SRRM2 – SRRM2-related Intellectual Developmental Disorder

The SRRM2 gene encodes the SRm300 splicing coactivator, a serine/arginine-rich protein essential for spliceosome catalytic function. Predicted to be intolerant to loss-of-function, SRRM2 has been recently implicated in intellectual developmental disorder, autosomal dominant 72 via de novo truncating variants (PMID:35567594).

In a retrospective exome review at a single tertiary children’s hospital, three patients were identified with de novo SRRM2 loss-of-function variants among ~3,100 exomes, in addition to one previously described case, totaling four probands (PMID:37212523). Separately, 22 unrelated individuals harboring de novo frameshift or nonsense SRRM2 variants were reported across international cohorts. Together, these 26 independent cases establish a reproducible genotype–phenotype correlation.

The variant spectrum comprises 12 frameshift, 8 nonsense, and 2 intragenic microdeletions, consistent with haploinsufficiency. A representative truncating allele is c.4616C>A (p.Ser1539Ter). All variants arose de novo, supporting an autosomal dominant inheritance pattern.

Affected individuals uniformly present with global developmental delay and predominant speech impairment, often accompanied by attention-deficit/hyperactivity disorder (HP:0007018), autism spectrum features (HP:0000717), macrocephaly (HP:0000256), generalized hypotonia (HP:0001252), and gastroesophageal reflux (HP:0002020). The severity of intellectual disability is variable among carriers.

Functional studies in yeast demonstrate that the Cwc21p ortholog of SRRM2 positions the 3′ splice site during the second step of splicing (PMID:25740649). In human cellular models of neurodegeneration, SRRM2 downregulation disrupts nuclear speckle integrity and promotes TDP-43 mislocalization, linking spliceosomal dysfunction to neuronal pathology (PMID:40291645). These data concordantly support a loss-of-function mechanism.

A heterozygous SRRM2 missense variant, c.1037C>T (p.Ser346Phe), was reported in a kindred with papillary thyroid carcinoma but also detected in sporadic cases and controls without neurodevelopmental features, indicating a distinct disease mechanism and no conflict with the neurodevelopmental phenotype (PMID:26135620).

Collectively, the genetic and experimental evidence meets ClinGen criteria for a Strong gene–disease association. Diagnostic sequencing of SRRM2 should be considered in individuals with unexplained developmental delay, macrocephaly, and behavioral features to enable early intervention.

Key Take-home: Loss-of-function variants in SRRM2 cause an autosomal dominant neurodevelopmental disorder characterized by developmental delay, behavioral anomalies, and spliceosomal dysfunction.

References

• Genetics in medicine : official journal of the American College of Medical Genetics • 2022 • Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder. PMID:35567594
• American journal of medical genetics. Part A • 2023 • Retrospective identification of patients with SRRM2-related neurodevelopmental disorder in a single tertiary children's hospital. PMID:37212523
• Nucleic acids research • 2015 • Cwc21p promotes the second step conformation of the spliceosome and modulates 3' splice site selection. PMID:25740649
• Scientific reports • 2015 • A germline mutation in SRRM2, a splicing factor gene, is implicated in papillary thyroid carcinoma predisposition. PMID:26135620
• bioRxiv : the preprint server for biology • 2025 • Context-dependent Interactors Regulate TDP-43 Dysfunction in ALS/FTLD. PMID:40291645

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