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Published on: August 15, 2019
Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder
Silvestre Cuinat1, Mathilde Nizon2, Bertrand Isidor2
1Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France.
Purpose:
SRRM2 encodes the SRm300 protein, 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. This gene, predicted to be highly intolerant to loss of function (LoF) and very conserved through evolution, has not been previously reported in constitutive human disease.
Methods:
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. Additional families were identified through GeneMatcher.
Results:
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. 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.
Conclusion:
We established SRRM2 as a gene responsible for a rare neurodevelopmental disease.
Insights
Loss of function variants in the SRRM2 gene are linked to a novel neurodevelopmental disorder. This condition presents with mild developmental delays, speech impairments, and behavioral features, impacting individuals with intellectual disability.
Area of Science:
- Genetics
- Neurodevelopmental Disorders
- Molecular Biology
Background:
- SRRM2 encodes the SRm300 protein, a crucial splicing factor involved in mRNA processing.
- The SRRM2 gene is highly conserved and predicted to be intolerant to loss-of-function variants.
- SRRM2 has not been previously associated with constitutive human diseases.
Purpose of the Study:
- To investigate the role of SRRM2 in human disease.
- To identify genetic causes of developmental delay and intellectual disability.
Main Methods:
- Analysis of 1000 probands with developmental delay and intellectual disability.
- Identification of de novo loss-of-function (LoF) variants in SRRM2.
- Phenotypic characterization of affected individuals.
Main Results:
- Identified 22 patients with LoF variants in SRRM2.
- Detected 12 frameshift, 8 nonsense variants, and 2 microdeletions.
- Observed phenotypes including mild developmental delay, speech delay, ADHD/autistic features, hypotonia, overweight, and dysmorphic features.
Conclusions:
- SRRM2 is a newly identified gene responsible for a rare neurodevelopmental disease.
- LoF variants in SRRM2 cause a spectrum of neurodevelopmental and behavioral abnormalities.
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