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

Silvestre Cuinat*, Mathilde Nizon, Bertrand Isidor, Alexander Stegmann, Richard H van Jaarsveld, Koen L van Gassen, Jasper J van der Smagt, Catharina M L Volker-Touw, Sjoerd J B Holwerda, Paulien A Terhal, Sarah Schuhmann, Georgia Vasileiou, Mohamed Khalifa, Alaa A Nugud, Hemad Yasaei, Lilian Bomme Ousager, Charlotte B. Andersen, Wallid Deb, Thomas Besnard, Marleen E H SimonKarin Huijsdens-van Amsterdam, Nienke E Verbeek, Dena Matalon, Natalie Dykzeul, Shana White, Elizabeth Spiteri, Koen Devriendt, Anneleen Boogaerts, Marjolein Willemsen, Han G Brunner, Margje Sinnema, Bert B A De Vries, Erica H Gerkes, Rolph Pfundt, Kosuke Izumi, Ian D Krantz, Zhou L Xu, Jill R Murrell, Irene Valenzuela, Ivon Cusco, Eulàlia Rovira-Moreno, Yaping Yang, Varoona Bizaoui, Olivier Patat, Laurence Faivre, Frederic Tran-Mau-Them, Antonio Vitobello, Anne-Sophie Denommé-Pichon, Christophe Philippe, Stéphane Bezieau, Benjamin Cogné

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review


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.

Original languageEnglish
JournalGenetics in medicine : official journal of the American College of Medical Genetics
Issue number8
Pages (from-to)1774-1780
Publication statusPublished - Aug 2022


  • Child
  • Developmental Disabilities/genetics
  • Humans
  • Intellectual Disability/genetics
  • Muscle Hypotonia/genetics
  • Neurodevelopmental Disorders/genetics
  • Phenotype
  • RNA-Binding Proteins/genetics


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