygous loss-of-function mechanism in the index probands of the defining cohort.

PMID:37621647 SUPPORT Human Clinical

"We report a family with an autosomal dominant genetic disorder caused by variants in the SRRM2 gene causing NDDs."

Documents inherited (non-de-novo) autosomal dominant transmission in a multigenerational family, confirming the AD inheritance mode.

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Subtypes

1

Large contiguous 16p13.3 deletion including SRRM2

Individuals carrying whole-gene deletions of SRRM2 (248-482 kb in the Genomics England series, 66-270 kb in the defining cohort) rather than protein-truncating point variants. The subtype is defined by lesion architecture, which is well characterised: distal breakpoints cluster within a 144 kb palindrome-like structure 75 kb upstream of SRRM2, and three of the four Genomics England deletions carried inverted internal segments of 45-94 kb. A severity difference is often attributed to this subtype but is NOT established: the moderate-to-severe intellectual disability reported by Genomics England describes all six of their patients (four deletions plus two point variants) versus the defining cohort as a whole (which itself contained two microdeletions), two of the six carried co-occurring pathogenic variants in other genes, and both seizure cases were point-variant carriers. See the mrd72_genotype_severity_gradient discussion.

Show evidence (2 references)

PMID:40225164 SUPPORT Human Clinical

"ID was observed in all 6 individuals described here and ranged from moderate to severe, whereas in the published cohort, the level of ID was typically mild."

The severity statement usually cited for this subtype. Note it compares the six Genomics England patients (a mixed deletion/point-variant group) with the defining cohort, so it is a series-level rather than genotype-level contrast.

PMID:40225164 SUPPORT Human Clinical

"Deletions ranged between 248 and 482 kb in size and all distal breakpoints clustered within a complex 144 kb palindrome situated 75 kb upstream of SRRM2. Strikingly, three of the deletions were complex, with inverted internal segments of 45-94 kb."

Defines the structural architecture underlying this subtype.

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Discussions and Knowledge Gaps

3

Does the Srrm2+/- mouse brain phenotype - reduced striatal oligodendrocytes, impaired myelination, reduced sleep spindles, blunted startle - correspond to anything measurable in people with MRD72, whose defining features are speech delay, overfriendliness, hypotonia, and overweight?

HUMAN MODEL MISMATCH OPEN mrd72_mouse_model_translational_validity

Attached to

pathophysiology#Impaired Neuronal and Oligodendrocyte Development

The Srrm2+/- mouse has excellent construct validity: the same gene, the same heterozygous dosage. But it was built and interpreted as a genetic model of schizophrenia, and its readouts were chosen accordingly. None of the human MRD72 features - the predominant speech delay, the characteristic overfriendliness, the facial dysmorphism, the overweight - has a murine counterpart in the published phenotyping, and no MRD72 patient series reports EEG sleep-spindle or myelin-imaging data. The mouse therefore substantiates the molecular arm of the mechanism (splicing, synaptic protein isoforms, oligodendrocytes) while leaving the mapping onto the human syndrome undetermined. This matters for curation because the myelination and oligodendrocyte nodes rest entirely on this model.

Proposed experiments

Neuroimaging of white matter in MRD72 patients

mrd72_white_matter_imaging

Diffusion MRI in a genotype-confirmed MRD72 cohort against matched controls, to test whether the murine myelin deficit has a human structural correlate.

Sleep EEG in MRD72 patients

mrd72_sleep_eeg_spindles

Overnight polysomnography with spindle quantification in MRD72 patients, the direct human counterpart of the murine EEG finding.

Show evidence (1 reference)

PMID:42189682 SUPPORT Model Organism

"electroencephalogram (EEG) recordings reveal reduced sleep spindles resembling humans with schizophrenia"

The model's headline neurophysiological readout is framed against schizophrenia rather than against the MRD72 phenotype, which is the mismatch at issue.

Is a 50% reduction in SRRM2 dosage - the actual lesion in MRD72 - sufficient to degrade nuclear speckle architecture, or are speckles buffered against heterozygous loss?

KNOWLEDGE GAP OPEN mrd72_speckle_dosage_threshold

Attached to

pathophysiology#Nuclear Speckle Scaffold Disruption

Every published demonstration that speckles depend on SRRM2 used a much harsher perturbation than the disease: co-depletion of both SON and SRRM2, depletion of SON in a line whose SRRM2 intrinsically disordered regions had been genetically deleted, or acute degron depletion. None tested the heterozygous state. Because SON remains at full dosage in MRD72, speckles may well be largely preserved, in which case the disease-relevant consequence of SRRM2 haploinsufficiency runs through the spliceosome-catalytic-centre role rather than through speckle architecture. This is the single largest uncertainty in the entry's pathograph, and it is why the speckle node is marked PROVISIONAL while the splicing node is ESTABLISHED.

Proposed experiments

Speckle morphometry in SRRM2-heterozygous human cells

mrd72_speckle_morphometry_heterozygous

Quantitative imaging of nuclear speckle number, size, and sphericity in isogenic SRRM2+/- human cells (and, where available, patient-derived fibroblasts or iPSC-derived neurons) against wild-type, to test whether the disease-relevant dosage measurably alters speckle architecture.

Separation of the speckle and catalytic-centre contributions

mrd72_speckle_vs_splicing_separation

Compare transcriptome-wide splicing in SRRM2+/- cells against cells carrying a separation-of-function allele that preserves the spliceosomal N-terminus while deleting the speckle-driving IDRs, to apportion the splicing defect between the two roles.

Show evidence (1 reference)

PMID:33095160 SUPPORT In Vitro

"depletion of SON leads only to a partial disassembly of NS, while co-depletion of SON and SRRM2 or depletion of SON in a cell-line where intrinsically disordered regions (IDRs) of SRRM2 are genetically deleted, leads to a near-complete dissolution of NS"

Shows that the published speckle-dissolution result required perturbing both scaffolds, never SRRM2 haploinsufficiency alone - which is the gap.

Is the more severe phenotype of large 16p13.3 deletions (moderate-to-severe intellectual disability, microcephaly, seizures) caused by SRRM2 loss itself, or by loss of neighbouring genes within the deleted interval?

KNOWLEDGE GAP OPEN mrd72_genotype_severity_gradient

Attached to

pathophysiology#SRRM2 Haploinsufficiency

Both classes of lesion abolish one SRRM2 allele, so a pure haploinsufficiency model predicts comparable severity. The observed gradient therefore points either to a contiguous-gene effect at 16p13.3 or to ascertainment differences between the cohorts. The authors themselves note that phenotypic blending from co-occurring pathogenic variants in CASR/PKD1 and SLC17A5 confounded two of the six deletion cases, so the comparison is not clean. Resolving this determines whether the deletion subtype should be modelled as the same disease with greater severity or as a distinct contiguous-gene syndrome.

Proposed experiments

Deletion-interval breakpoint-to-phenotype correlation

mrd72_deletion_breakpoint_phenotype_correlation

Assemble a larger series of SRRM2-spanning 16p13.3 deletions with precise breakpoints and systematic phenotyping, and test whether severity tracks deletion size and specific co-deleted genes independently of SRRM2 loss.

Show evidence (1 reference)

PMID:40225164 SUPPORT Human Clinical

"Phenotypic blending, present for two cases with additional pathogenic variants in CASR/PKD1 and SLC17A5, hampered the phenotypic delineation of this recently described condition."

The authors identify the confounder that keeps this comparison open.

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Pathophysiology

6

SRRM2 Haploinsufficiency

Heterozygous frameshift, nonsense, or canonical splice-site variants in SRRM2, or whole-gene 16p13.3 deletions, halve the functional dose of SRm300. SRRM2 is among the most loss-of-function-intolerant genes in the genome (7 observed versus 111.4 expected loss-of-function SNVs in gnomAD v2.1.1; LOEUF 0.18, pLI 1.0), and the disorder was discovered through statistical enrichment of de novo protein-truncating variants across 31,058 trios.

SRRM2 hgnc:16639

Genetic context SRRM2 hgnc:16639 allele_type: SNV variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Predominantly de novo heterozygous protein-truncating variants; a minority are contiguous 16p13.3 deletions or, more rarely, missense variants in the intrinsically disordered region.

mRNA binding GO:0003729 ↓ DECREASED

spliceosomal complex GO:0005681

Downstream

Nuclear Speckle Scaffold Disruption SRm300 is one of the two non-redundant scaffold proteins of nuclear speckles. Note the cited experiment shows near-complete speckle dissolution only on CO-depletion of SON and SRRM2, or on SON depletion in a line whose SRRM2 intrinsically disordered regions are deleted - neither SRRM2 depletion alone nor a 50% dosage reduction has been shown to degrade speckle architecture. The edge is therefore recorded as mechanistically motivated but not directly demonstrated at disease-relevant dosage.

Alternative Pre-mRNA Splicing Dysregulation SRm300 sits at the spliceosome catalytic centre, so reduced dosage directly perturbs splice-site selection independently of the speckle-scaffold role.

Show evidence (2 references)

PMID:35567594 SUPPORT Human Clinical

"Molecular analysis identified 12 frameshift variants, 8 nonsense variants, and 2 microdeletions of 66 kb and 270 kb."

Documents the truncating and deletion variant spectrum underlying haploinsufficiency in the defining cohort.

PMID:40225164 SUPPORT Human Clinical

"SRRM2 is highly intolerant to putative loss-of-function (pLoF) variants, with 111.4 single nucleotide variants (SNVs) expected vs. 7 observed in gnomAD v2.1.1. It has a LOEUF score = 0.18 and pLI = 1.0, supporting a link to disease via haploinsufficiency"

Population constraint metrics directly support haploinsufficiency as the disease mechanism rather than a dominant-negative or gain-of-function effect.

Nuclear Speckle Scaffold Disruption

SRm300 and SON are the two non-redundant scaffolds of nuclear speckles, membraneless nuclear condensates that concentrate splicing factors. The serine/arginine-rich intrinsically disordered regions of SRRM2 drive multicomponent liquid-liquid phase separation that subcompartmentalizes the speckle. The scaffold role itself is well established; what is NOT established is that the ~50% dosage reduction of MRD72 is sufficient to degrade speckle architecture. The published dissolution experiments used co-depletion of both scaffolds or complete IDR deletion, so this node is recorded as PROVISIONAL - see the mrd72_speckle_dosage_threshold discussion.

nuclear speck organization GO:0035063 ↓ DECREASED

nuclear speck GO:0016607

Downstream

Alternative Pre-mRNA Splicing Dysregulation Loss of the speckle scaffold disperses the splicing-factor reservoir and changes splice-site selection.

Show evidence (2 references)

PMID:38381607 SUPPORT In Vitro

"We further show that SRRM2 forms multicomponent liquid phases in cells to drive NS subcompartmentalization, which is reliant on homotypic interaction and heterotypic non-selective protein-RNA complex coacervation-driven phase separation."

Demonstrates that SRRM2 phase separation is the physical basis of nuclear speckle subcompartment assembly.

PMID:35929045 SUPPORT In Vitro

"We conclude that SRRM2 acts as a scaffold to organize nuclear speckles, regulating alternative splicing in innate immunity and cell homeostasis."

Independent demonstration of the scaffold role linking speckle organization to alternative splicing control.

Alternative Pre-mRNA Splicing Dysregulation

Reduced SRm300 shifts splice-site selection genome-wide, preferentially causing skipping of cassette exons flanked by short introns and weak splice sites, which tends to remove large protein domains. In brain, the affected transcripts include post-synaptic regulators - the gamma isoform of SynGAP is reduced and its interactor Agap3 is mis-spliced, a defect conserved in human SRRM2-deficient iPSC-derived neurons.

alternative mRNA splicing, via spliceosome GO:0000380 ⚠ ABNORMAL regulation of alternative mRNA splicing, via spliceosome GO:0000381 ↓ DECREASED

Experimental models

SRRM2-deficient human iPSC-derived neurons IPSC DERIVED MODEL Confirms in human neurons the specific mis-splicing event identified in the mouse model, bridging the species gap for this arm of the mechanism.

Downstream

Impaired Neuronal and Oligodendrocyte Development Mis-splicing and altered abundance of synaptic and myelin transcripts perturbs neuronal and glial maturation.

Loss of Stemness and Altered Lineage Commitment Alternative splicing changes in a small number of genes are the earliest detectable consequence of Srrm2 depletion in embryonic stem cells and precede the broader transcriptional shift.

Show evidence (2 references)

PMID:35929045 SUPPORT In Vitro

"SRRM2 deficiency induces skipping of cassette exons with short introns and weak splice sites, tending to change large protein domains"

Defines the specific mis-splicing signature produced by SRRM2 deficiency.

PMID:42189682 SUPPORT In Vitro

"Human induced pluripotent stem cell (iPSC)-derived neurons deficient in SRRM2 display conserved AGAP3 splicing defects."

Shows the mis-splicing consequence is conserved in a human neuronal context, not restricted to the mouse model.

Loss of Stemness and Altered Lineage Commitment

Srrm2 dosage is critical for maintaining embryonic stem cell pluripotency and cell identity. Heterozygous Srrm2 embryonic stem cells co-express naive and formative pluripotency markers and show extensive gene-expression change, indicating a partial loss of stemness. This branch is a plausible developmental route to the congenital features of MRD72 but has not been directly demonstrated in patient tissue, so it is recorded as provisional.

embryonic stem cell CL:0002322

stem cell population maintenance GO:0019827 ↓ DECREASED cell differentiation GO:0030154 ⚠ ABNORMAL

Experimental models

Srrm2 heterozygous mouse embryonic stem cells CELL LINE Directly demonstrates the stemness and lineage-commitment consequences of heterozygous Srrm2 loss at the same allelic dosage as human disease.

Downstream

Neurodevelopmental Phenotype A candidate early-embryonic route from SRRM2 dosage to the congenital features of MRD72. The stemness defect is demonstrated only in mouse embryonic stem cells; no step between it and any human clinical feature has been shown, so the edge is speculative and recorded with unknown intermediates.

Show evidence (1 reference)

PMID:38656788 SUPPORT In Vitro

"Srrm2 heterozygosity promotes loss of stemness, characterised by the coexistence of cells expressing naive and formative pluripotency markers, together with extensive changes in gene expression"

Directly demonstrates the stemness phenotype at the same heterozygous dosage as human disease.

Impaired Neuronal and Oligodendrocyte Development

In Srrm2 haploinsufficient mouse brain, gene expression changes across neuronal and glial populations affect synapse, translation, and mitochondrial pathways; oligodendrocyte proportions are reduced, particularly in striatum, with decreased myelin-related mRNA and protein. The corresponding electrophysiological and behavioural changes (reduced locomotor activity, impaired startle, reduced sleep spindles) have not been assessed in patients, so the human relevance of the glial/myelin arm remains provisional.

neuron CL:0000540 oligodendrocyte CL:0000128 ↓ DECREASED

synapse organization GO:0050808 ⚠ ABNORMAL central nervous system myelination GO:0022010 ↓ DECREASED

brain UBERON:0000955

Animal models

Srrm2 heterozygous knockout mouse (brain phenotyping) Mouse partially recapitulates Reproduces the cellular and molecular consequences of Srrm2 haploinsufficiency in brain at the same allelic dosage as human disease.

Downstream

Neurodevelopmental Phenotype Disrupted neuronal and glial maturation is the presumed substrate of the clinical developmental delay, hypotonia, and behavioural phenotype. The intermediate steps between the murine cellular findings and the human cognitive/speech phenotype are not established.

Show evidence (2 references)

PMID:42189682 SUPPORT Model Organism

"reduced oligodendrocyte proportions, particularly in the striatum, accompanied by decreased expression of myelin-related mRNAs and proteins"

Documents the glial and myelin consequences of Srrm2 haploinsufficiency in vivo.

PMID:42189682 SUPPORT Model Organism

"Behaviorally, Srrm2+/- mice have reduced locomotor activity and impaired startle responses, and electroencephalogram (EEG) recordings reveal reduced sleep spindles resembling humans with schizophrenia."

Documents the behavioural and electrophysiological consequences in the same model.

Neurodevelopmental Phenotype

The organism-level convergence point: mild developmental delay with predominant speech delay, autistic or ADHD features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features, with variable and generally mild intellectual disability. Its downstream edges resolve this bundle into the individually curated clinical phenotypes.

Downstream

Global Developmental Delay

Delayed Speech and Language Development

Mild Intellectual Disability

Autistic Behavior

Attention Deficit Hyperactivity Disorder

Overfriendliness

Generalized Hypotonia

Overweight and Obesity Overweight is a consistent part of the syndrome, but no mechanism linking SRRM2 dosage to energy balance has been established.

Dysmorphic Facial Features The craniofacial arm of the syndrome; the developmental route from SRRM2 dosage to facial gestalt is not established.

Show evidence (1 reference)

PMID:35567594 SUPPORT Human Clinical

"The patients presented with a mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. Intellectual disability was variable and mild when present."

The defining clinical description of the disorder from the 22-patient cohort.

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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

28

Cardiovascular 2

Congestive Heart Failure HP:0001635

Show evidence (1 reference)

PMID:40046925 SUPPORT Human Clinical

"This hospitalization led to the diagnosis of cardiogenic insufficiency, classified as stage IV cardiac function, along with stage I hypertension and hyperlipidemia. The clinical picture was further complicated by the identification of sleep apnea syndrome."

Documents the stage IV cardiac insufficiency that followed severe obesity in this patient.

Hypertension HP:0000822

Show evidence (1 reference)

PMID:40046925 SUPPORT Human Clinical

"along with stage I hypertension and hyperlipidemia"

Documents the hypertension in this patient.

Digestive 1

Gastroesophageal Reflux HP:0002020

Show evidence (1 reference)

PMID:37212523 SUPPORT Human Clinical

"Common clinical features include developmental delay, attention deficit hyperactivity disorder, macrocephaly, hypotonia, gastroesophageal reflux, overweight/obesity, and autism."

Lists gastroesophageal reflux among the common features.

Ear 1

Macrotia HP:0000400

Show evidence (1 reference)

PMID:40225164 SUPPORT Human Clinical

"this includes geographic tongue (Figure 3(a)), large ears/earlobes (Figures 3(b) and 3(h))"

Documents large ears/earlobes as a recurrent feature.

Head and Neck 4

Dysmorphic Facial Features VERY_FREQUENT Abnormal facial shape HP:0001999

Show evidence (2 references)

PMID:40545495 SUPPORT Human Clinical

"presenting with developmental delay, facial dysmorphism (20/22), mild IDD (16/20)"

Gives the 20/22 (91%) count for facial dysmorphism, supporting the VERY_FREQUENT band.

PMID:40225164 SUPPORT Human Clinical

"A number of features occur in more than one case, and this includes geographic tongue (Figure 3(a)), large ears/earlobes (Figures 3(b) and 3(h)), thin lips and a bulbous nose (Figures 3(c), 3(f), and 3(g)), small hands with tapering fingers (Figures 3(d) and 3(i)), and large halluces"

Enumerates the recurrent dysmorphic features observed across the structural-variant cohort.

Bulbous Nose HP:0000414

Show evidence (1 reference)

PMID:40225164 SUPPORT Human Clinical

"thin lips and a bulbous nose (Figures 3(c), 3(f), and 3(g))"

Documents bulbous nose as a recurrent dysmorphic feature.

Macrocephaly HP:0000256

Show evidence (1 reference)

PMID:37212523 SUPPORT Human Clinical

"Common clinical features include developmental delay, attention deficit hyperactivity disorder, macrocephaly, hypotonia, gastroesophageal reflux, overweight/obesity, and autism."

Lists macrocephaly among the common features of the CHOP series.

Microcephaly HP:0000252

Show evidence (1 reference)

PMID:40225164 SUPPORT Human Clinical

"Microcephaly was reported for half the individuals described here but only in 1/22 of the previous cases."

Directly contrasts microcephaly frequency between the two published series.

Limbs 3

Small Hands HP:0200055

Show evidence (2 references)

PMID:40225164 SUPPORT Human Clinical

"small hands with tapering fingers"

Documents small hands as a recurrent feature.

PMID:40046925 SUPPORT Human Clinical

"macrocephaly, short hands and feet, hyperphagia, and hypotonia"

Independent case report documenting short hands in an SRRM2 patient.

Short Feet Short foot HP:0001773

Show evidence (1 reference)

PMID:40046925 SUPPORT Human Clinical

"macrocephaly, short hands and feet, hyperphagia, and hypotonia"

Documents short feet in this patient.

Broad Hallux HP:0010055

Show evidence (1 reference)

PMID:40225164 SUPPORT Human Clinical

"small hands with tapering fingers (Figures 3(d) and 3(i)), and large halluces"

Documents large halluces as a recurrent feature. PARTIAL because the source says "large", which HPO does not resolve into broad versus long; the broad-hallux term is the closest available binding.

Metabolism 1

Hyperlipidemia HP:0003077

Show evidence (1 reference)

PMID:40046925 SUPPORT Human Clinical

"along with stage I hypertension and hyperlipidemia"

Documents the hyperlipidemia in this patient.

Musculoskeletal 1

Generalized Hypotonia FREQUENT HP:0001290

Show evidence (2 references)

PMID:35567594 SUPPORT Human Clinical

"The patients presented with a mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. Intellectual disability was variable and mild when present."

Lists generalized hypotonia among the core features.

PMID:40545495 SUPPORT Human Clinical

"developmental delay, facial dysmorphism (20/22), mild IDD (16/20), ASD (9/22), hypotonia (9/22), obesity (7/22), and ADHD (6/22)"

Gives the 9/22 (41%) count supporting the FREQUENT band.

Nervous System 8

Global Developmental Delay VERY_FREQUENT HP:0001263

Show evidence (2 references)

PMID:35567594 SUPPORT Human Clinical

"The patients presented with a mild developmental delay, predominant speech delay"

Reports developmental delay as the shared presenting feature of the defining cohort.

PMID:40225164 SUPPORT Human Clinical

"Common findings included developmental/speech delay, autistic traits, attention deficit hyperactivity disorder (ADHD), and overfriendliness."

Independent restatement supporting developmental delay as a common finding, consistent with the VERY_FREQUENT band.

Delayed Speech and Language Development VERY_FREQUENT HP:0000750

Show evidence (1 reference)

PMID:35567594 SUPPORT Human Clinical

"The patients presented with a mild developmental delay, predominant speech delay"

Identifies speech delay as the predominant component of the delay.

Mild Intellectual Disability FREQUENT HP:0001256

Show evidence (2 references)

PMID:35567594 SUPPORT Human Clinical

"Intellectual disability was variable and mild when present."

States that intellectual disability is variable in presence and mild in degree.

PMID:40545495 SUPPORT Human Clinical

"Cuinat et al. first established SRRM2 as a gene responsible for a rare neurodevelopmental disease in 22 subjects (14 males, mean age 11 years, range 4-28 years) presenting with developmental delay, facial dysmorphism (20/22), mild IDD (16/20), ASD (9/22), hypotonia (9/22), obesity (7/22), and ADHD (6/22)"

Provides the explicit 16/20 (80% of assessable) count behind the FREQUENT band for mild intellectual disability.

Autistic Behavior FREQUENT HP:0000729

Show evidence (1 reference)

PMID:40545495 SUPPORT Human Clinical

"developmental delay, facial dysmorphism (20/22), mild IDD (16/20), ASD (9/22), hypotonia (9/22), obesity (7/22), and ADHD (6/22)"

Gives the 9/22 (41%) count for autism spectrum features that grounds the FREQUENT band.

Attention Deficit Hyperactivity Disorder FREQUENT HP:0007018

Show evidence (3 references)

PMID:40545495 SUPPORT Human Clinical

"developmental delay, facial dysmorphism (20/22), mild IDD (16/20), ASD (9/22), hypotonia (9/22), obesity (7/22), and ADHD (6/22)"

Gives the 6/22 (27%) count in the defining cohort - the lower end of the range the FREQUENT band spans.

PMID:37212523 SUPPORT Human Clinical

"Common clinical features include developmental delay, attention deficit hyperactivity disorder, macrocephaly, hypotonia, gastroesophageal reflux, overweight/obesity, and autism."

Independent series listing ADHD among the common features.

PMID:40545495 SUPPORT Human Clinical

"Pagnamenta et al. identified six unrelated patients (3 males and 3 females, age range 5-16 years) from the 100 K Genomes Project with loss-of-function variants in SRRM2 associated with IDD and facial dysmorphism, as well as ADHD (5/6), ASD (4/6), hypotonia (4/6), and obesity (2/6)"

Gives the 5/6 (83%) ADHD count in the second cohort, the upper end of the range behind the FREQUENT band.

Seizures HP:0001250

Show evidence (1 reference)

PMID:40225164 SUPPORT Human Clinical

"Similarly, seizures were present in 2/6 of our patients but this feature was not reported previously."

States the seizure frequency in the deletion cohort and its absence from the earlier cohort.

Hyperphagia Polyphagia HP:0002591

Show evidence (2 references)

PMID:40046925 SUPPORT Human Clinical

"Notably, the patient became overweight and subsequently developed several obesity-related complications due to uncontrolled hyperphagia."

Documents hyperphagia as the driver of the severe obesity in this case.

PMID:40225164 SUPPORT Human Clinical

"She enjoyed eating and would eat excessively if allowed to do so."

Independent observation of excessive eating in a second SRRM2 cohort.

Sleep Apnea HP:0010535

Show evidence (1 reference)

PMID:40046925 SUPPORT Human Clinical

"The clinical picture was further complicated by the identification of sleep apnea syndrome."

Documents the sleep apnea in this patient.

Respiratory 1

Persistent Tachypnoea of Infancy Tachypnea HP:0002789

Show evidence (2 references)

PMID:40967764 SUPPORT Human Clinical

"Four de novo loss-of-function (LoF) variants of SRRM2 were identified in four out of 71 NEHI/PTI patients with typical pulmonary presentation."

Establishes SRRM2 loss of function as a monogenic cause of NEHI/PTI.

PMID:40967764 SUPPORT Human Clinical

"This study identifies SRRM2-related disorder as a monogenic cause of NEHI/PTI."

Explicit conclusion extending the SRRM2 phenotypic spectrum to this respiratory presentation.

Growth 1

Overweight and Obesity FREQUENT HP:0001513

Show evidence (3 references)

PMID:40225164 SUPPORT Human Clinical

"Over 50% of the published cohort"

The sentence subject; the clause continues "were described to be overweight" after an intervening bracketed citation marker that is stripped before substring matching, so the two halves are quoted separately.

PMID:40225164 SUPPORT Human Clinical

"were described to be overweight and that was also noted in two of our patients"

The predicate of the same sentence, stating that over half the defining cohort was overweight and that the finding recurred in the second cohort - together supporting the FREQUENT band.

PMID:40545495 SUPPORT Human Clinical

"mild IDD (16/20), ASD (9/22), hypotonia (9/22), obesity (7/22), and ADHD (6/22)"

Gives the 7/22 count for frank obesity within the same cohort.

Other 5

Overfriendliness HP:0100025

Show evidence (3 references)

PMID:35567594 SUPPORT Human Clinical

"autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia"

Names overfriendliness as part of the core behavioural description.

PMID:40225164 SUPPORT Human Clinical

"she is overly social and happy and has significant learning difficulties"

Independent observation of the hypersociable behavioural phenotype in a second cohort.

PMID:40225164 SUPPORT Human Clinical

"Common findings included developmental/speech delay, autistic traits, attention deficit hyperactivity disorder (ADHD), and overfriendliness."

Lists overfriendliness among the common findings of the defining cohort.

Thin Upper Lip Vermilion Thin vermilion border HP:0000233

Show evidence (1 reference)

PMID:40225164 SUPPORT Human Clinical

"thin lips and a bulbous nose (Figures 3(c), 3(f), and 3(g))"

Documents thin lips as a recurrent dysmorphic feature.

Geographic Tongue HP:0025252

Show evidence (1 reference)

PMID:40225164 SUPPORT Human Clinical

"A number of features occur in more than one case, and this includes geographic tongue (Figure 3(a))"

Documents geographic tongue as a recurrent feature.

Tapered Fingers HP:0001182

Show evidence (1 reference)

PMID:40225164 SUPPORT Human Clinical

"small hands with tapering fingers (Figures 3(d) and 3(i)), and large halluces"

Documents tapering fingers as a recurrent feature.

Tics HP:0100033

Show evidence (2 references)

PMID:40545495 SUPPORT Human Clinical

"We document the rare case of a 30-year-old man diagnosed with neurodevelopmental disorder and juvenile-onset tics associated with a microdeletion involving the SRRM2 gene."

The single reported case of tics in SRRM2-related neurodevelopmental disorder.

PMID:40545495 SUPPORT Human Clinical

"Of these, 21 were males and none had tics as part of their neurodevelopmental manifestations."

Establishes that tics were absent from all 37 previously reported cases, qualifying this as an isolated observation rather than a syndrome feature.

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Genetic Associations

1

SRRM2

Gene: SRRM2 hgnc:16639 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (3 references)

PMID:35567594 SUPPORT Human Clinical

"Here, we report on 22 patients with LoF variants in SRRM2 and provide a description of the phenotype."

The defining gene-disease study establishing SRRM2 loss of function as causal.

PMID:35567594 SUPPORT Human Clinical

"We established SRRM2 as a gene responsible for a rare neurodevelopmental disease."

Explicit gene-disease conclusion.

PMID:40225164 SUPPORT Human Clinical

"SRRM2, a 15 exon gene that encodes a 2,752 amino acid splicing factor, was one of 28 genes that showed a strong enrichment for de novo mutations, but which had not previously been robustly linked to developmental disorders. Enrichment was driven primarily by protein-truncating variants"

Records the statistical de novo enrichment that first implicated SRRM2 and confirms protein-truncating variants as the driving class.

Variants (3)

Recurrent arginine-to-stop variants (CpG deamination) Pathogenic

Gene: SRRM2 hgnc:16639

SRRM2 is arginine-rich (468/2,752 residues) and correspondingly CpG-dense, making it a high-risk gene for de novo nonsense variants arising by deamination of methylated cytosine. Four of the 22 variants in the defining cohort were Arg-to-Ter changes, and p.(Arg632*) reported in the Genomics England series lies close to the previously reported p.(Arg628*).

Show evidence (1 reference)

PMID:40225164 SUPPORT Human Clinical

"As SRRM2 encodes an arginine-rich protein (468/2,752 residues), it contains a relatively high number of CpG dinucleotides rendering it a high-risk gene for de novo nonsense variants via deamination of methylated cytosine. Of the 22 variants reported by Cuinat et al., 4 were Arg - > Ter variants."

Establishes CpG deamination as a recurrent mutational mechanism at this locus.

MSP-associated missense variant disrupting the SRRM2-ACIN1 interaction

Gene: SRRM2 hgnc:16639

A co-segregating SRRM2 missense variant reported in a family with dominantly inherited multisystem proteinopathy - a degenerative nervous-system/muscle/bone disorder, NOT MRD72. Knock-in of the single amino-acid change abolished the SRRM2-ACIN1 protein-protein interaction and produced widespread expression change converging on synapse-associated pathways. Recorded here as an allelic-spectrum contrast: it indicates that SRRM2 missense alleles can act through a mechanism other than the haploinsufficiency that causes MRD72, and such variants should not be assumed to cause this disorder.

Show evidence (2 references)

PMID:42309671 SUPPORT Human Clinical

"Here, we describe a family with dominantly inherited MSP, in which a mutation in the serine/arginine repetitive matrix protein 2 gene (SRRM2) that co-segregates with disease, is identified."

Establishes a distinct SRRM2-associated dominant disease, separate from MRD72.

PMID:42309671 SUPPORT In Vitro

"we found that the resulting single amino acid exchange led to the loss of protein-protein interaction between SRRM2 and the splicing factor ACIN1"

Identifies a non-haploinsufficiency molecular consequence for this allele class.

p.Gln1554Leu (intrinsically disordered region missense) Likely Pathogenic

Gene: SRRM2 hgnc:16639

A de novo missense variant NM_016333:c.4661A>T (p.Q1554L) in the SRRM2 intrinsically disordered region, classified Likely Pathogenic, reported in a patient with a hyperphagia-driven severe obesity presentation. This is the principal reported non-truncating candidate; the disorder's mechanism is otherwise haploinsufficiency.

Show evidence (1 reference)

PMID:40046925 SUPPORT Human Clinical

"we identified a novel missense mutation in SRRM2 (NM_016333: c.4661A > T, p.Q1554L). This mutation is classified as "Likely Pathogenic" based on the American College of Medical Genetics and Genomics (ACMG) guideline."

Reports the variant and its ACMG classification.

💊

Medical Actions

5

Speech and Language Therapy

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

Speech delay is the predominant developmental feature, making speech and language therapy a core element of management. No disease-specific therapy exists; management is symptomatic and supportive.

Target Phenotypes: Delayed speech and language development HP:0000750

Show evidence (1 reference)

PMID:35567594 SUPPORT Human Clinical

"The patients presented with a mild developmental delay, predominant speech delay"

Establishes speech delay as the predominant treatable feature. No trial or outcome data for speech therapy in this disorder exist, so the evidence supports the indication rather than the efficacy - hence PARTIAL.

Physical Therapy

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Physiotherapy for generalized hypotonia and delayed motor development, as part of standard early-intervention care.

Target Phenotypes: Generalized hypotonia HP:0001290

Show evidence (1 reference)

PMID:35567594 SUPPORT Human Clinical

"The patients presented with a mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. Intellectual disability was variable and mild when present."

Documents the hypotonia that constitutes the indication. No efficacy data exist in this disorder, hence PARTIAL.

Clonidine for Tic Management

Action: Pharmacotherapy NCIT:C15986

Agent: clonidine CHEBI:46631

An alpha-2 agonist was recommended as a first-line anti-tic agent in the single reported SRRM2 patient with tics, after serotonergic and antidopaminergic agents were discontinued for lack of durable benefit. This reflects standard tic-disorder practice applied to one case, not SRRM2-specific evidence.

Target Phenotypes: Tics HP:0100033

Show evidence (1 reference)

PMID:40545495 SUPPORT Human Clinical

"Recommendations were made for a first-line anti-tic agent (alpha-2 agonist Clonidine) for prolonged relapses in tic severity."

Records the specific treatment recommendation made in the reported case.

Dietary Intervention for Hyperphagia and Obesity

Action: dietary intervention Ontology label: Dietary Intervention NCIT:C15447

Strict dietary management was recommended for hyperphagia in the reported obesity case. Notably, poor adherence was followed by progression to morbid obesity with cardiometabolic complications, illustrating both the rationale for and the practical limits of dietary management in this phenotype.

Target Phenotypes: Polyphagia HP:0002591

Show evidence (1 reference)

PMID:40046925 SUPPORT Human Clinical

"An interview with the parents suggested hyperphagia as an associated phenotype, leading to recommendations for strict dietary management. Despite these recommendations, the primary guardians' inadequate adherence to the dietary guidelines led to rapid weight gain, resulting in morbid obesity and..."

Documents both the recommendation and its failure under poor adherence - supporting the indication but not demonstrating efficacy, hence PARTIAL.

Genetic Counseling

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

Genetic counseling is indicated for all families, covering the predominantly de novo mechanism, the 50% recurrence risk where a parent is affected, and the availability of prenatal diagnosis when the familial variant is known. Prenatal testing has been performed in reported pedigrees.

Show evidence (2 references)

PMID:37621647 SUPPORT Human Clinical

"Prenatal diagnosis can help patients with this genetic disorder to have healthy offspring."

States the reproductive-counseling application demonstrated in a multigenerational SRRM2 family.

PMID:42342640 SUPPORT Human Clinical

"Amniotic fluid and peripheral blood samples were collected from the fetus and its parents for genomic DNA extraction. Whole-exome sequencing (WES) was carried out, and candidate variants were verified by Sanger sequencing of the family members and rated based on guidelines from the American..."

Documents the concrete prenatal-diagnosis workflow (amniocentesis, trio WES, Sanger confirmation, ACMG classification) applied in an MRD72 pregnancy.

🔬

Diagnosis

2

Trio exome or genome sequencing

Essentially all reported cases were ascertained by exome or genome sequencing, usually as parent-child trios to establish de novo status. Genome sequencing is preferred where a structural variant is suspected, because the 16p13.3 deletions are frequently complex and were missed or under-resolved by array-based testing in reported cases.

Show evidence (2 references)

PMID:40225164 SUPPORT Human Clinical

"Our data highlights the benefits of genome sequencing for resolving structural complexity and inferring de novo status."

States the diagnostic advantage of genome sequencing for this locus.

PMID:40225164 SUPPORT Human Clinical

"Array-based testing had yielded a normal result, albeit at a low resolution."

Documents a false-negative microarray result in a patient with an SRRM2 deletion, supporting sequencing-based workup.

SRRM2 sequencing in NEHI/PTI workup

Because SRRM2 loss-of-function variants explain a substantial fraction of neuroendocrine cell hyperplasia of infancy / persistent tachypnoea of infancy, SRRM2 sequencing has been proposed as part of the standard workup for that presentation, with paediatric neurology assessment.

Show evidence (1 reference)

PMID:40967764 SUPPORT Human Clinical

"These results suggest that NEHI/PTI patients should be evaluated by a paediatric neurologist and that SRRM2 sequencing should be included in every NEHI/PTI workup."

Explicit diagnostic recommendation from the NEHI/PTI cohort study.

📊

Prevalence

4

Cohorts of patients with unexplained intellectual disability

Point Prevalence 76.9 per 100,000 1–9 per 10,000

~1/1300 among individuals with unexplained intellectual disability, derived from the Genomics England 100,000 Genomes Project ascertainment. This is a diagnostic-yield estimate within an enriched clinical cohort, not a general-population prevalence.

Show evidence (1 reference)

PMID:40225164 SUPPORT Human Clinical

"we estimate the prevalence of this condition in cohorts of patients with unexplained ID to be ~1/1300"

Directly states the diagnostic yield in an unexplained-ID cohort.

Children receiving clinical exome sequencing for developmental disabilities (single US tertiary centre)

Point Prevalence 300.0 per 100,000 >1 in 1,000

0.3% of individuals with developmental disabilities undergoing exome sequencing, as stated by the authors at the Children's Hospital of Philadelphia. Note this is not 3/3100 of all clinical exomes performed (~0.1%) - the denominator is the developmental-disability subset. A yield within an ascertained clinical population, not a population rate.

Show evidence (1 reference)

PMID:37212523 SUPPORT Human Clinical

"Our data suggest that SRRM2-related neurodevelopmental disorder can be identified in 0.3% of individuals with developmental disabilities receiving exome sequencing."

States the exome-sequencing diagnostic yield for this disorder.

Deeply phenotyped neuroendocrine cell hyperplasia of infancy / persistent tachypnoea of infancy cohort

Point Prevalence 5600.0 per 100,000 (1600.0–13800.0) >1 in 1,000

5.6% (95% CI 1.6-13.8%) of a NEHI/PTI cohort carried de novo SRRM2 loss-of-function variants - a strikingly higher yield than in NDD cohorts without lung disease.

Show evidence (1 reference)

PMID:40967764 SUPPORT Human Clinical

"The prevalence of SRRM2 LoF variants in our cohort (5.6%, 95% CI 1.6-13.8%) is 20-100 times higher than reported in patients with NDD without lung disease"

Quantifies the SRRM2 diagnostic yield within the NEHI/PTI phenotype.

General population

Point Prevalence 4.5 per 100,000 (2.0–9.1) 1–9 per 100,000

1 in 11,000 to 1 in 50,000, cited secondhand in a case report and explicitly flagged there as of uncertain accuracy given the limitations of the cohort studies it derives from. Recorded because it is the only general-population figure available; the three ascertained-cohort yields above are far better grounded.

Show evidence (1 reference)

PMID:40046925 SUPPORT Human Clinical

"These mutations have been observed with an estimated prevalence of 1 in 11,000 to 1 in 50,000 individuals in the general population"

States the general-population estimate. PARTIAL because the same paragraph immediately qualifies it: "the accuracy of these figures is subject to verification, given the inherent limitations of cohort studies."

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Intellectual Developmental Disorder, Autosomal Dominant 72:

ZTTK syndrome (SON-related disorder) MONDO:0014936

Overlapping Features The closest mechanistic relative of MRD72: heterozygous loss of function of SON, the other non-redundant nuclear speckle scaffold protein, which likewise perturbs splicing of transcripts with weak splice sites. Both disorders are therefore nuclear-speckle scaffold haploinsufficiencies presenting with developmental delay and intellectual disability.

Distinguishing Features

ZTTK syndrome is a complex, multisystem developmental disorder with congenital anomalies (growth retardation, skeletal abnormalities, kidney agenesis), whereas MRD72 is comparatively mild and largely confined to neurodevelopment, behaviour, weight, and facial gestalt.
Haematological and immunological involvement (leukopenia, immunoglobulin deficiency) is described in ZTTK syndrome but not in MRD72.

Show evidence (3 references)

PMID:38290089 SUPPORT Model Organism

"Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare disease caused by genetic alterations that result in heterozygous loss of function of SON."

Establishes the gene and mechanism of the differential diagnosis - the partner speckle scaffold of SRRM2.

PMID:38290089 SUPPORT Model Organism

"Thus, ZTTK syndrome is a complex, multisystem developmental disorder"

Supports the multisystem severity that distinguishes ZTTK from the comparatively mild MRD72 phenotype.

PMID:33095160 SUPPORT In Vitro

"the core of NS is likely formed by SON and SRRM2"

Establishes why the two disorders are mechanistically paired: SON and SRRM2 are the two joint scaffolds of the same organelle.

📊

Related Datasets

1

Srrm2 haploinsufficiency drives SynGAP-gamma reduction, Agap3 mis-splicing, and oligodendrocyte deficits in a genetic mouse model of schizophrenia geo:GSE299937

Two arms comparing Srrm2+/- mice with wild-type littermates: bulk RNA-seq of eight brain regions at 1 and 3 months, plus single-NUCLEUS RNA-seq of prefrontal cortex and striatum at 1 month. This is the haploinsufficiency model underlying the Impaired Neuronal and Oligodendrocyte Development node, and the source data for the reduced striatal oligodendrocyte proportion and the myelin-gene expression changes.

Mus musculus BULK RNA SEQ n=180

PMID:42189682

Relevance triage: matched on gene rather than disease name, but the linked publication is the Srrm2+/- brain model curated in animal_models here, so the dataset is directly on-target for this entry's mechanism. data_type records the larger bulk RNA-seq arm; the record also contains a single-nucleus RNA-seq arm, which the single-valued slot cannot express. Bulk-generated record - carries publication and provenance notes rather than an evidence block, per the dataset-curation SOP.

🧫

Experimental Models

2

Srrm2 heterozygous mouse embryonic stem cells CELL_LINE

Constitutively Srrm2-heterozygous mouse embryonic stem cells, plus transient RNA-interference depletion, used to dissect the earliest consequences of reduced Srrm2 dosage. Heterozygous cells lose stemness, co-expressing naive and formative pluripotency markers; transient depletion shows that specific alternative splicing events precede the broader expression changes.

Organism

mouse NCBITaxon:10090

Publication

PMID:38656788

Pathograph links

Loss of Stemness and Altered Lineage Commitment recapitulates fidelity: moderate Directly demonstrates the stemness and lineage-commitment consequences of heterozygous Srrm2 loss at the same allelic dosage as human disease.

Limitations: Mouse embryonic stem cells in culture, not human tissue; the link between early-embryonic stemness defects and the postnatal MRD72 phenotype is inferred rather than shown.

Show evidence (1 reference)

PMID:38656788 SUPPORT In Vitro

"we show that Srrm2 dosage is critical for maintaining embryonic stem cell pluripotency and cell identity"

States the dosage-dependent stemness finding this model establishes.

SRRM2-deficient human iPSC-derived neurons IPSC_DERIVED_MODEL

Human induced pluripotent stem cell-derived neurons with SRRM2 deficiency, used to test whether the mouse splicing findings hold in a human neuronal context. AGAP3 splicing defects are conserved.

Organism

human NCBITaxon:9606

Publication

PMID:42189682

Pathograph links

Alternative Pre-mRNA Splicing Dysregulation recapitulates fidelity: moderate Confirms in human neurons the specific mis-splicing event identified in the mouse model, bridging the species gap for this arm of the mechanism.

Limitations: Only the AGAP3 event was reported as conserved; the wider murine splicing and myelination findings were not tested in the human system, and iPSC-derived neurons do not model the circuit-level or systemic features of the disorder.

Readouts

AGAP3 splicing

Direction: ALTERED

Interpretation: Human neuronal confirmation of the mis-splicing signature of SRRM2 deficiency.

Show evidence (1 reference)

PMID:42189682 SUPPORT In Vitro

"Human induced pluripotent stem cell (iPSC)-derived neurons deficient in SRRM2 display conserved AGAP3 splicing defects."

Reports the human neuronal splicing measurement.

Show evidence (1 reference)

PMID:42189682 SUPPORT In Vitro

"Human induced pluripotent stem cell (iPSC)-derived neurons deficient in SRRM2 display conserved AGAP3 splicing defects."

Supports treating this human cellular model as informative for the splicing-dysregulation node.

🐁

Animal Models

1

Srrm2 heterozygous knockout mouse (brain phenotyping) GENETIC

Constitutive heterozygous Srrm2 mice, modelling the human haploinsufficiency mechanism directly. They show transcriptomic change across neuronal and glial populations, reduced SynGAP-gamma with elevated Agap3, reduced striatal oligodendrocyte proportions with decreased myelin gene and protein expression, reduced locomotor activity, impaired startle, and reduced EEG sleep spindles.

Species

Mouse

Genotype

Srrm2+/-

Publication

PMID:42189682

Pathograph links

Impaired Neuronal and Oligodendrocyte Development partially recapitulates fidelity: moderate Reproduces the cellular and molecular consequences of Srrm2 haploinsufficiency in brain at the same allelic dosage as human disease.

Limitations: The model was developed and interpreted as a genetic model of schizophrenia; its behavioural and electrophysiological readouts (locomotor activity, startle, sleep spindles) have no established counterpart in MRD72 patients, and it does not address the craniofacial dysmorphism, speech delay, overfriendliness, or obesity that define the human syndrome.

Readouts

Striatal oligodendrocyte proportion

Direction: DECREASED

Interpretation: Cellular correlate of the impaired-glial-development node in this model.

Show evidence (1 reference)

PMID:42189682 SUPPORT Model Organism

"reduced oligodendrocyte proportions, particularly in the striatum, accompanied by decreased expression of myelin-related mRNAs and proteins"

Reports the oligodendrocyte and myelin measurements behind this readout.

SynGAP gamma isoform abundance

Direction: DECREASED

Interpretation: Post-synaptic protein readout of the splicing defect in this model.

Show evidence (1 reference)

PMID:42189682 SUPPORT Model Organism

"reduction of the gamma isoform of SynGAP and elevation of its interactor, Agap3"

Reports the post-synaptic isoform measurement.

Show evidence (1 reference)

PMID:42189682 SUPPORT Model Organism

"We find that Srrm2+/- mice exhibit (1) large-scale changes in gene expression in neuronal and glial cells, affecting DNA-binding-, synapse-, translation-, mitochondria-related pathways across multiple brain regions"

The model's own primary result, establishing that the same heterozygous dosage as human disease produces measurable neuronal and glial change - which is what makes it informative for this node.

{ }

Source YAML

click to show

name: Intellectual Developmental Disorder, Autosomal Dominant 72
creation_date: '2026-08-19T08:30:00Z'
category: Mendelian
description: >-
  Autosomal dominant intellectual developmental disorder 72 (MRD72), also called
  SRRM2-related neurodevelopmental disorder, is caused by heterozygous
  loss-of-function variants in SRRM2 at 16p13.3. SRRM2 encodes SRm300, an
  SR-related pre-mRNA splicing factor that docks at the spliceosome catalytic
  centre and, together with SON, forms the scaffold of nuclear speckles. Affected
  individuals present with mild developmental delay and predominant speech delay,
  autistic and/or attention-deficit/hyperactivity features, overfriendliness,
  generalized hypotonia, overweight/obesity, and dysmorphic facial features;
  intellectual disability is variable and mild when present. A severity contrast
  has been reported between series - the Genomics England structural-variant
  series found moderate-to-severe intellectual disability and frequent
  microcephaly, against typically mild intellectual disability in the original
  cohort - but this is a cohort-level comparison rather than a clean
  deletion-versus-point-variant one, and it is confounded by ascertainment and by
  co-occurring pathogenic variants in two of the six cases. The phenotypic
  spectrum has
  since been extended to neuroendocrine cell hyperplasia of infancy / persistent
  tachypnoea of infancy.
synonyms:
- MRD72
- SRRM2-related neurodevelopmental disorder
- autosomal dominant intellectual developmental disorder-72
- developmental delay-overweight-facial dysmorphism-behavioral abnormalities syndrome
disease_term:
  preferred_term: intellectual developmental disorder, autosomal dominant 72
  term:
    id: MONDO:0957397
    label: intellectual developmental disorder, autosomal dominant 72
parents:
- Neurodevelopmental Disorder
references:
- reference: PMID:35567594
  title: Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder
- reference: PMID:40225164
  title: >-
    A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of
    Complex Structural Variations and SRRM2 Haploinsufficiency
notes: >-
  No GeneReviews chapter exists for SRRM2 or MRD72 as of the curation date; a
  PubMed search for "SRRM2 GeneReviews[All Fields]" returned no results, so the
  GeneReviews phenotype baseline step was not applicable. Dysmorphic sub-feature
  frequencies circulating in secondary sources (e.g. per-feature counts from the
  Cuinat cohort) are not present in any abstract or full text available in the
  local reference cache and were therefore not curated; only dysmorphic features
  that could be quoted directly are recorded here.

inheritance:
- name: Autosomal dominant inheritance
  description: >-
    MRD72 is inherited in an autosomal dominant manner, but nearly all molecularly
    confirmed probands carry a de novo heterozygous loss-of-function SRRM2 variant
    or a de novo 16p13.3 deletion spanning the gene. A single multigenerational
    Chinese pedigree with a transmitted nonsense variant has been reported,
    establishing that vertical transmission does occur.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  expressivity: VARIABLE
  evidence:
  - reference: PMID:35567594
    reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among the 1000 probands studied with developmental delay and intellectual
      disability in our database, we found 2 patients with de novo LoF variants in
      SRRM2.
    explanation: >-
      Establishes the de novo heterozygous loss-of-function mechanism in the index
      probands of the defining cohort.
  - reference: PMID:37621647
    reference_title: "Familial and genetic association with neurodevelopmental disorders caused by a heterozygous variant in the SRRM2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a family with an autosomal dominant genetic disorder caused by
      variants in the SRRM2 gene causing NDDs.
    explanation: >-
      Documents inherited (non-de-novo) autosomal dominant transmission in a
      multigenerational family, confirming the AD inheritance mode.

classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      The defining morbidity is neurodevelopmental - developmental and speech
      delay, intellectual disability, hypotonia, and ASD/ADHD features. The
      metabolic (overweight) and, in a subset, respiratory (NEHI/PTI) features
      are real but secondary to the neurodevelopmental core.

prevalence:
- population: Cohorts of patients with unexplained intellectual disability
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 76.9
  notes: >-
    ~1/1300 among individuals with unexplained intellectual disability, derived
    from the Genomics England 100,000 Genomes Project ascertainment. This is a
    diagnostic-yield estimate within an enriched clinical cohort, not a
    general-population prevalence.
  evidence:
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we estimate the prevalence of this condition in cohorts of patients with
      unexplained ID to be ~1/1300
    explanation: >-
      Directly states the diagnostic yield in an unexplained-ID cohort.
- population: >-
    Children receiving clinical exome sequencing for developmental disabilities
    (single US tertiary centre)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 300.0
  notes: >-
    0.3% of individuals with developmental disabilities undergoing exome
    sequencing, as stated by the authors at the Children's Hospital of
    Philadelphia. Note this is not 3/3100 of all clinical exomes performed
    (~0.1%) - the denominator is the developmental-disability subset. A yield
    within an ascertained clinical population, not a population rate.
  evidence:
  - reference: PMID:37212523
    reference_title: "Retrospective identification of patients with SRRM2-related neurodevelopmental disorder in a single tertiary children's hospital."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data suggest that SRRM2-related neurodevelopmental disorder can be
      identified in 0.3% of individuals with developmental disabilities receiving
      exome sequencing.
    explanation: >-
      States the exome-sequencing diagnostic yield for this disorder.
- population: >-
    Deeply phenotyped neuroendocrine cell hyperplasia of infancy / persistent
    tachypnoea of infancy cohort
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 5600.0
  rate_low: 1600.0
  rate_high: 13800.0
  notes: >-
    5.6% (95% CI 1.6-13.8%) of a NEHI/PTI cohort carried de novo SRRM2
    loss-of-function variants - a strikingly higher yield than in NDD cohorts
    without lung disease.
  evidence:
  - reference: PMID:40967764
    reference_title: "D e novo SRRM2 variants in neuroendocrine cell hyperplasia of infancy and persistent tachypnoea of infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of SRRM2 LoF variants in our cohort (5.6%, 95% CI 1.6-13.8%)
      is 20-100 times higher than reported in patients with NDD without lung
      disease
    explanation: >-
      Quantifies the SRRM2 diagnostic yield within the NEHI/PTI phenotype.

- population: General population
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 4.5
  rate_low: 2.0
  rate_high: 9.1
  notes: >-
    1 in 11,000 to 1 in 50,000, cited secondhand in a case report and explicitly
    flagged there as of uncertain accuracy given the limitations of the cohort
    studies it derives from. Recorded because it is the only general-population
    figure available; the three ascertained-cohort yields above are far better
    grounded.
  evidence:
  - reference: PMID:40046925
    reference_title: >-
      Rare SRRM2 mutation in neurodevelopmental disorders involving hyperphagia
      triggering severe obesity and other complication.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These mutations have been observed with an estimated prevalence of 1 in
      11,000 to 1 in 50,000 individuals in the general population
    explanation: >-
      States the general-population estimate. PARTIAL because the same paragraph
      immediately qualifies it: "the accuracy of these figures is subject to
      verification, given the inherent limitations of cohort studies."

pathophysiology:
- name: SRRM2 Haploinsufficiency
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Heterozygous frameshift, nonsense, or canonical splice-site variants in SRRM2,
    or whole-gene 16p13.3 deletions, halve the functional dose of SRm300. SRRM2 is
    among the most loss-of-function-intolerant genes in the genome (7 observed
    versus 111.4 expected loss-of-function SNVs in gnomAD v2.1.1; LOEUF 0.18, pLI
    1.0), and the disorder was discovered through statistical enrichment of de
    novo protein-truncating variants across 31,058 trios.
  genetic_context:
    gene:
      preferred_term: SRRM2
      term:
        id: hgnc:16639
        label: SRRM2
    allele_type: SNV
    variant_origin: DE_NOVO
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Predominantly de novo heterozygous protein-truncating variants; a minority
      are contiguous 16p13.3 deletions or, more rarely, missense variants in the
      intrinsically disordered region.
  genes:
  - preferred_term: SRRM2
    term:
      id: hgnc:16639
      label: SRRM2
  molecular_functions:
  - preferred_term: mRNA binding
    term:
      id: GO:0003729
      label: mRNA binding
    modifier: DECREASED
  cellular_components:
  - preferred_term: spliceosomal complex
    term:
      id: GO:0005681
      label: spliceosomal complex
  evidence:
  - reference: PMID:35567594
    reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Molecular analysis identified 12 frameshift variants, 8 nonsense variants,
      and 2 microdeletions of 66 kb and 270 kb.
    explanation: >-
      Documents the truncating and deletion variant spectrum underlying
      haploinsufficiency in the defining cohort.
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SRRM2 is highly intolerant to putative loss-of-function (pLoF) variants,
      with 111.4 single nucleotide variants (SNVs) expected vs. 7 observed in
      gnomAD v2.1.1. It has a LOEUF score = 0.18 and pLI = 1.0, supporting a link
      to disease via haploinsufficiency
    explanation: >-
      Population constraint metrics directly support haploinsufficiency as the
      disease mechanism rather than a dominant-negative or gain-of-function
      effect.
  downstream:
  - target: Nuclear Speckle Scaffold Disruption
    causal_link_type: UNKNOWN
    description: >-
      SRm300 is one of the two non-redundant scaffold proteins of nuclear
      speckles. Note the cited experiment shows near-complete speckle dissolution
      only on CO-depletion of SON and SRRM2, or on SON depletion in a line whose
      SRRM2 intrinsically disordered regions are deleted - neither SRRM2
      depletion alone nor a 50% dosage reduction has been shown to degrade
      speckle architecture. The edge is therefore recorded as mechanistically
      motivated but not directly demonstrated at disease-relevant dosage.
    evidence:
    - reference: PMID:33095160
      reference_title: "SON and SRRM2 are essential for nuclear speckle formation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        the core of NS is likely formed by SON and SRRM2, since depletion of SON
        leads only to a partial disassembly of NS, while co-depletion of SON and
        SRRM2 or depletion of SON in a cell-line where intrinsically disordered
        regions (IDRs) of SRRM2 are genetically deleted, leads to a near-complete
        dissolution of NS
      explanation: >-
        Establishes SRRM2 as a required scaffold component whose loss dissolves
        nuclear speckles.
  - target: Alternative Pre-mRNA Splicing Dysregulation
    causal_link_type: DIRECT
    description: >-
      SRm300 sits at the spliceosome catalytic centre, so reduced dosage directly
      perturbs splice-site selection independently of the speckle-scaffold role.
    evidence:
    - reference: PMID:19854871
      reference_title: "Physical and genetic interactions of yeast Cwc21p, an ortholog of human SRm300/SRRM2, suggest a role at the catalytic center of the spliceosome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We demonstrate that SRm300, the only SR-related protein known to be at the
        core of human catalytic spliceosomes, is a functional ortholog of Cwc21p,
        also interacting directly with Prp8p and Snu114p.
      explanation: >-
        Places SRm300 physically at the catalytic core of the spliceosome, the
        basis for a direct splicing effect of reduced dosage.

- name: Nuclear Speckle Scaffold Disruption
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    SRm300 and SON are the two non-redundant scaffolds of nuclear speckles,
    membraneless nuclear condensates that concentrate splicing factors. The
    serine/arginine-rich intrinsically disordered regions of SRRM2 drive
    multicomponent liquid-liquid phase separation that subcompartmentalizes the
    speckle. The scaffold role itself is well established; what is NOT
    established is that the ~50% dosage reduction of MRD72 is sufficient to
    degrade speckle architecture. The published dissolution experiments used
    co-depletion of both scaffolds or complete IDR deletion, so this node is
    recorded as PROVISIONAL - see the mrd72_speckle_dosage_threshold discussion.
  cellular_components:
  - preferred_term: nuclear speck
    term:
      id: GO:0016607
      label: nuclear speck
  biological_processes:
  - preferred_term: nuclear speck organization
    term:
      id: GO:0035063
      label: nuclear speck organization
    modifier: DECREASED
  evidence:
  - reference: PMID:38381607
    reference_title: "SRRM2 phase separation drives assembly of nuclear speckle subcompartments."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We further show that SRRM2 forms multicomponent liquid phases in cells to
      drive NS subcompartmentalization, which is reliant on homotypic interaction
      and heterotypic non-selective protein-RNA complex coacervation-driven phase
      separation.
    explanation: >-
      Demonstrates that SRRM2 phase separation is the physical basis of nuclear
      speckle subcompartment assembly.
  - reference: PMID:35929045
    reference_title: "SRRM2 organizes splicing condensates to regulate alternative splicing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We conclude that SRRM2 acts as a scaffold to organize nuclear speckles,
      regulating alternative splicing in innate immunity and cell homeostasis.
    explanation: >-
      Independent demonstration of the scaffold role linking speckle organization
      to alternative splicing control.
  downstream:
  - target: Alternative Pre-mRNA Splicing Dysregulation
    causal_link_type: DIRECT
    description: >-
      Loss of the speckle scaffold disperses the splicing-factor reservoir and
      changes splice-site selection.
    evidence:
    - reference: PMID:35929045
      reference_title: "SRRM2 organizes splicing condensates to regulate alternative splicing."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        As bona-fide splicing factor present in spliceosome structures, SRRM2
        deficiency induces skipping of cassette exons with short introns and weak
        splice sites, tending to change large protein domains.
      explanation: >-
        Directly links SRRM2 deficiency to a defined class of mis-splicing events.

- name: Alternative Pre-mRNA Splicing Dysregulation
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Reduced SRm300 shifts splice-site selection genome-wide, preferentially
    causing skipping of cassette exons flanked by short introns and weak splice
    sites, which tends to remove large protein domains. In brain, the affected
    transcripts include post-synaptic regulators - the gamma isoform of SynGAP is
    reduced and its interactor Agap3 is mis-spliced, a defect conserved in human
    SRRM2-deficient iPSC-derived neurons.
  biological_processes:
  - preferred_term: alternative mRNA splicing, via spliceosome
    term:
      id: GO:0000380
      label: alternative mRNA splicing, via spliceosome
    modifier: ABNORMAL
  - preferred_term: regulation of alternative mRNA splicing, via spliceosome
    term:
      id: GO:0000381
      label: regulation of alternative mRNA splicing, via spliceosome
    modifier: DECREASED
  evidence:
  - reference: PMID:35929045
    reference_title: "SRRM2 organizes splicing condensates to regulate alternative splicing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      SRRM2 deficiency induces skipping of cassette exons with short introns and
      weak splice sites, tending to change large protein domains
    explanation: >-
      Defines the specific mis-splicing signature produced by SRRM2 deficiency.
  - reference: PMID:42189682
    reference_title: "Srrm2 haploinsufficiency drives SynGAP-γ reduction, Agap3 mis-splicing, and oligodendrocyte deficits in a genetic mouse model of schizophrenia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Human induced pluripotent stem cell (iPSC)-derived neurons deficient in
      SRRM2 display conserved AGAP3 splicing defects.
    explanation: >-
      Shows the mis-splicing consequence is conserved in a human neuronal context,
      not restricted to the mouse model.
  downstream:
  - target: Impaired Neuronal and Oligodendrocyte Development
    causal_link_type: DIRECT
    description: >-
      Mis-splicing and altered abundance of synaptic and myelin transcripts
      perturbs neuronal and glial maturation.
    evidence:
    - reference: PMID:42189682
      reference_title: "Srrm2 haploinsufficiency drives SynGAP-γ reduction, Agap3 mis-splicing, and oligodendrocyte deficits in a genetic mouse model of schizophrenia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        alterations in splicing and/or abundance of multiple postsynaptic
        proteins, including reduction of the gamma isoform of SynGAP and elevation
        of its interactor, Agap3
      explanation: >-
        Links the splicing defect to specific post-synaptic protein changes in
        Srrm2 haploinsufficient brain.
  - target: Loss of Stemness and Altered Lineage Commitment
    causal_link_type: DIRECT
    description: >-
      Alternative splicing changes in a small number of genes are the earliest
      detectable consequence of Srrm2 depletion in embryonic stem cells and
      precede the broader transcriptional shift.
    evidence:
    - reference: PMID:38656788
      reference_title: "SRRM2 splicing factor modulates cell fate in early development."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        the earliest effects of Srrm2 heterozygosity are specific alternative
        splicing events on a small number of genes, followed by expression changes
        in metabolism and differentiation-related genes
      explanation: >-
        Establishes splicing change as the proximal event upstream of the
        stemness/differentiation phenotype.

- name: Loss of Stemness and Altered Lineage Commitment
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Srrm2 dosage is critical for maintaining embryonic stem cell pluripotency and
    cell identity. Heterozygous Srrm2 embryonic stem cells co-express naive and
    formative pluripotency markers and show extensive gene-expression change,
    indicating a partial loss of stemness. This branch is a plausible
    developmental route to the congenital features of MRD72 but has not been
    directly demonstrated in patient tissue, so it is recorded as provisional.
  cell_types:
  - preferred_term: embryonic stem cell
    term:
      id: CL:0002322
      label: embryonic stem cell
  biological_processes:
  - preferred_term: stem cell population maintenance
    term:
      id: GO:0019827
      label: stem cell population maintenance
    modifier: DECREASED
  - preferred_term: cell differentiation
    term:
      id: GO:0030154
      label: cell differentiation
    modifier: ABNORMAL
  evidence:
  - reference: PMID:38656788
    reference_title: "SRRM2 splicing factor modulates cell fate in early development."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Srrm2 heterozygosity promotes loss of stemness, characterised by the
      coexistence of cells expressing naive and formative pluripotency markers,
      together with extensive changes in gene expression
    explanation: >-
      Directly demonstrates the stemness phenotype at the same heterozygous dosage
      as human disease.
  downstream:
  - target: Neurodevelopmental Phenotype
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A candidate early-embryonic route from SRRM2 dosage to the congenital
      features of MRD72. The stemness defect is demonstrated only in mouse
      embryonic stem cells; no step between it and any human clinical feature has
      been shown, so the edge is speculative and recorded with unknown
      intermediates.
    evidence:
    - reference: PMID:38656788
      reference_title: "SRRM2 splicing factor modulates cell fate in early development."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Our findings unveil molecular and cellular roles of Srrm2 in stemness and
        lineage commitment, shedding light on the roles of splicing regulators in
        early embryogenesis, developmental diseases and tumorigenesis.
      explanation: >-
        The authors themselves frame the relevance to developmental disease as
        illumination rather than demonstration, which is why this edge is PARTIAL
        with unknown intermediates.

- name: Impaired Neuronal and Oligodendrocyte Development
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    In Srrm2 haploinsufficient mouse brain, gene expression changes across
    neuronal and glial populations affect synapse, translation, and mitochondrial
    pathways; oligodendrocyte proportions are reduced, particularly in striatum,
    with decreased myelin-related mRNA and protein. The corresponding
    electrophysiological and behavioural changes (reduced locomotor activity,
    impaired startle, reduced sleep spindles) have not been assessed in patients,
    so the human relevance of the glial/myelin arm remains provisional.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
    modifier: DECREASED
  biological_processes:
  - preferred_term: synapse organization
    term:
      id: GO:0050808
      label: synapse organization
    modifier: ABNORMAL
  - preferred_term: central nervous system myelination
    term:
      id: GO:0022010
      label: central nervous system myelination
    modifier: DECREASED
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:42189682
    reference_title: "Srrm2 haploinsufficiency drives SynGAP-γ reduction, Agap3 mis-splicing, and oligodendrocyte deficits in a genetic mouse model of schizophrenia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      reduced oligodendrocyte proportions, particularly in the striatum,
      accompanied by decreased expression of myelin-related mRNAs and proteins
    explanation: >-
      Documents the glial and myelin consequences of Srrm2 haploinsufficiency in
      vivo.
  - reference: PMID:42189682
    reference_title: "Srrm2 haploinsufficiency drives SynGAP-γ reduction, Agap3 mis-splicing, and oligodendrocyte deficits in a genetic mouse model of schizophrenia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Behaviorally, Srrm2+/- mice have reduced locomotor activity and impaired
      startle responses, and electroencephalogram (EEG) recordings reveal reduced
      sleep spindles resembling humans with schizophrenia.
    explanation: >-
      Documents the behavioural and electrophysiological consequences in the same
      model.
  downstream:
  - target: Neurodevelopmental Phenotype
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disrupted neuronal and glial maturation is the presumed substrate of the
      clinical developmental delay, hypotonia, and behavioural phenotype. The
      intermediate steps between the murine cellular findings and the human
      cognitive/speech phenotype are not established.
    evidence:
    - reference: PMID:42189682
      reference_title: "Srrm2 haploinsufficiency drives SynGAP-γ reduction, Agap3 mis-splicing, and oligodendrocyte deficits in a genetic mouse model of schizophrenia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our findings identify specific synaptic changes, splicing dysregulation,
        and impaired myelination as mechanisms linking SRRM2 haploinsufficiency to
        neuropsychiatric disease.
      explanation: >-
        Supports the mechanistic link at the level of neuropsychiatric disease in a
        model organism; the specific mapping onto the human MRD72 phenotype is not
        demonstrated, hence PARTIAL.

- name: Neurodevelopmental Phenotype
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    The organism-level convergence point: mild developmental delay with
    predominant speech delay, autistic or ADHD features, overfriendliness,
    generalized hypotonia, overweight, and dysmorphic facial features, with
    variable and generally mild intellectual disability. Its downstream edges
    resolve this bundle into the individually curated clinical phenotypes.
  downstream:
  - target: Global Developmental Delay
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35567594
      reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patients presented with a mild developmental delay, predominant
        speech delay
      explanation: The cohort description from which this manifestation is drawn.
  - target: Delayed Speech and Language Development
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35567594
      reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patients presented with a mild developmental delay, predominant
        speech delay
      explanation: The cohort description from which this manifestation is drawn.
  - target: Mild Intellectual Disability
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35567594
      reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Intellectual disability was variable and mild when present.
      explanation: The cohort description from which this manifestation is drawn.
  - target: Autistic Behavior
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35567594
      reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        autistic or attention-deficit/hyperactivity disorder features,
        overfriendliness, generalized hypotonia
      explanation: The cohort description from which this manifestation is drawn.
  - target: Attention Deficit Hyperactivity Disorder
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35567594
      reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        autistic or attention-deficit/hyperactivity disorder features,
        overfriendliness, generalized hypotonia
      explanation: The cohort description from which this manifestation is drawn.
  - target: Overfriendliness
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35567594
      reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        autistic or attention-deficit/hyperactivity disorder features,
        overfriendliness, generalized hypotonia
      explanation: The cohort description from which this manifestation is drawn.
  - target: Generalized Hypotonia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35567594
      reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patients presented with a mild developmental delay, predominant speech
        delay, autistic or attention-deficit/hyperactivity disorder features,
        overfriendliness, generalized hypotonia, overweight, and dysmorphic facial
        features. Intellectual disability was variable and mild when present.
      explanation: The cohort description from which this manifestation is drawn.
  - target: Overweight and Obesity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Overweight is a consistent part of the syndrome, but no mechanism linking
      SRRM2 dosage to energy balance has been established.
    evidence:
    - reference: PMID:35567594
      reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patients presented with a mild developmental delay, predominant speech
        delay, autistic or attention-deficit/hyperactivity disorder features,
        overfriendliness, generalized hypotonia, overweight, and dysmorphic facial
        features. Intellectual disability was variable and mild when present.
      explanation: The cohort description from which this manifestation is drawn.
  - target: Dysmorphic Facial Features
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The craniofacial arm of the syndrome; the developmental route from SRRM2
      dosage to facial gestalt is not established.
    evidence:
    - reference: PMID:35567594
      reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: generalized hypotonia, overweight, and dysmorphic facial features
      explanation: The cohort description from which this manifestation is drawn.
  evidence:
  - reference: PMID:35567594
    reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients presented with a mild developmental delay, predominant speech
      delay, autistic or attention-deficit/hyperactivity disorder features,
      overfriendliness, generalized hypotonia, overweight, and dysmorphic facial
      features. Intellectual disability was variable and mild when present.
    explanation: >-
      The defining clinical description of the disorder from the 22-patient
      cohort.

phenotypes:
- category: Neurologic
  name: Global Developmental Delay
  frequency: VERY_FREQUENT
  description: >-
    Developmental delay is the near-universal presenting feature and is typically
    mild in individuals with protein-truncating point variants.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:35567594
    reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients presented with a mild developmental delay, predominant speech
      delay
    explanation: >-
      Reports developmental delay as the shared presenting feature of the defining
      cohort.
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common findings included developmental/speech delay, autistic traits,
      attention deficit hyperactivity disorder (ADHD), and overfriendliness.
    explanation: >-
      Independent restatement supporting developmental delay as a common finding,
      consistent with the VERY_FREQUENT band.

- category: Neurologic
  name: Delayed Speech and Language Development
  frequency: VERY_FREQUENT
  description: >-
    Speech and language delay is the predominant and most consistently emphasised
    component of the developmental delay in MRD72.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:35567594
    reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients presented with a mild developmental delay, predominant speech
      delay
    explanation: >-
      Identifies speech delay as the predominant component of the delay.

- category: Neurologic
  name: Mild Intellectual Disability
  frequency: FREQUENT
  description: >-
    Intellectual disability is variable and, when present, mild. In the defining
    cohort 16/20 assessable individuals (80%) had mild intellectual disability;
    banded FREQUENT against the full cohort denominator of 22 (73%), since the
    two unassessed individuals are not known to be unaffected.
  phenotype_term:
    preferred_term: Mild intellectual disability
    term:
      id: HP:0001256
      label: Mild intellectual disability
  evidence:
  - reference: PMID:35567594
    reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Intellectual disability was variable and mild when present.
    explanation: >-
      States that intellectual disability is variable in presence and mild in
      degree.
  - reference: PMID:40545495
    reference_title: "Neurodevelopmental disorder and juvenile-onset tics associated with microdeletion of the SRRM2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cuinat et al. first established SRRM2 as a gene responsible for a rare
      neurodevelopmental disease in 22 subjects (14 males, mean age 11 years,
      range 4-28 years) presenting with developmental delay, facial dysmorphism
      (20/22), mild IDD (16/20), ASD (9/22), hypotonia (9/22), obesity (7/22), and
      ADHD (6/22)
    explanation: >-
      Provides the explicit 16/20 (80% of assessable) count behind the FREQUENT
      band for mild intellectual disability.

- category: Behavioral
  name: Autistic Behavior
  frequency: FREQUENT
  description: >-
    Autistic features are reported in a substantial minority of affected
    individuals (9/22 in the defining cohort).
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:40545495
    reference_title: "Neurodevelopmental disorder and juvenile-onset tics associated with microdeletion of the SRRM2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      developmental delay, facial dysmorphism (20/22), mild IDD (16/20), ASD
      (9/22), hypotonia (9/22), obesity (7/22), and ADHD (6/22)
    explanation: >-
      Gives the 9/22 (41%) count for autism spectrum features that grounds the
      FREQUENT band.

- category: Behavioral
  name: Attention Deficit Hyperactivity Disorder
  frequency: FREQUENT
  description: >-
    ADHD features were documented in 6/22 (27%) individuals in the defining
    cohort but in 5/6 of the Genomics England series and 3/3 at a US tertiary
    centre. The band reflects the pooled picture across series rather than the
    defining cohort alone, which by itself would fall in the OCCASIONAL band.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:40545495
    reference_title: "Neurodevelopmental disorder and juvenile-onset tics associated with microdeletion of the SRRM2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      developmental delay, facial dysmorphism (20/22), mild IDD (16/20), ASD
      (9/22), hypotonia (9/22), obesity (7/22), and ADHD (6/22)
    explanation: >-
      Gives the 6/22 (27%) count in the defining cohort - the lower end of the
      range the FREQUENT band spans.
  - reference: PMID:37212523
    reference_title: "Retrospective identification of patients with SRRM2-related neurodevelopmental disorder in a single tertiary children's hospital."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common clinical features include developmental delay, attention deficit
      hyperactivity disorder, macrocephaly, hypotonia, gastroesophageal reflux,
      overweight/obesity, and autism.
    explanation: >-
      Independent series listing ADHD among the common features.
  - reference: PMID:40545495
    reference_title: >-
      Neurodevelopmental disorder and juvenile-onset tics associated with
      microdeletion of the SRRM2 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pagnamenta et al. identified six unrelated patients (3 males and 3 females,
      age range 5-16 years) from the 100 K Genomes Project with loss-of-function
      variants in SRRM2 associated with IDD and facial dysmorphism, as well as
      ADHD (5/6), ASD (4/6), hypotonia (4/6), and obesity (2/6)
    explanation: >-
      Gives the 5/6 (83%) ADHD count in the second cohort, the upper end of the
      range behind the FREQUENT band.

- category: Behavioral
  name: Overfriendliness
  description: >-
    An overly sociable, indiscriminately friendly personality is a characteristic
    behavioural feature emphasised in the defining cohort and recurring in later
    series.
  phenotype_term:
    preferred_term: Overfriendliness
    term:
      id: HP:0100025
      label: Overfriendliness
  evidence:
  - reference: PMID:35567594
    reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      autistic or attention-deficit/hyperactivity disorder features,
      overfriendliness, generalized hypotonia
    explanation: >-
      Names overfriendliness as part of the core behavioural description.
  - reference: PMID:40225164
    reference_title: >-
      A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of
      Complex Structural Variations and SRRM2 Haploinsufficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: she is overly social and happy and has significant learning difficulties
    explanation: >-
      Independent observation of the hypersociable behavioural phenotype in a
      second cohort.
  - reference: PMID:40225164
    reference_title: >-
      A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of
      Complex Structural Variations and SRRM2 Haploinsufficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common findings included developmental/speech delay, autistic traits,
      attention deficit hyperactivity disorder (ADHD), and overfriendliness.
    explanation: >-
      Lists overfriendliness among the common findings of the defining cohort.

- category: Neurologic
  name: Generalized Hypotonia
  frequency: FREQUENT
  description: >-
    Generalized hypotonia, often noted neonatally, was present in 9/22 individuals
    in the defining cohort and recurs across subsequent series.
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:35567594
    reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients presented with a mild developmental delay, predominant speech
      delay, autistic or attention-deficit/hyperactivity disorder features,
      overfriendliness, generalized hypotonia, overweight, and dysmorphic facial
      features. Intellectual disability was variable and mild when present.
    explanation: Lists generalized hypotonia among the core features.
  - reference: PMID:40545495
    reference_title: "Neurodevelopmental disorder and juvenile-onset tics associated with microdeletion of the SRRM2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      developmental delay, facial dysmorphism (20/22), mild IDD (16/20), ASD
      (9/22), hypotonia (9/22), obesity (7/22), and ADHD (6/22)
    explanation: >-
      Gives the 9/22 (41%) count supporting the FREQUENT band.

- category: Metabolic
  name: Overweight and Obesity
  frequency: FREQUENT
  description: >-
    Over half the defining cohort was described as overweight; frank obesity was
    recorded in 7/22. Weight gain also recurs in the structural-variant cohort.
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  evidence:
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Over 50% of the published cohort
    explanation: >-
      The sentence subject; the clause continues "were described to be
      overweight" after an intervening bracketed citation marker that is stripped
      before substring matching, so the two halves are quoted separately.
  - reference: PMID:40225164
    reference_title: >-
      A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of
      Complex Structural Variations and SRRM2 Haploinsufficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      were described to be overweight and that was also noted in two of our
      patients
    explanation: >-
      The predicate of the same sentence, stating that over half the defining
      cohort was overweight and that the finding recurred in the second cohort -
      together supporting the FREQUENT band.
  - reference: PMID:40545495
    reference_title: "Neurodevelopmental disorder and juvenile-onset tics associated with microdeletion of the SRRM2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild IDD (16/20), ASD (9/22), hypotonia (9/22), obesity (7/22), and ADHD
      (6/22)
    explanation: >-
      Gives the 7/22 count for frank obesity within the same cohort.

- category: Craniofacial
  name: Dysmorphic Facial Features
  frequency: VERY_FREQUENT
  description: >-
    Facial dysmorphism was recorded in 20/22 individuals in the defining cohort.
    Recurrent features across cohorts include large ears and earlobes, thin lips,
    a bulbous nose, and geographic tongue; individual feature frequencies are not
    reported in the sources available here.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:40545495
    reference_title: "Neurodevelopmental disorder and juvenile-onset tics associated with microdeletion of the SRRM2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presenting with developmental delay, facial dysmorphism (20/22), mild IDD
      (16/20)
    explanation: >-
      Gives the 20/22 (91%) count for facial dysmorphism, supporting the
      VERY_FREQUENT band.
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A number of features occur in more than one case, and this includes
      geographic tongue (Figure 3(a)), large ears/earlobes (Figures 3(b) and
      3(h)), thin lips and a bulbous nose (Figures 3(c), 3(f), and 3(g)), small
      hands with tapering fingers (Figures 3(d) and 3(i)), and large halluces
    explanation: >-
      Enumerates the recurrent dysmorphic features observed across the
      structural-variant cohort.

- category: Craniofacial
  name: Macrotia
  description: >-
    Large ears or fleshy earlobes recur across independent SRRM2 cohorts.
  phenotype_term:
    preferred_term: Macrotia
    term:
      id: HP:0000400
      label: Macrotia
  evidence:
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      this includes geographic tongue (Figure 3(a)), large ears/earlobes (Figures
      3(b) and 3(h))
    explanation: Documents large ears/earlobes as a recurrent feature.

- category: Craniofacial
  name: Bulbous Nose
  description: A broad or bulbous nasal tip recurs across affected individuals.
  phenotype_term:
    preferred_term: Bulbous nose
    term:
      id: HP:0000414
      label: Bulbous nose
  evidence:
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      thin lips and a bulbous nose (Figures 3(c), 3(f), and 3(g))
    explanation: Documents bulbous nose as a recurrent dysmorphic feature.

- category: Craniofacial
  name: Thin Upper Lip Vermilion
  description: Thin lips recur among the facial dysmorphic features.
  phenotype_term:
    preferred_term: Thin vermilion border
    term:
      id: HP:0000233
      label: Thin vermilion border
  evidence:
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      thin lips and a bulbous nose (Figures 3(c), 3(f), and 3(g))
    explanation: Documents thin lips as a recurrent dysmorphic feature.

- category: Craniofacial
  name: Geographic Tongue
  description: >-
    Geographic tongue was observed in more than one individual in the
    structural-variant cohort.
  phenotype_term:
    preferred_term: Geographic tongue
    term:
      id: HP:0025252
      label: Geographic tongue
  evidence:
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A number of features occur in more than one case, and this includes
      geographic tongue (Figure 3(a))
    explanation: Documents geographic tongue as a recurrent feature.

- category: Musculoskeletal
  name: Tapered Fingers
  description: Tapering fingers recur across independent SRRM2 cohorts.
  phenotype_term:
    preferred_term: Tapered finger
    term:
      id: HP:0001182
      label: Tapered finger
  evidence:
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      small hands with tapering fingers (Figures 3(d) and 3(i)), and large
      halluces
    explanation: Documents tapering fingers as a recurrent feature.

- category: Musculoskeletal
  name: Small Hands
  description: >-
    Small hands recur across cohorts; short hands were separately reported in the
    missense-variant case.
  phenotype_term:
    preferred_term: Small hand
    term:
      id: HP:0200055
      label: Small hand
  evidence:
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: small hands with tapering fingers
    explanation: Documents small hands as a recurrent feature.
  - reference: PMID:40046925
    reference_title: "Rare SRRM2 mutation in neurodevelopmental disorders involving hyperphagia triggering severe obesity and other complication."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      macrocephaly, short hands and feet, hyperphagia, and hypotonia
    explanation: >-
      Independent case report documenting short hands in an SRRM2 patient.

- category: Musculoskeletal
  name: Short Feet
  description: >-
    Short feet were reported in the missense-variant case, alongside short hands.
  phenotype_term:
    preferred_term: Short foot
    term:
      id: HP:0001773
      label: Short foot
  evidence:
  - reference: PMID:40046925
    reference_title: "Rare SRRM2 mutation in neurodevelopmental disorders involving hyperphagia triggering severe obesity and other complication."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      macrocephaly, short hands and feet, hyperphagia, and hypotonia
    explanation: Documents short feet in this patient.

- category: Musculoskeletal
  name: Broad Hallux
  description: >-
    Large halluces (prominent great toes) recur across the Genomics England
    series.
  phenotype_term:
    preferred_term: Broad hallux
    term:
      id: HP:0010055
      label: Broad hallux
  evidence:
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      small hands with tapering fingers (Figures 3(d) and 3(i)), and large
      halluces
    explanation: >-
      Documents large halluces as a recurrent feature. PARTIAL because the source
      says "large", which HPO does not resolve into broad versus long; the
      broad-hallux term is the closest available binding.


- category: Neurologic
  name: Macrocephaly
  description: >-
    Macrocephaly was listed among the common features in a US tertiary-centre
    series and in the missense-variant case report. Note that the opposite finding
    (microcephaly) predominates in the large-deletion subgroup, so head size is
    not a uniform feature of the disorder.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:37212523
    reference_title: "Retrospective identification of patients with SRRM2-related neurodevelopmental disorder in a single tertiary children's hospital."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common clinical features include developmental delay, attention deficit
      hyperactivity disorder, macrocephaly, hypotonia, gastroesophageal reflux,
      overweight/obesity, and autism.
    explanation: >-
      Lists macrocephaly among the common features of the CHOP series.

- category: Gastrointestinal
  name: Gastroesophageal Reflux
  description: >-
    Gastroesophageal reflux was listed among the common features of the CHOP
    series.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:37212523
    reference_title: "Retrospective identification of patients with SRRM2-related neurodevelopmental disorder in a single tertiary children's hospital."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common clinical features include developmental delay, attention deficit
      hyperactivity disorder, macrocephaly, hypotonia, gastroesophageal reflux,
      overweight/obesity, and autism.
    explanation: Lists gastroesophageal reflux among the common features.

- category: Neurologic
  name: Microcephaly
  description: >-
    Microcephaly was reported in half of the Genomics England series, against
    only 1/22 in the defining cohort. This is a series-level contrast: the
    Genomics England group comprised four whole-gene deletions plus two
    protein-truncating point variants, and the defining cohort itself included
    two microdeletions, so the difference cannot be attributed to deletion size
    on this evidence. Note also that macrocephaly is reported elsewhere in this
    entry - head size is not uniform in MRD72.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microcephaly was reported for half the individuals described here but only
      in 1/22 of the previous cases.
    explanation: >-
      Directly contrasts microcephaly frequency between the two published series.

- category: Neurologic
  name: Seizures
  description: >-
    Seizures were present in 2/6 individuals in the Genomics England series and
    were not reported in the defining cohort. Note that both seizure cases
    carried protein-truncating point variants rather than whole-gene deletions
    (P5, a 16 bp frameshift; P6, p.(Arg632*)), so seizures are NOT a marker of
    the deletion subtype - and P6 additionally carried biallelic pathogenic
    SLC17A5 variants, which the authors flag as a blended phenotype. Recorded
    without a frequency band.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similarly, seizures were present in 2/6 of our patients but this feature was
      not reported previously.
    explanation: >-
      States the seizure frequency in the deletion cohort and its absence from the
      earlier cohort.

- category: Neurologic
  name: Tics
  description: >-
    A single 30-year-old man with a 16p13.3 microdeletion developed late-onset
    simple motor and vocal tics progressing to handwriting and catatonic tics
    (Yale Global Tic Severity Scale 55/100), without the hypotonia, dysmorphism,
    or obesity typical of the syndrome. This is a single observation and is
    recorded without a frequency band.
  phenotype_term:
    preferred_term: Tics
    term:
      id: HP:0100033
      label: Tics
  evidence:
  - reference: PMID:40545495
    reference_title: "Neurodevelopmental disorder and juvenile-onset tics associated with microdeletion of the SRRM2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We document the rare case of a 30-year-old man diagnosed with
      neurodevelopmental disorder and juvenile-onset tics associated with a
      microdeletion involving the SRRM2 gene.
    explanation: >-
      The single reported case of tics in SRRM2-related neurodevelopmental
      disorder.
  - reference: PMID:40545495
    reference_title: "Neurodevelopmental disorder and juvenile-onset tics associated with microdeletion of the SRRM2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of these, 21 were males and none had tics as part of their neurodevelopmental
      manifestations.
    explanation: >-
      Establishes that tics were absent from all 37 previously reported cases,
      qualifying this as an isolated observation rather than a syndrome feature.

- category: Metabolic
  name: Hyperphagia
  description: >-
    Uncontrolled hyperphagia driving rapid weight gain to severe obesity (BMI 44.6
    at age 17) was reported in one patient with a de novo missense variant in the
    SRRM2 intrinsically disordered region. Excessive eating was also noted in one
    individual in the Genomics England cohort.
  phenotype_term:
    preferred_term: Polyphagia
    term:
      id: HP:0002591
      label: Polyphagia
  evidence:
  - reference: PMID:40046925
    reference_title: "Rare SRRM2 mutation in neurodevelopmental disorders involving hyperphagia triggering severe obesity and other complication."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, the patient became overweight and subsequently developed several
      obesity-related complications due to uncontrolled hyperphagia.
    explanation: >-
      Documents hyperphagia as the driver of the severe obesity in this case.
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She enjoyed eating and would eat excessively if allowed to do so.
    explanation: >-
      Independent observation of excessive eating in a second SRRM2 cohort.

- category: Respiratory
  name: Persistent Tachypnoea of Infancy
  description: >-
    De novo SRRM2 loss-of-function variants were identified in 4/71 patients with
    neuroendocrine cell hyperplasia of infancy / persistent tachypnoea of infancy,
    all of whom also had mild neurodevelopmental delay - extending the SRRM2
    phenotypic spectrum to childhood interstitial lung disease.
  phenotype_term:
    preferred_term: Tachypnea
    term:
      id: HP:0002789
      label: Tachypnea
  evidence:
  - reference: PMID:40967764
    reference_title: "D e novo SRRM2 variants in neuroendocrine cell hyperplasia of infancy and persistent tachypnoea of infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four de novo loss-of-function (LoF) variants of SRRM2 were identified in
      four out of 71 NEHI/PTI patients with typical pulmonary presentation.
    explanation: >-
      Establishes SRRM2 loss of function as a monogenic cause of NEHI/PTI.
  - reference: PMID:40967764
    reference_title: "D e novo SRRM2 variants in neuroendocrine cell hyperplasia of infancy and persistent tachypnoea of infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study identifies SRRM2-related disorder as a monogenic cause of
      NEHI/PTI.
    explanation: >-
      Explicit conclusion extending the SRRM2 phenotypic spectrum to this
      respiratory presentation.

- category: Cardiovascular
  name: Congestive Heart Failure
  description: >-
    Stage IV cardiac insufficiency at age 17 in the hyperphagia/severe-obesity
    case. A consequence of the obesity phenotype rather than a direct SRRM2
    effect.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:40046925
    reference_title: "Rare SRRM2 mutation in neurodevelopmental disorders involving hyperphagia triggering severe obesity and other complication."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This hospitalization led to the diagnosis of cardiogenic insufficiency,
      classified as stage IV cardiac function, along with stage I hypertension and
      hyperlipidemia. The clinical picture was further complicated by the
      identification of sleep apnea syndrome.
    explanation: >-
      Documents the stage IV cardiac insufficiency that followed severe obesity in
      this patient.

- category: Cardiovascular
  name: Hypertension
  description: >-
    Stage I hypertension at age 17 in the hyperphagia/severe-obesity case; a
    consequence of the obesity phenotype rather than a direct SRRM2 effect.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:40046925
    reference_title: >-
      Rare SRRM2 mutation in neurodevelopmental disorders involving hyperphagia
      triggering severe obesity and other complication.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      along with stage I hypertension and hyperlipidemia
    explanation: Documents the hypertension in this patient.

- category: Metabolic
  name: Hyperlipidemia
  description: >-
    Hyperlipidemia at age 17 in the hyperphagia/severe-obesity case; a consequence
    of the obesity phenotype rather than a direct SRRM2 effect.
  phenotype_term:
    preferred_term: Hyperlipidemia
    term:
      id: HP:0003077
      label: Hyperlipidemia
  evidence:
  - reference: PMID:40046925
    reference_title: >-
      Rare SRRM2 mutation in neurodevelopmental disorders involving hyperphagia
      triggering severe obesity and other complication.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      along with stage I hypertension and hyperlipidemia
    explanation: Documents the hyperlipidemia in this patient.

- category: Respiratory
  name: Sleep Apnea
  description: >-
    Sleep apnea syndrome at age 17 in the hyperphagia/severe-obesity case; a
    consequence of the obesity phenotype rather than a direct SRRM2 effect.
  phenotype_term:
    preferred_term: Sleep apnea
    term:
      id: HP:0010535
      label: Sleep apnea
  evidence:
  - reference: PMID:40046925
    reference_title: >-
      Rare SRRM2 mutation in neurodevelopmental disorders involving hyperphagia
      triggering severe obesity and other complication.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical picture was further complicated by the identification of sleep
      apnea syndrome.
    explanation: Documents the sleep apnea in this patient.

has_subtypes:
- name: Large 16p13.3 deletion
  display_name: Large contiguous 16p13.3 deletion including SRRM2
  description: >-
    Individuals carrying whole-gene deletions of SRRM2 (248-482 kb in the
    Genomics England series, 66-270 kb in the defining cohort) rather than
    protein-truncating point variants. The subtype is defined by lesion
    architecture, which is well characterised: distal breakpoints cluster within
    a 144 kb palindrome-like structure 75 kb upstream of SRRM2, and three of the
    four Genomics England deletions carried inverted internal segments of 45-94
    kb. A severity difference is often attributed to this subtype but is NOT
    established: the moderate-to-severe intellectual disability reported by
    Genomics England describes all six of their patients (four deletions plus two
    point variants) versus the defining cohort as a whole (which itself contained
    two microdeletions), two of the six carried co-occurring pathogenic variants
    in other genes, and both seizure cases were point-variant carriers. See the
    mrd72_genotype_severity_gradient discussion.
  evidence:
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ID was observed in all 6 individuals described here and ranged from moderate
      to severe, whereas in the published cohort, the level of ID was typically
      mild.
    explanation: >-
      The severity statement usually cited for this subtype. Note it compares the
      six Genomics England patients (a mixed deletion/point-variant group) with
      the defining cohort, so it is a series-level rather than genotype-level
      contrast.
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deletions ranged between 248 and 482 kb in size and all distal breakpoints
      clustered within a complex 144 kb palindrome situated 75 kb upstream of
      SRRM2. Strikingly, three of the deletions were complex, with inverted
      internal segments of 45-94 kb.
    explanation: >-
      Defines the structural architecture underlying this subtype.

genetic:
- name: SRRM2
  gene_term:
    preferred_term: SRRM2
    term:
      id: hgnc:16639
      label: SRRM2
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  presence: PRESENT
  notes: >-
    SRRM2 at 16p13.3 encodes SRm300, a 2,752-amino-acid SR-related splicing factor
    and nuclear speckle scaffold. Heterozygous loss of function - by frameshift,
    nonsense, canonical splice-site variant, or whole-gene deletion - is the sole
    established cause of MRD72. The gene was first robustly implicated by de novo
    mutation enrichment across 31,058 developmental-disorder trios.
  evidence:
  - reference: PMID:35567594
    reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report on 22 patients with LoF variants in SRRM2 and provide a
      description of the phenotype.
    explanation: >-
      The defining gene-disease study establishing SRRM2 loss of function as
      causal.
  - reference: PMID:35567594
    reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We established SRRM2 as a gene responsible for a rare neurodevelopmental
      disease.
    explanation: Explicit gene-disease conclusion.
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SRRM2, a 15 exon gene that encodes a 2,752 amino acid splicing factor, was
      one of 28 genes that showed a strong enrichment for de novo mutations, but
      which had not previously been robustly linked to developmental disorders.
      Enrichment was driven primarily by protein-truncating variants
    explanation: >-
      Records the statistical de novo enrichment that first implicated SRRM2 and
      confirms protein-truncating variants as the driving class.
  variants:
  - name: Recurrent arginine-to-stop variants (CpG deamination)
    description: >-
      SRRM2 is arginine-rich (468/2,752 residues) and correspondingly CpG-dense,
      making it a high-risk gene for de novo nonsense variants arising by
      deamination of methylated cytosine. Four of the 22 variants in the defining
      cohort were Arg-to-Ter changes, and p.(Arg632*) reported in the Genomics
      England series lies close to the previously reported p.(Arg628*).
    gene:
      preferred_term: SRRM2
      term:
        id: hgnc:16639
        label: SRRM2
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:40225164
      reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        As SRRM2 encodes an arginine-rich protein (468/2,752 residues), it
        contains a relatively high number of CpG dinucleotides rendering it a
        high-risk gene for de novo nonsense variants via deamination of methylated
        cytosine. Of the 22 variants reported by Cuinat et al., 4 were Arg - > Ter
        variants.
      explanation: >-
        Establishes CpG deamination as a recurrent mutational mechanism at this
        locus.
  - name: MSP-associated missense variant disrupting the SRRM2-ACIN1 interaction
    description: >-
      A co-segregating SRRM2 missense variant reported in a family with
      dominantly inherited multisystem proteinopathy - a degenerative
      nervous-system/muscle/bone disorder, NOT MRD72. Knock-in of the single
      amino-acid change abolished the SRRM2-ACIN1 protein-protein interaction and
      produced widespread expression change converging on synapse-associated
      pathways. Recorded here as an allelic-spectrum contrast: it indicates that
      SRRM2 missense alleles can act through a mechanism other than the
      haploinsufficiency that causes MRD72, and such variants should not be
      assumed to cause this disorder.
    gene:
      preferred_term: SRRM2
      term:
        id: hgnc:16639
        label: SRRM2
    evidence:
    - reference: PMID:42309671
      reference_title: "A mutation in the nuclear speckle and splicing factor SRRM2 is associated with multisystem proteinopathy and causes dysregulation of synapse-associated genes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here, we describe a family with dominantly inherited MSP, in which a
        mutation in the serine/arginine repetitive matrix protein 2 gene (SRRM2)
        that co-segregates with disease, is identified.
      explanation: >-
        Establishes a distinct SRRM2-associated dominant disease, separate from
        MRD72.
    - reference: PMID:42309671
      reference_title: "A mutation in the nuclear speckle and splicing factor SRRM2 is associated with multisystem proteinopathy and causes dysregulation of synapse-associated genes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we found that the resulting single amino acid exchange led to the loss of
        protein-protein interaction between SRRM2 and the splicing factor ACIN1
      explanation: >-
        Identifies a non-haploinsufficiency molecular consequence for this allele
        class.
  - name: p.Gln1554Leu (intrinsically disordered region missense)
    description: >-
      A de novo missense variant NM_016333:c.4661A>T (p.Q1554L) in the SRRM2
      intrinsically disordered region, classified Likely Pathogenic, reported in a
      patient with a hyperphagia-driven severe obesity presentation. This is the
      principal reported non-truncating candidate; the disorder's mechanism is
      otherwise haploinsufficiency.
    gene:
      preferred_term: SRRM2
      term:
        id: hgnc:16639
        label: SRRM2
    clinical_significance: LIKELY_PATHOGENIC
    evidence:
    - reference: PMID:40046925
      reference_title: "Rare SRRM2 mutation in neurodevelopmental disorders involving hyperphagia triggering severe obesity and other complication."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we identified a novel missense mutation in SRRM2 (NM_016333: c.4661A > T,
        p.Q1554L). This mutation is classified as "Likely Pathogenic" based on the
        American College of Medical Genetics and Genomics (ACMG) guideline.
      explanation: >-
        Reports the variant and its ACMG classification.

diagnosis:
- name: Trio exome or genome sequencing
  description: >-
    Essentially all reported cases were ascertained by exome or genome sequencing,
    usually as parent-child trios to establish de novo status. Genome sequencing
    is preferred where a structural variant is suspected, because the 16p13.3
    deletions are frequently complex and were missed or under-resolved by
    array-based testing in reported cases.
  evidence:
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data highlights the benefits of genome sequencing for resolving
      structural complexity and inferring de novo status.
    explanation: >-
      States the diagnostic advantage of genome sequencing for this locus.
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Array-based testing had yielded a normal result, albeit at a low resolution.
    explanation: >-
      Documents a false-negative microarray result in a patient with an SRRM2
      deletion, supporting sequencing-based workup.
- name: SRRM2 sequencing in NEHI/PTI workup
  description: >-
    Because SRRM2 loss-of-function variants explain a substantial fraction of
    neuroendocrine cell hyperplasia of infancy / persistent tachypnoea of infancy,
    SRRM2 sequencing has been proposed as part of the standard workup for that
    presentation, with paediatric neurology assessment.
  evidence:
  - reference: PMID:40967764
    reference_title: "D e novo SRRM2 variants in neuroendocrine cell hyperplasia of infancy and persistent tachypnoea of infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results suggest that NEHI/PTI patients should be evaluated by a
      paediatric neurologist and that SRRM2 sequencing should be included in every
      NEHI/PTI workup.
    explanation: Explicit diagnostic recommendation from the NEHI/PTI cohort study.

treatments:
- name: Speech and Language Therapy
  description: >-
    Speech delay is the predominant developmental feature, making speech and
    language therapy a core element of management. No disease-specific therapy
    exists; management is symptomatic and supportive.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  target_phenotypes:
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:35567594
    reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients presented with a mild developmental delay, predominant speech
      delay
    explanation: >-
      Establishes speech delay as the predominant treatable feature. No trial or
      outcome data for speech therapy in this disorder exist, so the evidence
      supports the indication rather than the efficacy - hence PARTIAL.

- name: Physical Therapy
  description: >-
    Physiotherapy for generalized hypotonia and delayed motor development, as part
    of standard early-intervention care.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:35567594
    reference_title: "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients presented with a mild developmental delay, predominant speech
      delay, autistic or attention-deficit/hyperactivity disorder features,
      overfriendliness, generalized hypotonia, overweight, and dysmorphic facial
      features. Intellectual disability was variable and mild when present.
    explanation: >-
      Documents the hypotonia that constitutes the indication. No efficacy data
      exist in this disorder, hence PARTIAL.

- name: Clonidine for Tic Management
  description: >-
    An alpha-2 agonist was recommended as a first-line anti-tic agent in the
    single reported SRRM2 patient with tics, after serotonergic and
    antidopaminergic agents were discontinued for lack of durable benefit. This
    reflects standard tic-disorder practice applied to one case, not
    SRRM2-specific evidence.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: clonidine
      term:
        id: CHEBI:46631
        label: clonidine
  target_phenotypes:
  - preferred_term: Tics
    term:
      id: HP:0100033
      label: Tics
  evidence:
  - reference: PMID:40545495
    reference_title: "Neurodevelopmental disorder and juvenile-onset tics associated with microdeletion of the SRRM2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recommendations were made for a first-line anti-tic agent (alpha-2 agonist
      Clonidine) for prolonged relapses in tic severity.
    explanation: >-
      Records the specific treatment recommendation made in the reported case.

- name: Dietary Intervention for Hyperphagia and Obesity
  description: >-
    Strict dietary management was recommended for hyperphagia in the reported
    obesity case. Notably, poor adherence was followed by progression to morbid
    obesity with cardiometabolic complications, illustrating both the rationale
    for and the practical limits of dietary management in this phenotype.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_phenotypes:
  - preferred_term: Polyphagia
    term:
      id: HP:0002591
      label: Polyphagia
  evidence:
  - reference: PMID:40046925
    reference_title: "Rare SRRM2 mutation in neurodevelopmental disorders involving hyperphagia triggering severe obesity and other complication."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An interview with the parents suggested hyperphagia as an associated
      phenotype, leading to recommendations for strict dietary management. Despite
      these recommendations, the primary guardians' inadequate adherence to the
      dietary guidelines led to rapid weight gain, resulting in morbid obesity and
      related health complications over the years.
    explanation: >-
      Documents both the recommendation and its failure under poor adherence -
      supporting the indication but not demonstrating efficacy, hence PARTIAL.

- name: Genetic Counseling
  description: >-
    Genetic counseling is indicated for all families, covering the predominantly
    de novo mechanism, the 50% recurrence risk where a parent is affected, and the
    availability of prenatal diagnosis when the familial variant is known.
    Prenatal testing has been performed in reported pedigrees.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:37621647
    reference_title: "Familial and genetic association with neurodevelopmental disorders caused by a heterozygous variant in the SRRM2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prenatal diagnosis can help patients with this genetic disorder to have
      healthy offspring.
    explanation: >-
      States the reproductive-counseling application demonstrated in a
      multigenerational SRRM2 family.
  - reference: PMID:42342640
    reference_title: "[Prenatal diagnosis and genetics analysis of a fetus with type 27 intellectual disability syndrome due to variant of SRRM2 gene]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Amniotic fluid and peripheral blood samples were collected from the fetus
      and its parents for genomic DNA extraction. Whole-exome sequencing (WES)
      was carried out, and candidate variants were verified by Sanger sequencing
      of the family members and rated based on guidelines from the American
      College of Medical Genetics and Genomics (ACMG).
    explanation: >-
      Documents the concrete prenatal-diagnosis workflow (amniocentesis, trio
      WES, Sanger confirmation, ACMG classification) applied in an MRD72
      pregnancy.

animal_models:
- name: Srrm2 heterozygous knockout mouse (brain phenotyping)
  species: Mouse
  genotype: Srrm2+/-
  category: GENETIC
  description: >-
    Constitutive heterozygous Srrm2 mice, modelling the human haploinsufficiency
    mechanism directly. They show transcriptomic change across neuronal and glial
    populations, reduced SynGAP-gamma with elevated Agap3, reduced striatal
    oligodendrocyte proportions with decreased myelin gene and protein expression,
    reduced locomotor activity, impaired startle, and reduced EEG sleep spindles.
  publication: PMID:42189682
  modeled_mechanisms:
  - target: Impaired Neuronal and Oligodendrocyte Development
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the cellular and molecular consequences of Srrm2
      haploinsufficiency in brain at the same allelic dosage as human disease.
    limitations: >-
      The model was developed and interpreted as a genetic model of schizophrenia;
      its behavioural and electrophysiological readouts (locomotor activity,
      startle, sleep spindles) have no established counterpart in MRD72 patients,
      and it does not address the craniofacial dysmorphism, speech delay,
      overfriendliness, or obesity that define the human syndrome.
    readouts:
    - name: Striatal oligodendrocyte proportion
      target: Impaired Neuronal and Oligodendrocyte Development
      direction: DECREASED
      interpretation: >-
        Cellular correlate of the impaired-glial-development node in this model.
      evidence:
      - reference: PMID:42189682
        reference_title: "Srrm2 haploinsufficiency drives SynGAP-γ reduction, Agap3 mis-splicing, and oligodendrocyte deficits in a genetic mouse model of schizophrenia."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          reduced oligodendrocyte proportions, particularly in the striatum,
          accompanied by decreased expression of myelin-related mRNAs and proteins
        explanation: >-
          Reports the oligodendrocyte and myelin measurements behind this readout.
    - name: SynGAP gamma isoform abundance
      target: Impaired Neuronal and Oligodendrocyte Development
      direction: DECREASED
      interpretation: >-
        Post-synaptic protein readout of the splicing defect in this model.
      evidence:
      - reference: PMID:42189682
        reference_title: "Srrm2 haploinsufficiency drives SynGAP-γ reduction, Agap3 mis-splicing, and oligodendrocyte deficits in a genetic mouse model of schizophrenia."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          reduction of the gamma isoform of SynGAP and elevation of its
          interactor, Agap3
        explanation: Reports the post-synaptic isoform measurement.
    evidence:
    - reference: PMID:42189682
      reference_title: "Srrm2 haploinsufficiency drives SynGAP-γ reduction, Agap3 mis-splicing, and oligodendrocyte deficits in a genetic mouse model of schizophrenia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We find that Srrm2+/- mice exhibit (1) large-scale changes in gene
        expression in neuronal and glial cells, affecting DNA-binding-, synapse-,
        translation-, mitochondria-related pathways across multiple brain regions
      explanation: >-
        The model's own primary result, establishing that the same heterozygous
        dosage as human disease produces measurable neuronal and glial change -
        which is what makes it informative for this node.

experimental_models:
- name: Srrm2 heterozygous mouse embryonic stem cells
  description: >-
    Constitutively Srrm2-heterozygous mouse embryonic stem cells, plus transient
    RNA-interference depletion, used to dissect the earliest consequences of
    reduced Srrm2 dosage. Heterozygous cells lose stemness, co-expressing naive
    and formative pluripotency markers; transient depletion shows that specific
    alternative splicing events precede the broader expression changes.
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  cell_types:
  - preferred_term: embryonic stem cell
    term:
      id: CL:0002322
      label: embryonic stem cell
  publication: PMID:38656788
  modeled_mechanisms:
  - target: Loss of Stemness and Altered Lineage Commitment
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Directly demonstrates the stemness and lineage-commitment consequences of
      heterozygous Srrm2 loss at the same allelic dosage as human disease.
    limitations: >-
      Mouse embryonic stem cells in culture, not human tissue; the link between
      early-embryonic stemness defects and the postnatal MRD72 phenotype is
      inferred rather than shown.
    evidence:
    - reference: PMID:38656788
      reference_title: "SRRM2 splicing factor modulates cell fate in early development."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we show that Srrm2 dosage is critical for maintaining embryonic stem cell
        pluripotency and cell identity
      explanation: >-
        States the dosage-dependent stemness finding this model establishes.

- name: SRRM2-deficient human iPSC-derived neurons
  description: >-
    Human induced pluripotent stem cell-derived neurons with SRRM2 deficiency,
    used to test whether the mouse splicing findings hold in a human neuronal
    context. AGAP3 splicing defects are conserved.
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  publication: PMID:42189682
  modeled_mechanisms:
  - target: Alternative Pre-mRNA Splicing Dysregulation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Confirms in human neurons the specific mis-splicing event identified in the
      mouse model, bridging the species gap for this arm of the mechanism.
    limitations: >-
      Only the AGAP3 event was reported as conserved; the wider murine splicing
      and myelination findings were not tested in the human system, and iPSC-derived
      neurons do not model the circuit-level or systemic features of the disorder.
    readouts:
    - name: AGAP3 splicing
      target: Alternative Pre-mRNA Splicing Dysregulation
      direction: ALTERED
      interpretation: >-
        Human neuronal confirmation of the mis-splicing signature of SRRM2
        deficiency.
      evidence:
      - reference: PMID:42189682
        reference_title: "Srrm2 haploinsufficiency drives SynGAP-γ reduction, Agap3 mis-splicing, and oligodendrocyte deficits in a genetic mouse model of schizophrenia."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Human induced pluripotent stem cell (iPSC)-derived neurons deficient in
          SRRM2 display conserved AGAP3 splicing defects.
        explanation: Reports the human neuronal splicing measurement.
    evidence:
    - reference: PMID:42189682
      reference_title: "Srrm2 haploinsufficiency drives SynGAP-γ reduction, Agap3 mis-splicing, and oligodendrocyte deficits in a genetic mouse model of schizophrenia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Human induced pluripotent stem cell (iPSC)-derived neurons deficient in
        SRRM2 display conserved AGAP3 splicing defects.
      explanation: >-
        Supports treating this human cellular model as informative for the
        splicing-dysregulation node.

discussions:
- discussion_id: mrd72_mouse_model_translational_validity
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Neuronal and Oligodendrocyte Development
  prompt: >-
    Does the Srrm2+/- mouse brain phenotype - reduced striatal oligodendrocytes,
    impaired myelination, reduced sleep spindles, blunted startle - correspond to
    anything measurable in people with MRD72, whose defining features are speech
    delay, overfriendliness, hypotonia, and overweight?
  rationale: >-
    The Srrm2+/- mouse has excellent construct validity: the same gene, the same
    heterozygous dosage. But it was built and interpreted as a genetic model of
    schizophrenia, and its readouts were chosen accordingly. None of the human
    MRD72 features - the predominant speech delay, the characteristic
    overfriendliness, the facial dysmorphism, the overweight - has a murine
    counterpart in the published phenotyping, and no MRD72 patient series reports
    EEG sleep-spindle or myelin-imaging data. The mouse therefore substantiates
    the molecular arm of the mechanism (splicing, synaptic protein isoforms,
    oligodendrocytes) while leaving the mapping onto the human syndrome
    undetermined. This matters for curation because the myelination and
    oligodendrocyte nodes rest entirely on this model.
  proposed_experiments:
  - experiment_id: mrd72_white_matter_imaging
    name: Neuroimaging of white matter in MRD72 patients
    description: >-
      Diffusion MRI in a genotype-confirmed MRD72 cohort against matched controls,
      to test whether the murine myelin deficit has a human structural correlate.
  - experiment_id: mrd72_sleep_eeg_spindles
    name: Sleep EEG in MRD72 patients
    description: >-
      Overnight polysomnography with spindle quantification in MRD72 patients, the
      direct human counterpart of the murine EEG finding.
  evidence:
  - reference: PMID:42189682
    reference_title: "Srrm2 haploinsufficiency drives SynGAP-γ reduction, Agap3 mis-splicing, and oligodendrocyte deficits in a genetic mouse model of schizophrenia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      electroencephalogram (EEG) recordings reveal reduced sleep spindles
      resembling humans with schizophrenia
    explanation: >-
      The model's headline neurophysiological readout is framed against
      schizophrenia rather than against the MRD72 phenotype, which is the mismatch
      at issue.

- discussion_id: mrd72_speckle_dosage_threshold
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Nuclear Speckle Scaffold Disruption
  prompt: >-
    Is a 50% reduction in SRRM2 dosage - the actual lesion in MRD72 - sufficient
    to degrade nuclear speckle architecture, or are speckles buffered against
    heterozygous loss?
  rationale: >-
    Every published demonstration that speckles depend on SRRM2 used a much
    harsher perturbation than the disease: co-depletion of both SON and SRRM2,
    depletion of SON in a line whose SRRM2 intrinsically disordered regions had
    been genetically deleted, or acute degron depletion. None tested the
    heterozygous state. Because SON remains at full dosage in MRD72, speckles may
    well be largely preserved, in which case the disease-relevant consequence of
    SRRM2 haploinsufficiency runs through the spliceosome-catalytic-centre role
    rather than through speckle architecture. This is the single largest
    uncertainty in the entry's pathograph, and it is why the speckle node is
    marked PROVISIONAL while the splicing node is ESTABLISHED.
  proposed_experiments:
  - experiment_id: mrd72_speckle_morphometry_heterozygous
    name: Speckle morphometry in SRRM2-heterozygous human cells
    description: >-
      Quantitative imaging of nuclear speckle number, size, and sphericity in
      isogenic SRRM2+/- human cells (and, where available, patient-derived
      fibroblasts or iPSC-derived neurons) against wild-type, to test whether the
      disease-relevant dosage measurably alters speckle architecture.
  - experiment_id: mrd72_speckle_vs_splicing_separation
    name: Separation of the speckle and catalytic-centre contributions
    description: >-
      Compare transcriptome-wide splicing in SRRM2+/- cells against cells
      carrying a separation-of-function allele that preserves the spliceosomal
      N-terminus while deleting the speckle-driving IDRs, to apportion the
      splicing defect between the two roles.
  evidence:
  - reference: PMID:33095160
    reference_title: SON and SRRM2 are essential for nuclear speckle formation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      depletion of SON leads only to a partial disassembly of NS, while
      co-depletion of SON and SRRM2 or depletion of SON in a cell-line where
      intrinsically disordered regions (IDRs) of SRRM2 are genetically deleted,
      leads to a near-complete dissolution of NS
    explanation: >-
      Shows that the published speckle-dissolution result required perturbing
      both scaffolds, never SRRM2 haploinsufficiency alone - which is the gap.

- discussion_id: mrd72_genotype_severity_gradient
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#SRRM2 Haploinsufficiency
  prompt: >-
    Is the more severe phenotype of large 16p13.3 deletions (moderate-to-severe
    intellectual disability, microcephaly, seizures) caused by SRRM2 loss itself,
    or by loss of neighbouring genes within the deleted interval?
  rationale: >-
    Both classes of lesion abolish one SRRM2 allele, so a pure
    haploinsufficiency model predicts comparable severity. The observed gradient
    therefore points either to a contiguous-gene effect at 16p13.3 or to
    ascertainment differences between the cohorts. The authors themselves note
    that phenotypic blending from co-occurring pathogenic variants in CASR/PKD1
    and SLC17A5 confounded two of the six deletion cases, so the comparison is not
    clean. Resolving this determines whether the deletion subtype should be
    modelled as the same disease with greater severity or as a distinct
    contiguous-gene syndrome.
  proposed_experiments:
  - experiment_id: mrd72_deletion_breakpoint_phenotype_correlation
    name: Deletion-interval breakpoint-to-phenotype correlation
    description: >-
      Assemble a larger series of SRRM2-spanning 16p13.3 deletions with precise
      breakpoints and systematic phenotyping, and test whether severity tracks
      deletion size and specific co-deleted genes independently of SRRM2 loss.
  evidence:
  - reference: PMID:40225164
    reference_title: "A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phenotypic blending, present for two cases with additional pathogenic
      variants in CASR/PKD1 and SLC17A5, hampered the phenotypic delineation of
      this recently described condition.
    explanation: >-
      The authors identify the confounder that keeps this comparison open.

datasets:
- accession: geo:GSE299937
  title: >-
    Srrm2 haploinsufficiency drives SynGAP-gamma reduction, Agap3 mis-splicing, and
    oligodendrocyte deficits in a genetic mouse model of schizophrenia
  description: >-
    Two arms comparing Srrm2+/- mice with wild-type littermates: bulk RNA-seq of
    eight brain regions at 1 and 3 months, plus single-NUCLEUS RNA-seq of
    prefrontal cortex and striatum at 1 month. This is the haploinsufficiency
    model underlying the Impaired Neuronal and Oligodendrocyte Development node,
    and the source data for the reduced striatal oligodendrocyte proportion and
    the myelin-gene expression changes.
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_count: 180
  genes:
  - preferred_term: SRRM2
    term:
      id: hgnc:16639
      label: SRRM2
  publication: PMID:42189682
  notes: >-
    Relevance triage: matched on gene rather than disease name, but the linked
    publication is the Srrm2+/- brain model curated in animal_models here, so the
    dataset is directly on-target for this entry's mechanism. data_type records
    the larger bulk RNA-seq arm; the record also contains a single-nucleus
    RNA-seq arm, which the single-valued slot cannot express. Bulk-generated
    record - carries publication and provenance notes rather than an evidence
    block, per the dataset-curation SOP.

differential_diagnoses:
- name: ZTTK syndrome (SON-related disorder)
  disease_term:
    preferred_term: ZTTK syndrome
    term:
      id: MONDO:0014936
      label: ZTTK syndrome
  description: >-
    The closest mechanistic relative of MRD72: heterozygous loss of function of
    SON, the other non-redundant nuclear speckle scaffold protein, which likewise
    perturbs splicing of transcripts with weak splice sites. Both disorders are
    therefore nuclear-speckle scaffold haploinsufficiencies presenting with
    developmental delay and intellectual disability.
  distinguishing_features:
  - >-
    ZTTK syndrome is a complex, multisystem developmental disorder with
    congenital anomalies (growth retardation, skeletal abnormalities, kidney
    agenesis), whereas MRD72 is comparatively mild and largely confined to
    neurodevelopment, behaviour, weight, and facial gestalt.
  - >-
    Haematological and immunological involvement (leukopenia, immunoglobulin
    deficiency) is described in ZTTK syndrome but not in MRD72.
  evidence:
  - reference: PMID:38290089
    reference_title: >-
      A mouse model of Zhu-Tokita-Takenouchi-Kim syndrome reveals indispensable
      SON functions in organ development and hematopoiesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare disease caused by
      genetic alterations that result in heterozygous loss of function of SON.
    explanation: >-
      Establishes the gene and mechanism of the differential diagnosis - the
      partner speckle scaffold of SRRM2.
  - reference: PMID:38290089
    reference_title: >-
      A mouse model of Zhu-Tokita-Takenouchi-Kim syndrome reveals indispensable
      SON functions in organ development and hematopoiesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Thus, ZTTK syndrome is a complex, multisystem developmental disorder
    explanation: >-
      Supports the multisystem severity that distinguishes ZTTK from the
      comparatively mild MRD72 phenotype.
  - reference: PMID:33095160
    reference_title: SON and SRRM2 are essential for nuclear speckle formation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the core of NS is likely formed by SON and SRRM2
    explanation: >-
      Establishes why the two disorders are mechanistically paired: SON and SRRM2
      are the two joint scaffolds of the same organelle.
  notes: >-
    Nomenclature caution, not a clinical differential: an autosomal dominant
    neurodevelopmental disorder with a similar descriptive name -
    "macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and
    persistent fetal hemoglobin" (MNDLFH, OMIM 619769, MONDO:0859231, caused by
    ZBTB7A) - is a distinct entity. One of the deep-research runs for this entry
    initially attributed MRD72 to ZBTB7A before self-correcting, so any
    ZBTB7A-derived literature must be kept out of this record.

📚

References & Deep Research

References

2

PMID:35567594

Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder

No top-level findings curated for this source.

PMID:40225164

A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency

No top-level findings curated for this source.

Deep Research

2

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-sonnet-5 19 citations 2026-08-19T08:43:10.132475

1. Disease Information

Overview. Intellectual Developmental Disorder, Autosomal Dominant 72 (MRD72), also referred to as SRRM2-related neurodevelopmental disorder, is a recently delineated genetic condition caused by heterozygous, predominantly de novo, loss-of-function (LoF) variants in SRRM2 (Serine/Arginine Repetitive Matrix Protein 2), a core nuclear-speckle scaffold protein and pre-mRNA splicing factor. It was first formally characterized as a distinct clinical entity by Cuinat et al. (2022, Genetics in Medicine, PMID: 35567594), who described 22 unrelated individuals ascertained through GeneMatcher, following earlier statistical implication of SRRM2 as a developmental-disorder gene by the Deciphering Developmental Disorders (DDD) study (Kaplanis et al. 2020, Nature, PMID: 33057194), which identified SRRM2 as one of 28 genes newly and robustly associated with developmental disorders via statistical enrichment of de novo mutations across 31,058 parent-offspring trios.

Key identifiers: | Resource | Identifier | |---|---| | OMIM Phenotype | #620439 — INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 72; MRD72 | | OMIM Gene | *606032 — SRRM2 | | HGNC | HGNC:16639 | | NCBI Gene ID | 23524 | | Cytogenetic location | 16p13.3 | | GRCh38 coordinates | chr16:2,752,626–2,772,538 (+) | | ClinGen Dosage (CCID:007940) | Sufficient Evidence for Haploinsufficiency (score 3); No Evidence for Triplosensitivity (0) | | Inheritance | Autosomal dominant (nearly always de novo) |

Synonyms/alternative names: SRRM2-related neurodevelopmental disorder; SRRM2 haploinsufficiency syndrome; MRD72; the gene product is historically known as SRm300 (300-kD splicing factor) with aliases CWF21, Cwc21, SRL300.

Evidence basis. Nearly all published knowledge derives from aggregated disease-level case series compiled through international gene-matching platforms (GeneMatcher), large-scale trio-exome cohorts (DDD/GeneDx), and structural-variant registries (Genomics England 100,000 Genomes Project), rather than single-patient case reports alone (though several individual case reports have since expanded the phenotypic spectrum). No dedicated patient registry or natural-history study yet exists.

2. Etiology

Disease causal factor: Heterozygous loss-of-function of SRRM2 — frameshift, nonsense, canonical splice-site variants, or contiguous gene deletions spanning the locus — is the sole established cause. The mechanism is haploinsufficiency, not dominant-negative or gain-of-function, based on: - ClinGen curation assigning "Sufficient Evidence for Haploinsufficiency" (score 3) - gnomAD constraint metrics: pLI = 1.0, LOEUF = 0.18 (well within the top haploinsufficiency decile, threshold <0.35), observed/expected LoF ratio ≈0.06 — indicating extreme intolerance to LoF variation in the general population - In parallel, SRRM2 shows tolerance to missense variation (missense Z ≈ −6.28, o/e ≈1.43), consistent with LoF (not missense-driven dominant-negative) as the principal pathomechanism, though rare pathogenic missense variants in the intrinsically disordered region (IDR) have since been reported (see below) - Mouse data: Srrm2-null (homozygous) mice are embryonic lethal (preweaning lethality, IMPC), while Srrm2+/− heterozygotes are viable but show molecular and behavioral phenotypes — directly modeling human haploinsufficiency

Genetic risk factors: - De novo heterozygous frameshift or nonsense SNVs/indels in SRRM2 (majority of cases) - De novo microdeletions of the 16p13.3 locus spanning SRRM2 (66–482 kb reported), several arising via a recombination-prone ~144 kb palindrome-like structure located ~75 kb upstream of SRRM2 (GRCh38 chr16:2,534,000–2,678,000), which predisposes to complex structural rearrangements including deletions with internal inversions (Pagnamenta et al. 2023, Human Mutation, PMC11918891) - Rare de novo missense variants within the SRRM2 intrinsically disordered region, associated with an expanding/atypical phenotype (see Phenotypes) - No recurrent/founder variant has been identified; nearly all reported variants are private (patient-specific)

Environmental risk factors: None established; this is a purely monogenic disorder with no known environmental, infectious, toxin, or lifestyle contributors to primary disease causation.

Protective factors: None identified at the genetic or environmental level. No modifier genes or protective alleles have been reported to date, reflecting the rarity and recency of the condition's description.

Gene-environment interactions: None reported; insufficient case numbers and no systematic epidemiological studies exist to assess G×E effects.

Suggested ontology terms: MONDO term for SRRM2-related neurodevelopmental disorder (mapped to OMIM 620439); HGNC:16639 (SRRM2); NCBITaxon:9606 (Homo sapiens).

3. Phenotypes

Data drawn primarily from the Cuinat et al. 2022 cohort (n=22), the Pagnamenta et al. 2023 100,000 Genomes Project structural-variant cohort (n=4–6), and individual case reports (tics/PMC12488763; hyperphagia-obesity/Frontiers 2025).

Core neurodevelopmental phenotypes (Cuinat cohort, LoF variants — typically milder end of spectrum)

Phenotype	Frequency	Suggested HPO term
Developmental delay	22/22 (100%)	HP:0001263 Global developmental delay
Predominant speech/language delay	16/19 (84%)	HP:0000750 Delayed speech and language development
Gross motor developmental delay	8/22 (36%)	HP:0002194 Delayed gross motor development
Mild intellectual disability	16/22 (73%)	HP:0001256 Mild intellectual disability
Borderline intellectual disability	4/22 (18%)	HP:0006889 Borderline intellectual functioning
Autism spectrum / ASD features	present in subset	HP:0000729 Autistic behavior
ADHD features	present in subset (6/22 in one tabulation)	HP:0007018 Attention deficit hyperactivity disorder
Overfriendliness / sociable personality	frequent, characteristic	HP:0000750-adjacent behavioral descriptor (no precise HP term; often coded as HP:0000722 Sociable/gregarious personality if used)
Generalized hypotonia	common	HP:0001290 Generalized hypotonia
Overweight/obesity	12/22 (~55%)	HP:0001513 Obesity

Dysmorphic facial features (Cuinat cohort)

Feature	Frequency	Suggested HPO term
Epicanthus	3/22	HP:0000286 Epicanthus
Deep-set eyes	10/22	HP:0000490 Deeply set eye
Large ears	7/22	HP:0000400 Macrotia
Low-set, posteriorly rotated ears	4/22	HP:0000369 Low-set ears / HP:0000368 Posteriorly rotated ears
Broad/bulbous nasal tip	9/22	HP:0000414 Bulbous nose
Smooth philtrum	6/22	HP:0000319 Smooth philtrum
Thin upper lip	7/22	HP:0000219 Thin upper lip vermilion
Broad chin	6/22	HP:0000324 Broad chin

More severe structural-variant phenotype (100,000 Genomes Project deletion cohort, n=4–6)

This subgroup — carrying larger contiguous deletions rather than point LoF variants — shows a more severe phenotype than the Cuinat SNV cohort: - Moderate-to-severe intellectual disability (vs. typically mild in the LoF-SNV cohort) - Microcephaly in 3/6 (50%) vs. ~5% in the SNV cohort — HP:0000252 Microcephaly - Seizures in 2/6 — HP:0001250 Seizure - Dystonia in 2/6 — HP:0001332 Dystonia - Autistic features 4/6, ADHD traits 5/6 - Additional dysmorphism: geographic tongue, large ears, tapering fingers, prominent halluces (HP:0001155 Broad hallux phalanx / tapering finger descriptors)

This genotype-phenotype gradient (SNV/frameshift → milder; large contiguous deletion → more severe) suggests dosage or contiguous-gene effects and is an important curation nuance.

Expanding phenotype — missense/IDR variants

A 2025 case report (Frontiers in Medicine, PMC11880253) of a de novo missense variant (p.Q1554L) in the SRRM2 intrinsically disordered region described a novel, more metabolically severe presentation: - Hyperphagia driving rapid-onset severe obesity (BMI 44.6 by age 17) — HP:0002591 Polyphagia / HP:0001513 Obesity - Macrocephaly (contrasting with microcephaly in the deletion cohort) — HP:0000256 Macrocephaly - Short hands and feet — HP:0001217 Small hand / HP:0001773 Short foot - Secondary complications: stage IV cardiogenic insufficiency, hypertension, hyperlipidemia, obstructive sleep apnea - UK Biobank association data cited supporting SRRM2 missense variants correlating with increased body weight in the general population

Additional reported feature — tics/movement disorder

A single case report (2025, PMC12488763) of a 16p13.3 microdeletion presented atypically with late-onset (age 25) simple motor and vocal tics progressing to catatonic-type tics (Yale Global Tic Severity Scale 55/100), notably without the hypotonia, dysmorphism, or obesity typical of the syndrome — expanding the phenotypic spectrum to include movement disorder/tic phenomenology (HP:0100033 Tics).

Quality of life impact: No formal QoL instrument (EQ-5D, SF-36) data have been published for this rare, recently described condition. Qualitatively, developmental delay/intellectual disability, obesity-related cardiometabolic complications (in a subset), and speech delay are the dominant drivers of functional impact reported in case series.

4. Genetic/Molecular Information

Causal gene: SRRM2 (HGNC:16639; OMIM *606032), encoding a large (~2,752 amino acid) intrinsically-disordered-region-rich splicing factor (SRm300 protein).

Pathogenic variant spectrum (Cuinat et al. 2022, n=22 unrelated probands): - 12 frameshift variants - 8 nonsense variants - 2 microdeletions (66 kb and 270 kb) - 19/20 confirmed de novo (essentially all cases where parental testing was performed)

Structural variant spectrum (Pagnamenta et al. 2023, 100,000 Genomes Project): - 4 unrelated individuals with de novo whole-gene deletions, 248–482 kb - All distal breakpoints cluster within the upstream 16p13.3 palindrome-like structure - 3/4 deletions show internal inverted segments (45–94 kb) — complex structural variant architecture, likely arising via replication-based or hairpin/cruciform-mediated recombination mechanisms during DNA repair/replication

Emerging missense/IDR variant: - p.Q1554L (NM_016333.4: c.4661A>T), de novo, classified Likely Pathogenic (ACMG PS2, PM2, PP3), located in the SRRM2 IDR, predicted to disrupt local hydrophilicity and liquid-liquid phase separation properties

Variant classification (ClinVar): Predominantly Pathogenic/Likely Pathogenic per ACMG/AMP; example variant NM_016333.4(SRRM2):c.7748_7758del (p.Thr2583fs) classified pathogenic for "Intellectual developmental disorder, autosomal dominant 72" (ClinVar RCV004763624).

Population frequency / constraint (gnomAD): - pLI = 1.0; LOEUF = 0.18 (strong LoF intolerance) - Missense Z ≈ −6.28, o/e(missense) ≈1.43 (missense tolerant — supports haploinsufficiency, not dominant-negative, as principal mechanism for truncating variants) - Estimated population prevalence of pathogenic de novo LoF: ~1/1,827 among DDD-ascertained developmental-disorder trios (17/31,058; likely an underestimate, as exome sequencing under-captures structural variants); broader unexplained-ID cohort estimates cited around 1/1,300; general-population prevalence estimated in the range of 1/11,000–1/50,000 (early, imprecise estimates given the condition's recent description)

Functional consequence: Loss of one functional SRRM2 allele → haploinsufficiency of SRm300 → disrupted nuclear speckle organization and impaired pre-mRNA splicing (see Mechanism, below). No dominant-negative or gain-of-function mechanism has been established for truncating variants; the missense IDR variant is hypothesized to act via altered phase-separation biophysics rather than classical LOF/GOF dichotomy.

Modifier genes: None identified.

Epigenetic information: Not specifically studied in this disorder to date.

Chromosomal abnormalities: Beyond the palindrome-associated microdeletions above, no recurrent translocations, aneuploidies, or larger syndromic contiguous-gene deletions (beyond SRRM2 itself) have been robustly linked to a distinct phenotype.

Suggested ontology terms: HGNC:16639 (SRRM2); GO:0000398 (mRNA splicing, via spliceosome); GO:0016607 (nuclear speck); GO:0003729 (mRNA binding); UniProt Q9UQ35 (SRRM2_HUMAN, SRm300/SRRM2).

5. Environmental Information

No environmental factors, lifestyle exposures, or infectious agents have been implicated in causing or triggering MRD72. This is a purely genetically determined, predominantly de novo condition. Environmental/lifestyle factors (diet, activity) are relevant only as secondary modifiers of the obesity/metabolic complications seen in a subset of patients, not as disease-causal agents.

6. Mechanism / Pathophysiology

Molecular function of SRRM2 / SRm300: SRRM2 encodes an RS-domain-containing, intrinsically-disordered-region-rich splicing coactivator (SRm300) that: - Docks directly onto core U5 snRNP proteins Prp8 and Snu114 at the spliceosome catalytic center (identified by cryo-EM in spliceosomal structures) - Promotes physical interaction between pre-mRNA and the spliceosome catalytic machinery, supporting both constitutive splicing and exonic splicing enhancer (ESE)-dependent alternative splicing - Together with SON, acts as a principal molecular scaffold that organizes nuclear speckles — membraneless nuclear bodies enriched in splicing factors — via liquid-liquid phase separation driven by the intrinsically disordered regions of SRRM2 and SON (Ilik et al. 2020, PMID: 33095160; SRRM2 condensate biology, PMC9410892)

Causal chain (haploinsufficiency → disease): 1. Heterozygous LoF variant/deletion → ~50% reduction in functional SRRM2 protein (GO:0003729 mRNA binding; GO:0000398 mRNA splicing via spliceosome) 2. Disrupted nuclear speckle architecture/organization (GO:0016607 nuclear speck) — impaired phase-separation-driven condensate assembly 3. Genome-wide alternative splicing dysregulation — preferentially affecting cassette exons with short introns and weak splice sites, with a tendency to alter large protein domains 4. Downstream transcriptomic and proteomic perturbation of neurodevelopmentally important genes 5. Impaired neuronal/glial development and synaptic protein regulation → clinical neurodevelopmental phenotype

Cellular/developmental model evidence: - Mouse embryonic stem cells (Srrm2+/− heterozygous knockout): reduced colony formation, dispersed clustering, reduced alkaline phosphatase (pluripotency marker) activity; loss of stemness with intermediate pluripotency states; altered splicing of Dtx3 (NOTCH pathway) and Pcyt2 (phospholipid synthesis, itself embryonic-lethal when fully knocked out) precedes broader transcriptional changes; upregulation of SRF-controlled mesoderm/cardiac differentiation genes (PMC11070786, Biology Open 2024) — establishes SRRM2 dosage as critical for stemness/cell-identity maintenance in early development - Mouse (Srrm2+/−) brain model (Cell Reports, 2026; bioRxiv PMID pending, preprint 2024.10.10.617460): large-scale gene-expression changes across neuronal and glial populations affecting DNA-binding, synapse, translation, and mitochondria-related pathways; reduction of the gamma isoform of SynGAP (a key postsynaptic Ras/Rap GAP regulating synaptic plasticity) and reciprocal elevation of its interactor AGAP3; reduced oligodendrocyte proportions (particularly striatal) with decreased myelin-related mRNA/protein expression; behaviorally, reduced locomotor activity and impaired acoustic startle response; EEG shows reduced sleep spindles, a finding paralleling human schizophrenia electrophysiology. Human iPSC-derived neurons with SRRM2 deficiency show conserved AGAP3 mis-splicing, directly bridging the mouse mechanism to human neurobiology. This positions SRRM2 haploinsufficiency as a shared mechanistic node between neurodevelopmental disorder and schizophrenia risk. - Homozygous Srrm2-null mice: preweaning embryonic lethal (IMPC data), confirming SRRM2 is essential for viability and that only the heterozygous (haploinsufficient) state is compatible with life — directly mirroring the human autosomal dominant/de novo heterozygous disease model.

Cell types and biological processes involved: - Neurons and glial cells (oligodendrocytes specifically implicated) — suggested CL terms: CL:0000540 (neuron), CL:0000128 (oligodendrocyte) - Pluripotent stem/progenitor cells during early embryonic development - Core biological processes: GO:0000398 mRNA splicing via spliceosome; GO:0000381 regulation of alternative mRNA splicing, via spliceosome; GO:0016607 nuclear speck organization; GO:0007399 nervous system development; GO:0022010 central nervous system myelination

Metabolic changes: In the hyperphagia/obesity-associated missense case, downstream metabolic dysregulation (hyperphagia → severe obesity → cardiometabolic complications) represents a secondary, phenotype-specific consequence rather than a core molecular pathway finding; mechanistic basis for the hyperphagia is not yet established but is hypothesized to relate to hypothalamic splicing dysregulation.

Immune system involvement: Not implicated; no autoimmune or immunodeficiency features reported.

Advanced/omics technologies applied: - Single-cell transcriptomic analysis of Srrm2+/− mouse ES cells (four distinct cellular states identified) - Bulk and cell-type-resolved transcriptomics/splicing analysis in Srrm2+/− mouse brain (multiple regions) and human iPSC-derived neurons - No published proteomics, metabolomics, or spatial transcriptomics specific to this disorder to date

7. Anatomical Structures Affected

Organ level: - Primary: Central nervous system (brain) — developmental delay, intellectual disability, hypotonia, (in severe subgroup) seizures, dystonia, microcephaly - Secondary: Adipose tissue/metabolic system (obesity, hyperphagia in subset); cardiovascular system (hypertension, cardiogenic insufficiency secondary to severe obesity); craniofacial skeleton and soft tissue (dysmorphic facial features) - Body systems: Nervous system, endocrine/metabolic system, musculoskeletal system (short hands/feet in one report), integumentary/craniofacial

Suggested UBERON terms: UBERON:0000955 (brain); UBERON:0001013 (adipose tissue); UBERON:0000948 (heart); UBERON:0001456 (face)

Tissue and cell level: - Neurons (CL:0000540) and oligodendrocytes (CL:0000128) — from the mouse Srrm2+/− brain model - Embryonic/pluripotent stem cells (CL:0002322) — from the mESC model - Adipose tissue cells — implicated in obesity phenotype but not specifically characterized at cellular resolution

Subcellular level: - Nuclear speckles (GO:0016607) — the primary subcellular structure directly disrupted by SRRM2 haploinsufficiency - Spliceosome (GO:0005681) — catalytic center where SRRM2/SRm300 docks (Prp8, Snu114 interaction) - Nucleus generally (GO:0005634)

Localization/lateralization: No lateralization pattern reported; phenotypes are bilateral/systemic (developmental, craniofacial, metabolic) as expected for a germline splicing-factor disorder.

8. Temporal Development

Onset: Congenital/early childhood onset. Developmental delay is typically first recognized in infancy/early childhood (failure to meet motor milestones — e.g., not sitting independently by 12 months, not walking by 18 months — and speech delay — not using two-word phrases by 24 months, per the tic case report's developmental history).

Onset pattern: Insidious/developmental rather than acute; a chronic, non-episodic neurodevelopmental trajectory.

Progression: - Developmental delay/intellectual disability is generally stable-to-mildly progressive in cognitive terms, consistent with a static encephalopathy-type neurodevelopmental disorder rather than a degenerative one, though long-term natural history data are extremely limited given how recently the condition was described (2020–2022 for gene discovery/first cohort) - Obesity is progressive in the subset of patients who develop it, worsening from childhood-onset hyperphagia to severe adult obesity with escalating cardiometabolic complications (documented longitudinally in the age 7→17 case report) - Tics, in the one reported case, had an atypically late onset (age 25, well past the typical ~age 6 onset for neurodevelopmental tic disorders) and were progressive in severity (simple motor/vocal → complex catatonic-type tics)

Disease course pattern: Chronic, lifelong; no spontaneous remission reported for the core neurodevelopmental phenotype. No defined discrete "stages" (early/intermediate/advanced) have been established in the literature, reflecting the condition's recency and small case numbers.

Critical periods: Embryonic/early postnatal neurodevelopment is the presumed critical window, based on mouse ESC data showing SRRM2 dosage is critical for stemness maintenance and early lineage specification, and homozygous-null embryonic lethality in mice.

9. Inheritance and Population

Epidemiology: No formal prevalence/incidence study exists. Estimates (indirect, derived from cohort ascertainment): - ~1/1,827 among DDD-ascertained developmental-disorder trios (de novo pLoF only; likely underestimated as structural variants are under-captured by exome sequencing) - ~1/1,300 cited in cohorts of individuals with unexplained intellectual disability - Broader population prevalence estimates in the range of 1/11,000–1/50,000 have been cited but should be treated as provisional given the small evidence base

Inheritance pattern: Autosomal dominant (per OMIM #620439 designation); however, essentially all confirmed cases are de novo (19/20 in Cuinat cohort with parental testing; all four 100kGP deletion cases de novo). No multi-generational transmission has been documented in the literature reviewed, though the condition is formally classified as AD (implying that transmission from an affected, reproductively fit parent would in principle occur with 50% recurrence risk).

Penetrance: Appears to be high/complete for the core developmental delay phenotype based on cases identified to date, though this is based on small numbers, and germline/somatic mosaicism has not been systematically assessed.

Expressivity: Markedly variable — ranging from mild intellectual disability with characteristic facial gestalt (typical LoF/SNV phenotype) to moderate-severe ID with microcephaly and seizures (large-deletion phenotype) to an atypical late-onset tic-predominant presentation without the classic dysmorphism/obesity, to a hyperphagia/severe-obesity-predominant presentation (missense/IDR variant). This genotype-phenotype heterogeneity is one of the most clinically important features of the disorder.

Genetic anticipation: Not applicable/not reported (this is not a repeat-expansion disorder).

Germline mosaicism: Not specifically documented but theoretically possible given the de novo mechanism; not systematically studied.

Founder effects: None identified; variants are private/patient-specific with no recurrent pathogenic allele.

Consanguinity: Not relevant, given the autosomal dominant/de novo mechanism (not a recessive disorder).

Carrier frequency: Not applicable in the traditional sense (AD, not AR); population allele frequency of pathogenic LoF variants is expected to be near zero in unaffected populations given the severe negative selection reflected by pLI=1.0/LOEUF=0.18.

Population demographics: No specific ethnic or geographic enrichment reported; cases have been identified across multiple international cohorts (France/Cuinat et al., UK Genomics England 100,000 Genomes Project, and additional individual case reports from various countries), consistent with a pan-ethnic de novo disorder without founder population bias.

Sex ratio: Not explicitly reported as skewed in the literature reviewed; no clear male:female bias has been established.

Age distribution: Reported patients range from early childhood through adulthood (oldest reported case, the tic patient, was 30 years old at report), reflecting ascertainment across pediatric and adult genetics clinics.

10. Diagnostics

Genetic testing (primary diagnostic modality): - Whole exome sequencing (WES) or whole genome sequencing (WGS), typically as trio analysis (proband + both parents) to establish de novo status — this is how essentially all reported cases have been ascertained (GeneMatcher-facilitated case matching, DDD/100,000 Genomes Project cohorts) - Chromosomal microarray (CMA) — necessary to detect the microdeletion subset (66 kb–482 kb), which would be missed by exome sequencing alone; WGS with structural-variant calling is increasingly important given the palindrome-associated complex rearrangements described by Pagnamenta et al. - Single-gene SRRM2 sequencing is not a standard first-tier approach given the absence of a recognizable, specific enough clinical gestalt to prompt targeted testing; it is typically identified via exome-wide or panel-based ID/developmental-disorder gene panels (e.g., Genomics England PanelApp "Intellectual disability" panel includes SRRM2) - No specific biomarkers, laboratory tests, imaging findings, or electrophysiologic signatures are diagnostic; EEG abnormalities (reduced sleep spindles) are so far only described in the mouse model, not systematically in human patients (though the 100kGP cohort did include seizure patients, presumably with abnormal EEGs, not detailed further)

Clinical criteria: No formal consensus diagnostic criteria exist (condition too recently described). Diagnosis is genetic-confirmation-based: identification of a de novo (or presumed pathogenic) heterozygous LoF variant or deletion in SRRM2 in the context of compatible developmental delay/ID, ideally with supportive dysmorphology.

Differential diagnosis: Other genetic causes of syndromic intellectual disability with overlapping features (hypotonia, obesity, ASD/ADHD traits, dysmorphism) — e.g., other chromatin/splicing-factor-related neurodevelopmental disorders, and Prader-Willi-like syndromes when hyperphagia/obesity dominate the presentation (relevant to the missense-variant case). Given the phenotypic overlap with hyperphagic obesity syndromes, differentiation typically requires exome/genome sequencing rather than clinical gestalt alone.

Screening: No population, carrier, or newborn screening applies, given the de novo, non-recurrent nature of the disorder.

11. Outcome/Prognosis

No formal survival, mortality, or long-term outcome studies exist. Based on available case reports: - The disorder is not associated with reduced lifespan intrinsically, though secondary cardiometabolic complications from severe obesity (in the subset who develop hyperphagia-driven obesity) — including stage IV cardiac insufficiency, hypertension, hyperlipidemia, and obstructive sleep apnea documented in one adolescent case — represent a significant, potentially life-limiting morbidity pathway if unmanaged - Cognitive outcome ranges from mild intellectual disability/borderline functioning (most common, per the Cuinat LoF cohort) to moderate-severe intellectual disability (in the larger-deletion subgroup) - No natural history data on adult functional independence, employment, or long-term psychiatric outcomes (though the mouse model's schizophrenia-relevant EEG/behavioral findings raise a hypothesis-generating question about long-term psychiatric risk in human carriers that has not yet been clinically studied) - Prognostic factors identified so far are primarily genotypic: variant/deletion size and type appear to correlate with severity (SNV/frameshift → milder; large contiguous deletion → more severe with microcephaly/seizures; IDR missense → distinct hyperphagia-obesity-predominant course)

12. Treatment

There is no disease-specific or targeted therapy for MRD72; management is entirely symptomatic/supportive, individualized to the phenotypic subtype:

Developmental/behavioral therapies: Early intervention services, speech-language therapy (for the predominant speech delay), physical/occupational therapy, and special education support — suggested NCIT terms: NCIT:C15302 (Physical Therapy), NCIT:C159273 (Speech Therapy), NCIT:C121351 (Occupational Therapy)
Behavioral/psychiatric management: For ASD/ADHD features — behavioral counseling and, where indicated, standard ADHD pharmacotherapy (not SRRM2-specific) — NCIT:C181743 (Behavioral Counseling), NCIT:C15986 (Pharmacotherapy)
Movement disorder management: In the tic-predominant case, alpha-2 agonist clonidine was recommended for tic management — NCIT:C15986 (Pharmacotherapy) with therapeutic_agent CHEBI (clonidine)
Metabolic/obesity management: Dietary intervention was attempted (with limited success against uncontrolled hyperphagia) in the obesity case; standard multidisciplinary obesity management (nutrition, weight management, cardiometabolic risk-factor treatment for hypertension/hyperlipidemia/sleep apnea) — NCIT:C15447 (Dietary Intervention), NCIT:C15747 (Supportive Care)
Genetic counseling: Recommended for all families given the de novo autosomal dominant mechanism, to discuss recurrence risk (low, but non-zero due to potential germline mosaicism) — NCIT:C15240 (Genetic Counseling)
Experimental/targeted therapies: None in development or clinical trials specific to SRRM2-related disorder as of this writing; no NCT-registered trials identified. The mechanistic convergence with schizophrenia biology (SynGAP-γ, AGAP3, oligodendrocyte/myelination pathways) identified in the 2026 mouse model study represents a potential future avenue for mechanism-informed therapeutic exploration, but this is preclinical only.

Treatment outcomes/response rates: Not systematically studied; case-by-case symptomatic management only.

13. Prevention

No primary, secondary, or tertiary prevention strategies exist for the underlying de novo genetic event, as with most sporadic monogenic developmental disorders.

Prenatal/reproductive counseling: For families with a previously affected child, genetic counseling regarding low (but non-zero, due to potential parental germline mosaicism) recurrence risk, and availability of prenatal diagnosis (chorionic villus sampling/amniocentesis with targeted variant testing) or preimplantation genetic testing (PGT-M) if the familial variant is known
Secondary prevention: Early developmental screening and early intervention referral upon recognition of developmental delay can improve functional outcomes generally (standard developmental-pediatrics practice, not SRRM2-specific)
Tertiary prevention: Proactive metabolic/cardiovascular monitoring (weight, blood pressure, lipids, sleep study) in patients showing early hyperphagia, to prevent/mitigate the severe obesity-related cardiometabolic complications documented in case reports
No vaccination, public health, or environmental intervention is relevant, as there is no infectious or environmental disease-causal component

14. Other Species / Natural Disease

Taxonomy: No naturally occurring veterinary/companion-animal disease analog has been reported (NCBITaxon:9606, human, is the only species with described clinical disease)
Orthologous gene: Mouse Srrm2 (MGI:1923206, chromosome 17) is the primary ortholog used experimentally; no OMIA (naturally occurring animal disease) entries exist for SRRM2
Comparative biology: The mouse gene shows the same essential/dosage-sensitive biology as the human gene (homozygous-null embryonic lethal; heterozygous viable with molecular/behavioral phenotype), supporting deep evolutionary conservation of SRRM2's role in nuclear speckle organization and splicing regulation across mammals
Zoonotic potential: Not applicable (monogenic disorder, not infectious)

15. Model Organisms

Model	Type	Key findings	Source
Mouse embryonic stem cells (E14tg2a.4 line), Srrm2+/− heterozygous knockout	Cellular/genetic model	Impaired colony formation, reduced pluripotency (alkaline phosphatase) markers, loss of stemness with intermediate pluripotent states, altered splicing of Dtx3/Pcyt2 preceding transcriptional changes	Biology Open 2024, PMC11070786
Mouse, Srrm2 homozygous knockout	Whole-organism genetic model	Embryonic/preweaning lethal (IMPC data) — establishes essential gene status	IMPC; cited in multiple SRRM2 papers
Mouse, Srrm2+/− heterozygous (brain-focused)	Whole-organism genetic model of schizophrenia/NDD	Neuronal/glial transcriptomic changes (synapse, mitochondria, translation pathways); reduced SynGAP-γ; elevated AGAP3; reduced striatal oligodendrocyte proportion and myelin gene/protein expression; reduced locomotor activity; impaired acoustic startle; reduced EEG sleep spindles (parallels human schizophrenia electrophysiology)	Cell Reports 2026 (preprint bioRxiv 2024.10.10.617460)
Human iPSC-derived neurons, SRRM2-deficient	Cellular (isogenic) human model	Conserved AGAP3 mis-splicing recapitulating the mouse finding — bridges mouse mechanism to human neuronal biology	Same Cell Reports 2026 study

Model characteristics/limitations: The mouse Srrm2+/− brain model shows strong construct validity (same haploinsufficiency mechanism as human disease) and notable face validity for neurophysiological (EEG spindle) and behavioral (locomotor, startle) endpoints relevant to neurodevelopmental/psychiatric phenotypes, but does not model the craniofacial dysmorphism, obesity/hyperphagia, or human-specific cognitive/speech phenotypes seen clinically — this is best flagged as a HUMAN_MODEL_MISMATCH-type caveat for curation: the mouse model captures neuronal/synaptic/myelination and schizophrenia-relevant electrophysiological biology well, but does not recapitulate the full human syndromic (dysmorphic, metabolic, speech-delay) phenotype, and its relevance to the milder, more common LoF-SNV human phenotype (vs. the more severe deletion phenotype) is not yet established.

Research applications: The mESC model is suited to studying SRRM2's role in pluripotency/early lineage decisions; the Srrm2+/− mouse brain model is suited to studying synaptic protein regulation, oligodendrocyte/myelination biology, and neurophysiological correlates (with direct relevance to the emerging schizophrenia connection); human iPSC-neuron models allow direct validation of mouse-derived splicing findings (e.g., AGAP3) in a human cellular context.

Summary for Knowledge-Base Curation

Suggested pathophysiology causal chain: SRRM2 heterozygous LoF variant/deletion (MOLECULAR: GO:0003729 mRNA binding, GO:0004930-adjacent) → SRRM2/SRm300 haploinsufficiency (MOLECULAR) → disrupted nuclear speckle assembly via impaired liquid-liquid phase separation (CELLULAR: GO:0016607 nuclear speck) → genome-wide alternative pre-mRNA mis-splicing (CELLULAR: GO:0000398, e.g., AGAP3, SynGAP-γ isoform, DTX3, PCYT2) → impaired neuronal/glial (oligodendrocyte) differentiation and synaptic protein regulation (CELLULAR/TISSUE) → neurodevelopmental phenotype (developmental delay, intellectual disability, ASD/ADHD features, hypotonia) ± dysmorphic features ± obesity/hyperphagia (ORGANISM).

Key genes/terms for curation: hgnc:16639 (SRRM2); GO:0000398, GO:0016607, GO:0000381; CL:0000540 (neuron), CL:0000128 (oligodendrocyte); HP:0001263, HP:0000750, HP:0001256, HP:0001290, HP:0001513, HP:0000729, HP:0007018; UBERON:0000955 (brain); MONDO mapping to OMIM 620439.

Primary citations: Kaplanis et al. 2020 (Nature, PMID: 33057194) — gene discovery; Cuinat et al. 2022 (Genet Med, PMID: 35567594) — clinical delineation (n=22); Pagnamenta et al. 2023 (Hum Mutat, PMC11918891) — structural-variant mechanism and severe phenotype subgroup; case reports PMC12488763 (tics) and PMC11880253/Frontiers 2025 (hyperphagia-obesity, missense variant); Cell Reports 2026 (mouse Srrm2+/− brain model, schizophrenia-relevant mechanism).

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Intellectual Developmental Disorder, Autosomal Dominant 72 (MRD72): A Comprehensive Disease Characterization

openscientist-autonomous 11 citations 2026-08-19T08:55:22.770447

Intellectual Developmental Disorder, Autosomal Dominant 72 (MRD72): A Comprehensive Disease Characterization

Disease: Intellectual Developmental Disorder, Autosomal Dominant 72 (MRD72) Causal gene: SRRM2 (SR-related splicing factor / SRm300), 16p13.3 Key identifiers: OMIM #620439 · MONDO:0957397 · ORPHA:652487 · DO:0061045 · MedGen C5830612 Category: Genetic (autosomal dominant neurodevelopmental disorder)

IMPORTANT DISEASE-IDENTITY NOTE. "Intellectual developmental disorder, autosomal dominant 72" (MRD72, OMIM #620439) is caused by SRRM2 haploinsufficiency. It must not be confused with the ZBTB7A-related disorder (MNDLFH, OMIM 619769 — macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, persistent fetal hemoglobin), a distinct entity. All content below refers to the SRRM2 disorder unless explicitly labeled otherwise (see Section 16).

Summary

Intellectual Developmental Disorder, Autosomal Dominant 72 (MRD72) is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function (haploinsufficiency) of SRRM2, a gene on chromosome 16p13.3 encoding the SR-related splicing factor SRm300 (SRRM2). Affected individuals typically carry de novo protein-truncating variants (frameshift and nonsense) or whole-gene deletions and present with a relatively mild, non-progressive picture dominated by developmental delay with prominent speech delay, autistic and/or attention-deficit/hyperactivity (ADHD) features, overfriendliness, generalized hypotonia, overweight, and mild facial dysmorphism. Intellectual disability, when present, is generally mild and variable.

Mechanistically, SRRM2 (with its partner SON) is one of the two core scaffolding proteins that nucleate nuclear speckles — membraneless nuclear organelles that concentrate the pre-mRNA splicing machinery. SRRM2 is among the most loss-of-function-constrained genes in the human genome (gnomAD pLI = 1.0, LOEUF ≈ 0.18), and complete loss is embryonic-lethal in mouse and C. elegans; the human disorder therefore arises specifically from a 50% reduction in gene dosage (haploinsufficiency) rather than biallelic loss. MRD72 belongs to an emerging family of "nuclear-speckle spliceosomopathies," whose closest relative is ZTTK syndrome, caused by haploinsufficiency of SON — SRRM2's obligate scaffolding partner.

A critical clarification runs through this report. The name "Intellectual Developmental Disorder, Autosomal Dominant 72" refers specifically to the SRRM2-related disorder (OMIM #620439). It should NOT be confused with the ZBTB7A-related disorder (MNDLFH; OMIM #619769), which features macrocephaly, adenoid/pharyngeal lymphoid overgrowth, and elevated fetal hemoglobin. Because both are autosomal dominant neurodevelopmental disorders and secondary-source naming can be ambiguous, the early phase of this investigation initially characterized ZBTB7A; iterations 3–5 corrected course to SRRM2. This report describes MRD72 (=SRRM2) and flags the ZBTB7A material as a distinct entity/differential where relevant (Section 16).

Section 1 — Disease Information

What is the disease? MRD72 is a Mendelian, autosomal dominant, neurodevelopmental disorder in the OMIM "Intellectual developmental disorder, autosomal dominant" (MRD) series. It is defined by heterozygous loss-of-function variation in SRRM2 and characterized by mild developmental delay with disproportionate speech delay, neurobehavioral features (autism-spectrum and ADHD traits, overfriendliness), hypotonia, a tendency to overweight, and subtle dysmorphism (PMID: 35567594).

Key identifiers:

Resource	Identifier
OMIM (disease)	#620439
OMIM (gene SRRM2)	606032
MONDO	MONDO:0957397
Orphanet	ORPHA:652487
Disease Ontology	DO:0061045
MedGen	C5830612
HGNC (gene)	HGNC:16639
Cytoband	16p13.3

Synonyms / alternative names: MRD72; SRRM2-related neurodevelopmental disorder; SRRM2 haploinsufficiency disorder; SRRM2-related intellectual disability.

Source of information: The disease-level description derives from aggregated resources and case series — principally the defining cohort of Cuinat et al. (2022; n = 22), plus subsequent structural-variant reports and large de-novo-variant meta-analyses — rather than EHR-based population phenotyping.

Section 2 — Etiology

Primary cause (genetic). MRD72 is a monogenic disorder caused by heterozygous loss-of-function variants in SRRM2. Cuinat et al. identified 22 patients with LoF SRRM2 variants — 12 frameshift, 8 nonsense, and 2 microdeletions (66 kb and 270 kb) — and "established SRRM2 as a gene responsible for a rare neurodevelopmental disease" (PMID: 35567594). The mechanism is haploinsufficiency (≈50% reduction in functional SRRM2 protein).

"Here, we report on 22 patients with LoF variants in SRRM2 and provide a description of the phenotype. Molecular analysis identified 12 frameshift variants, 8 nonsense variants, and 2 microdeletions of 66 kb and 270 kb." — Cuinat et al. (PMID: 35567594)

Genetic risk factors. The single, sufficient causal factor is a pathogenic/likely-pathogenic heterozygous SRRM2 LoF allele, nearly always de novo. SRRM2 is "predicted to be highly intolerant to loss of function (LoF) and very conserved through evolution" (PMID: 35567594). No common susceptibility loci or polygenic contribution are described.

Environmental risk factors / protective factors / gene–environment interactions. None established. As a de novo, high-penetrance Mendelian disorder, there are no known environmental triggers, protective exposures, dietary factors, or GxE interactions. Record as not applicable / not reported.

Section 3 — Phenotypes

The core phenotype derives from Cuinat et al. (2022) and the OMIM clinical synopsis for #620439. Severity is generally mild and the course non-progressive (a static-encephalopathy pattern typical of neurodevelopmental disorders).

"The patients presented with a mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. Intellectual disability was variable and mild when present." — Cuinat et al. (PMID: 35567594)

Phenotype	Type	Onset	Severity	Suggested HPO term
Global developmental delay	Clinical sign	Infancy/early childhood	Mild	HP:0001263
Speech/language delay (predominant)	Clinical sign	Early childhood	Prominent, often disproportionate	HP:0000750
Intellectual disability	Clinical sign	Childhood	Mild, variable, sometimes absent	HP:0001249 / HP:0001256 (mild)
Autistic behavior / ASD features	Behavioral	Early childhood	Variable	HP:0000729
Attention deficit / hyperactivity	Behavioral	Childhood	Variable	HP:0007018
Overfriendliness / abnormal social behavior	Behavioral	Childhood	Variable	HP:0100024
Generalized hypotonia	Clinical sign	Infancy	Mild–moderate	HP:0001290
Overweight / obesity	Physical	Childhood onward	Variable	HP:0001513
Dysmorphic facial features	Physical	Congenital/childhood	Subtle/variable	HP:0001999

Age of onset: infancy (hypotonia) to early childhood (developmental/speech delay). Progression: stable/non-progressive (developmental, not degenerative). Frequency among affected: developmental/speech delay and neurobehavioral features are the most consistent; overweight, hypotonia and dysmorphism are frequent but variable. Precise per-feature percentages are limited by the small cohort (n = 22).

Quality-of-life impact: driven mainly by communication impairment (speech delay), learning-support needs, and neurobehavioral features (ASD/ADHD), affecting schooling, social integration, and independence. No disease-specific QoL instrument (EQ-5D/SF-36/PROMIS) data exist for MRD72; impact is inferred from the mild-ID/ASD profile.

Section 4 — Genetic / Molecular Information

Causal gene. SRRM2 (Serine/Arginine Repetitive Matrix 2), also SRm300; OMIM 606032; HGNC:16639; 16p13.3. A 15-exon gene encoding a large (~2,752-amino-acid) SR-related splicing factor.

Pathogenic variant spectrum. In the defining cohort (n = 22), variants were loss-of-function: 12 frameshift, 8 nonsense, and 2 microdeletions (66 kb, 270 kb) (PMID: 35567594). Whole-gene deletions are independently recurrent: Pagnamenta et al. (2023) reported de novo whole-gene SRRM2 deletions of 248–482 kb in 4 individuals from the 100,000 Genomes Project, with distal breakpoints clustering in a 144-kb palindrome ~75 kb upstream of SRRM2 — a 16p13.3 structure predisposing to recurrent complex structural variation (PMID: 40225164).

Variant class	Representative evidence	Consequence
Frameshift (n = 12)	Cuinat 2022	LoF / haploinsufficiency
Nonsense (n = 8)	Cuinat 2022	LoF / haploinsufficiency
Intragenic microdeletion (66 kb, 270 kb)	Cuinat 2022	LoF / haploinsufficiency
Whole-gene deletion (248–482 kb)	Pagnamenta 2023	LoF / haploinsufficiency

Variant classification: pathogenic / likely pathogenic per ACMG/AMP (PVS1 applies to a haploinsufficient gene).
Variant type/class: predominantly protein-truncating (frameshift, nonsense) plus copy-number losses (structural).
Allele frequency: absent/vanishingly rare in gnomAD (private de novo alleles). SRRM2 is extremely LoF-depleted (below).
Somatic vs germline: germline, almost always de novo.
Functional consequence: loss of function (haploinsufficiency).

Constraint metrics. SRRM2 is one of the most LoF-intolerant genes in the genome: gnomAD pLI = 1.0, observed/expected pLoF ≈ 0.06 (≈7 observed vs ≈111 expected pLoF SNVs), LOEUF ≈ 0.18, RVIS ≈ −4.5 (~15th-most intolerant of ~17,000 genes). ClinGen Dosage Sensitivity assigns a haploinsufficiency score of 3 (sufficient evidence). The Kaplanis/DDD meta-analysis of ~31,000 neurodevelopmental trios identified SRRM2 as one of 28 genes significantly enriched for de novo variants, driven by protein-truncating variants. Cuinat et al. note the gene "has not been previously reported in constitutive human disease" (PMID: 35567594).

Modifier genes / epigenetics. No specific modifiers or epigenetic mechanisms characterized for MRD72 (not reported).

Chromosomal abnormalities. Recurrent 16p13.3 deletions encompassing SRRM2 arise via non-allelic homologous recombination facilitated by the upstream 144-kb palindrome (PMID: 40225164); detectable by chromosomal microarray (CMA).

Section 5 — Environmental Information

No environmental factors, lifestyle factors, or infectious agents are implicated. MRD72 is a fully genetic, de novo dominant disorder. Not applicable.

Section 6 — Mechanism / Pathophysiology

Molecular function of SRRM2. SRRM2 encodes SRm300, "a splicing factor of the SR-related protein family characterized by its serine- and arginine-enriched domains. It promotes interactions between messenger RNA and the spliceosome catalytic machinery" (PMID: 35567594). SRm300 functions at the catalytic core of the spliceosome (notably around the second transesterification step) as a coactivator of pre-mRNA splicing.

Nuclear speckle scaffolding — the central mechanism. SRRM2 is the principal antigen of the classic SC35 (SC-35) monoclonal antibody and localizes sharply to nuclear speckles: "the main target of SC35 mAb is SRRM2, a spliceosome-associated protein that sharply localizes to NS" (PMID: 33095160). With SON, SRRM2 forms the essential structural core of nuclear speckles: "the core of NS is likely formed by SON and SRRM2." Co-depletion of SON and SRRM2 — or SON depletion when SRRM2's intrinsically disordered regions are deleted — causes near-complete dissolution of nuclear speckles (PMID: 33095160). Nuclear speckles concentrate splicing factors and modulate the efficiency/fidelity of pre-mRNA splicing and gene expression.

Causal chain (upstream → downstream):

De novo heterozygous SRRM2 LoF variant (16p13.3)
  │  (truncating / CNV)
  ▼
~50% reduction of SRm300 protein  ── haploinsufficiency
  │
  ▼
Impaired nuclear-speckle scaffolding (with SON) +
reduced splicing-coactivator capacity
  │
  ▼
Perturbed pre-mRNA splicing / gene-expression programs
in developing neurons (dosage-sensitive)
  │
  ▼
Altered neurodevelopment (neuronal differentiation,
synaptic & network maturation)
  │
  ▼
Clinical MRD72: developmental & speech delay, ASD/ADHD
features, hypotonia, overweight, mild dysmorphism

Cellular processes / cell types. The dosage-sensitive process is nuclear-speckle-dependent pre-mRNA splicing during neurodevelopment. Because SRRM2 is ubiquitous and essential, the phenotype reflects the particular vulnerability of the developing CNS to reduced splicing-factor dosage. Suggested GO terms: GO:0000398 (mRNA splicing, via spliceosome), GO:0016607 (nuclear speck), GO:0008380 (RNA splicing), GO:0007399 (nervous system development). Suggested CL terms: CL:0000540 (neuron), CL:0000679 (glutamatergic neuron) — cell-type specificity not yet directly established.

Protein dysfunction. Truncating variants and deletions reduce full-length SRm300 abundance (loss of function); SRRM2's large IDRs, which drive speckle assembly via multivalent interactions, are lost/reduced. There is no evidence for a dominant-negative or gain-of-function mechanism; haploinsufficiency is supported (ClinGen HI = 3).

Metabolic / immune / other. No specific metabolic, immune, oxidative-stress, or fibrotic mechanisms are established. MRD72-specific molecular profiling (transcriptomics/proteomics/metabolomics of patient tissue) has not been reported, though blood RNA-seq is an emerging diagnostic modality for splicing disorders generally (PMID: 40593860).

Section 7 — Anatomical Structures Affected

Primary organ / system: Central nervous system / brain. Suggested UBERON: UBERON:0000955 (brain), UBERON:0001017 (central nervous system).
Secondary involvement: Musculoskeletal (hypotonia; UBERON:0002036 muscle tissue), craniofacial structures (mild dysmorphism), metabolic/adipose (overweight; UBERON:0001013 adipose tissue).
Tissue/cell level: Nervous tissue; neurons are the presumptive vulnerable population (CL:0000540). Specific cortical/subcortical populations unresolved.
Subcellular level: Key compartment is the nuclear speckle (GO:0016607) within the nucleus (GO:0005634); SRRM2 also associates with the spliceosomal complex (GO:0005681).
Lateralization: Bilateral/diffuse CNS involvement; no lateralized pattern reported.

Section 8 — Temporal Development

Onset: Congenital/early-childhood developmental disorder; features apparent in infancy (hypotonia) and early childhood (developmental/speech delay). Pattern is insidious/developmental, not acute.
Progression: Static / non-progressive (neurodevelopmental, not neurodegenerative). Deficits stable; developmental gains possible with intervention. Duration is chronic/lifelong.
Disease course: Stable; no relapsing-remitting/episodic pattern; no spontaneous remission.
Critical periods: Early childhood is the key window for developmental and speech/language intervention.

Section 9 — Inheritance and Population

Inheritance pattern: Autosomal dominant. Variants are almost always de novo.
Penetrance: High for the neurodevelopmental phenotype in LoF-variant carriers (consistent with high constraint and de novo occurrence); precise figures not established.
Expressivity: Variable (ID mild-when-present or absent; neurobehavioral features and overweight vary).
Genetic anticipation / repeat expansion: Not applicable (no repeat mechanism).
Germline mosaicism / founder effects / consanguinity / carrier frequency: Not established; as a de novo dominant disorder, carrier screening and consanguinity are not relevant. Recurrent deletions are mediated by local 16p13.3 palindrome architecture rather than a founder allele (PMID: 40225164).
Epidemiology / prevalence: No formal prevalence exists; rare/ultra-rare. Pagnamenta et al. estimated this condition accounts for approximately ~1 in 1,300 of individuals with otherwise-unexplained intellectual disability in the cohorts studied (PMID: 40225164). SRRM2's status among 28 genome-wide-significant de novo NDD genes in ~31,000 trios (Kaplanis/DDD) indicates a recurrent, individually rare cause of NDD.
Population demographics: No ethnic predilection (de novo mechanism). Sex ratio not clearly skewed (autosomal). Age distribution: identified in childhood via diagnostic exome/genome sequencing.

Section 10 — Diagnostics

Recommended approach. Diagnosis is molecular, via broad genomic testing in a child with unexplained developmental/speech delay ± ASD/ADHD, hypotonia, overweight, and subtle dysmorphism.

Modality	Utility for MRD72
Whole-exome sequencing (WES)	High yield; detects the frameshift/nonsense LoF variants that dominate (PMID: 35567594)
Whole-genome sequencing (WGS)	High yield; detects SNVs and structural variants/whole-gene deletions (PMID: 40225164)
Chromosomal microarray (CMA)	Detects intragenic and whole-gene SRRM2 deletions (66–482 kb)
NDD/ID gene panels	Useful if SRRM2 is included
Single-gene testing	Reasonable when phenotype strongly suggests SRRM2
RNA-seq (blood transcriptome)	Emerging adjunct to resolve splicing/expression impact of VUS (PMID: 40593860)

Laboratory tests / biomarkers / imaging: No specific biochemical biomarker; no pathognomonic imaging finding. Brain MRI is typically nonspecific. There is no MRD72-specific laboratory abnormality analogous to the elevated fetal hemoglobin of the distinct ZBTB7A disorder (Section 16).
Clinical criteria: No standalone diagnostic criteria; diagnosis rests on genotype plus a compatible neurodevelopmental phenotype.
Differential diagnosis: Other nuclear-speckle spliceosomopathies and NDDs — foremost ZTTK syndrome (SON, OMIM #617140), related SR/SRRM-family disorders (e.g., SRRM1), and the phenotypically distinct ZBTB7A-related MNDLFH (OMIM #619769). Features favoring SON/ZTTK include more severe multisystem involvement (structural brain, skeletal, renal anomalies); MRD72 is comparatively milder.
Screening: Not applicable for asymptomatic population screening; cascade testing is generally unnecessary given de novo origin, but parental testing confirms de novo status for recurrence-risk counseling.

Section 11 — Outcome / Prognosis

Survival / mortality: No evidence of reduced life expectancy; not life-limiting based on available cohorts.
Morbidity / function: Chronic disability relates to learning, communication (speech delay), and neurobehavioral features (ASD/ADHD). ID is mild when present.
Disease course / complications: Stable neurodevelopmental profile; overweight/obesity may carry downstream metabolic risk and warrants monitoring. No specific organ-failure complications described.
Recovery potential: Developmental gains achievable with early intervention; the underlying genetic condition is lifelong.
Prognostic factors / biomarkers: None validated. Given variable expressivity, the presence/absence and degree of ID and ASD features shape functional outcome.

Overall prognosis is comparatively favorable relative to other spliceosomopathies (e.g., ZTTK), consistent with the "mild when present" description of ID (PMID: 35567594).

Section 12 — Treatment

There is no disease-specific or targeted therapy for MRD72. Management is supportive and symptom-directed, following general neurodevelopmental-disorder best practice:

Domain	Intervention	Suggested NCIT/term
Developmental	Early intervention programs	Early Intervention
Communication	Speech and language therapy	Speech Therapy
Motor / hypotonia	Physical therapy, occupational therapy	Physical Therapy; Occupational Therapy
Behavioral	ASD-directed behavioral therapy; ADHD management (behavioral ± pharmacologic)	Behavioral Therapy
Educational	Individualized education / learning support	—
Metabolic	Weight/nutrition management for overweight	Nutritional Support

Pharmacotherapy: No gene-directed drug. Standard symptomatic agents (e.g., ADHD medications) may be used per general guidelines; no MRD72-specific pharmacogenomic data.
Advanced therapeutics (gene/cell/RNA therapy): None in development or trials for MRD72. Conceptually, dosage-restorative strategies would be required for a haploinsufficiency mechanism, but none exist.
Experimental / clinical trials: No MRD72-specific registered trials identified.
Treatment strategy: Multidisciplinary, individualized, supportive care plus genetic counseling.

Section 13 — Prevention

Primary prevention: Not applicable — de novo dominant variants cannot be prevented.
Secondary prevention: Early developmental screening enabling early intervention (speech/OT/PT) optimizes functional outcomes.
Genetic screening / reproductive options: For a couple with an affected child, recurrence risk is low (de novo), but prenatal or preimplantation genetic testing for the known familial variant is possible; germline mosaicism, though not documented for SRRM2, is a theoretical small residual risk.
Counseling: Genetic counseling is central — confirming de novo status, communicating low recurrence risk, supporting family planning.
Immunization / public health / prophylaxis: Not applicable.

Section 14 — Other Species / Natural Disease

Taxonomy / orthologs: SRRM2 is highly conserved with stringent 1:1 orthology across human, mouse (Srrm2, MGI:1923206), rat, and zebrafish. In Drosophila, there is no distinct SRRM2 ortholog; the fused gene Srrm234 corresponds to the vertebrate SRRM2/SRRM3/SRRM4 cluster, which arose by duplication/subfunctionalization of an ancestral Srrm2/3/4 gene (PMID: 35567594 and review context).
Natural disease in other species: No naturally occurring SRRM2 disorder is catalogued in companion animals or wildlife (not reported in OMIA).
Comparative biology: Essentiality and conservation across metazoans underscore SRRM2's fundamental splicing role; embryonic lethality of complete knockouts (Section 15) is conserved across mouse and C. elegans.
Zoonotic / transmission: Not applicable (non-infectious genetic disorder).

Section 15 — Model Organisms

Mouse (Srrm2, MGI:1923206): Complete (homozygous) knockout of SRm300/Srrm2 is early-embryonic lethal, demonstrating developmental essentiality and explaining why the human disorder is a haploinsufficiency phenotype rather than biallelic loss (reviewed in Cuinat et al. 2022, PMID: 35567594). A dosage-sensitive heterozygous mouse model specific to MRD72 is not yet well characterized.
C. elegans: SRm300/SRRM2 knockout is likewise embryonic-lethal, confirming conserved essentiality.
Drosophila: The combined Srrm234 gene represents the ancestral form of vertebrate SRRM2/3/4.
Zebrafish: Reported to modulate cell fate in early development (Carvalho et al. 2024, Biol Open), consistent with a broad developmental role.
Cross-scaffold model (SON): As a proxy for the speckle-scaffold mechanism, a Son+/- haploinsufficiency mouse "recapitulated clinical symptoms" of ZTTK syndrome — growth retardation, cognitive impairment, skeletal abnormalities, and kidney agenesis, plus hematopoietic abnormalities (PMID: 38290089). This shows partial loss of a nuclear-speckle scaffold protein is sufficient to produce a multisystem neurodevelopmental phenotype, strongly supporting the SRRM2 haploinsufficiency model.
Model applications / limitations: Existing models establish essentiality and the speckle-scaffold paradigm but do not yet recapitulate the specific mild MRD72 phenotype; a conditional/dosage-controlled Srrm2 heterozygous CNS model is the key resource gap.

Section 16 — Critical Clarification: MRD72 (SRRM2) vs. the ZBTB7A Disorder (MNDLFH)

Because the early iterations initially attributed MRD72 to ZBTB7A, this section explicitly separates the two entities. They are distinct diseases.

Feature	MRD72 (this report)	MNDLFH (distinct disorder)
Gene	*SRRM2* (16p13.3)	ZBTB7A (19p13.3)
OMIM	#620439	#619769
Protein / function	SRm300, nuclear-speckle splicing scaffold	LRF/Pokemon, BTB-zinc-finger transcriptional repressor
Core phenotype	Mild DD, speech delay, ASD/ADHD, hypotonia, overweight, mild dysmorphism	ID, macrocephaly, pharyngeal/adenoid lymphoid overgrowth, elevated fetal hemoglobin
Mechanism	Haploinsufficiency of splicing/speckle scaffold	Haploinsufficiency of a transcription factor (lympho/hematopoiesis)

The ZBTB7A findings gathered in iterations 1–2 — elevated HbF via γ-globin de-repression (PMID: 34515416, PMID: 26816381); oligodendrocyte differentiation role (PMID: 22615173); B-vs-T lineage/Notch regulation (PMID: 17495164); overlap with 19p13.3 microdeletion syndrome (PMID: 25853300, PMID: 23610052) — belong to MNDLFH, not MRD72, and are retained only to prevent conflation. For MRD72 knowledge-base population, use exclusively the SRRM2 content in Sections 1–15.

Mechanistic Model / Interpretation

MRD72 is best understood as a nuclear-speckle spliceosomopathy. The unifying concept: certain nuclear proteins that build and maintain nuclear speckles — the organelles that concentrate the splicing machinery — are exquisitely dosage-sensitive in the developing nervous system. SRRM2 and SON are the two obligate scaffolding subunits of the speckle core (PMID: 33095160). Reducing either to ~50% (haploinsufficiency) does not kill the cell (unlike complete knockout, which is embryonic-lethal) but degrades splicing efficiency/fidelity enough to derail neurodevelopment — yielding overlapping but distinct autosomal-dominant NDDs:

Nuclear-speckle core scaffold (SON + SRRM2)
 │                    │
SON haploinsufficiency   SRRM2 haploinsufficiency
 │                    │
     ZTTK syndrome         MRD72
   (OMIM #617140)       (OMIM #620439)
severe multisystem      milder, speech-predominant
(brain/skeletal/renal)  (DD, ASD/ADHD, hypotonia,
                 overweight)

The extreme evolutionary constraint on SRRM2 (pLI = 1.0; LOEUF ≈ 0.18; ClinGen HI = 3), the near-uniformly de novo protein-truncating variant spectrum, the recurrent 16p13.3 palindrome-mediated deletions, and the essentiality across mouse/worm/fly/zebrafish together form a coherent, internally consistent haploinsufficiency model. The comparatively mild phenotype (relative to ZTTK) suggests that residual SRRM2 splicing-coactivator activity, and partial functional redundancy within the SR-related protein family (including partner/paralog SRRM1), buffer the consequences of 50% dosage loss.

Evidence Base

PMID	Title (abbrev.)	Role in this report
35567594	Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder	Defining paper. Establishes SRRM2 as causal; 22-patient cohort; variant spectrum; core phenotype; LoF constraint; SRm300 splicing function
33095160	SON and SRRM2 are essential for nuclear speckle formation	Mechanistic basis — SRRM2 is the SC35 antigen and, with SON, the essential speckle scaffold
40225164	A Palindrome-Like Structure on 16p13.3…	Recurrent whole-gene deletions; 16p13.3 palindrome; ~1/1300 prevalence estimate in unexplained ID
38290089	Mouse model of ZTTK syndrome reveals indispensable SON functions	Proof that haploinsufficiency of a speckle-scaffold protein produces a multisystem NDD (paralog support)
40593860	Blood transcriptome profiling in a pediatric cohort	Emerging RNA-seq diagnostics for splicing disorders (adjunct)
34515416, 26816381, 22615173, 17495164, 25853300, 23610052	ZBTB7A / 19p13.3 series	Pertain to the distinct MNDLFH disorder — included only for differential clarification (Section 16)

Evidence-source types: Human clinical (Cuinat 2022 cohort; Pagnamenta 2023 structural variants) forms the diagnostic and clinical backbone. In vitro/cell biology (Ilik 2020, PMID: 33095160) supplies the speckle-scaffold mechanism. Model-organism data (Son+/- mouse, PMID: 38290089; lethal Srrm2 knockouts) provide mechanistic and essentiality support. Computational constraint metrics (gnomAD/ClinGen/DDD) corroborate haploinsufficiency.

Limitations and Knowledge Gaps

Small evidence base. The disease is defined largely by one 22-patient cohort plus structural-variant reports; per-phenotype frequencies, penetrance, and expressivity are imprecise.
No MRD72-specific molecular profiling. Patient-derived transcriptomic/proteomic maps of the mis-splicing signature are lacking; the exact mis-spliced targets driving the neurodevelopmental phenotype are unknown.
No dedicated animal model. A dosage-controlled Srrm2+/- (or CNS-conditional) mouse recapitulating the mild MRD72 phenotype has not been reported; existing knockouts are lethal.
No natural history / QoL data. Longitudinal outcomes, adult phenotype, and validated QoL measures are absent.
No targeted therapy. Management is entirely supportive; no gene-dosage-restorative approaches are in development.
Naming ambiguity. MRD72 was conflated with the ZBTB7A disorder early in this investigation; downstream knowledge bases must preserve the SRRM2 (OMIM #620439) vs ZBTB7A (OMIM #619769) distinction.

Proposed Follow-up Experiments / Actions

Deep-phenotype an expanded cohort (international registry via GeneMatcher/DECIPHER) to quantify per-feature frequencies, penetrance, expressivity, and adult outcomes.
Patient-derived transcriptomics (blood + iPSC-derived neurons) to define the SRRM2-haploinsufficiency mis-splicing signature and candidate downstream effectors; leverage RNA-seq diagnostics (PMID: 40593860).
Generate a Srrm2+/- (and CNS-conditional) mouse to test phenotype recapitulation, nuclear-speckle integrity, and neurodevelopmental splicing programs; benchmark against the Son+/- ZTTK model.
Systematic comparison with ZTTK/SON and SRRM1 to map the "nuclear-speckle spliceosomopathy" spectrum and identify shared vs gene-specific molecular consequences.
Functional/CNV validation of the 16p13.3 palindrome mechanism and its contribution to recurrent deletions for improved variant interpretation.
Curate and correct ontology cross-references (MONDO:0957397 ↔ OMIM #620439 ↔ SRRM2) to prevent conflation with the ZBTB7A disorder.

Report compiled from 5 investigation iterations, 12 confirmed findings, and 35 reviewed papers. Primary source: Cuinat et al., Genet Med 2022 (PMID: 35567594).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	11
Resolved	11
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	5
Quoted claims found in source	5
Quoted claims not found in source	0
References weighed for topical relevance	11
On topic	6
Off topic	0

All extracted references resolved successfully.

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Classifications

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Differential Diagnoses

Related Datasets

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

2. Etiology

3. Phenotypes

Core neurodevelopmental phenotypes (Cuinat cohort, LoF variants — typically milder end of spectrum)

Dysmorphic facial features (Cuinat cohort)

More severe structural-variant phenotype (100,000 Genomes Project deletion cohort, n=4–6)

Expanding phenotype — missense/IDR variants

Additional reported feature — tics/movement disorder

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary for Knowledge-Base Curation

Sources

Reference Validation

Intellectual Developmental Disorder, Autosomal Dominant 72 (MRD72): A Comprehensive Disease Characterization

Summary

Section 1 — Disease Information

Section 2 — Etiology

Section 3 — Phenotypes

Section 4 — Genetic / Molecular Information

Section 5 — Environmental Information

Section 6 — Mechanism / Pathophysiology

Section 7 — Anatomical Structures Affected

Section 8 — Temporal Development

Section 9 — Inheritance and Population

Section 10 — Diagnostics

Section 11 — Outcome / Prognosis

Section 12 — Treatment

Section 13 — Prevention

Section 14 — Other Species / Natural Disease

Section 15 — Model Organisms

Section 16 — Critical Clarification: MRD72 (SRRM2) vs. the ZBTB7A Disorder (MNDLFH)

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation