SRSF1 haploinsufficiency is responsible for a syndromic developmental disorder associated with intellectual disability.

TitleSRSF1 haploinsufficiency is responsible for a syndromic developmental disorder associated with intellectual disability.
Publication TypeJournal Article
Year of Publication2023
AuthorsBogaert, E, Garde, A, Gautier, T, Rooney, K, Duffourd, Y, LeBlanc, P, van Reempts, E, Mau-Them, FTran, Wentzensen, IM, Au, KSing, Richardson, K, Northrup, H, Gatinois, V, Geneviève, D, Louie, RJ, Lyons, MJ, Laulund, LWalentin, Brasch-Andersen, C, Juul, TMaxel, It, FEl, Marle, N, Callier, P, Relator, R, Haghshenas, S, McConkey, H, Kerkhof, J, Cesario, C, Novelli, A, Brunetti-Pierri, N, Pinelli, M, Pennamen, P, Naudion, S, Legendre, M, Courdier, C, Trimouille, A, Fenzy, MDoco, Pais, L, Yeung, A, Nugent, K, Roeder, ER, Mitani, T, Posey, JE, Calame, D, Yonath, H, Rosenfeld, JA, Musante, L, Faletra, F, Montanari, F, Sartor, G, Vancini, A, Seri, M, Besmond, C, Poirier, K, Hubert, L, Hemelsoet, D, Munnich, A, Lupski, JR, Philippe, C, Thauvin-Robinet, C, Faivre, L, Sadikovic, B, Govin, J, Dermaut, B, Vitobello, A
JournalAm J Hum Genet
Date Published2023 May 04
KeywordsChild, Developmental Disabilities, Female, Haploinsufficiency, Humans, Intellectual Disability, Male, Mutation, Missense, Neurodevelopmental Disorders, Phenotype

SRSF1 (also known as ASF/SF2) is a non-small nuclear ribonucleoprotein (non-snRNP) that belongs to the arginine/serine (R/S) domain family. It recognizes and binds to mRNA, regulating both constitutive and alternative splicing. The complete loss of this proto-oncogene in mice is embryonically lethal. Through international data sharing, we identified 17 individuals (10 females and 7 males) with a neurodevelopmental disorder (NDD) with heterozygous germline SRSF1 variants, mostly de novo, including three frameshift variants, three nonsense variants, seven missense variants, and two microdeletions within region 17q22 encompassing SRSF1. Only in one family, the de novo origin could not be established. All individuals featured a recurrent phenotype including developmental delay and intellectual disability (DD/ID), hypotonia, neurobehavioral problems, with variable skeletal (66.7%) and cardiac (46%) anomalies. To investigate the functional consequences of SRSF1 variants, we performed in silico structural modeling, developed an in vivo splicing assay in Drosophila, and carried out episignature analysis in blood-derived DNA from affected individuals. We found that all loss-of-function and 5 out of 7 missense variants were pathogenic, leading to a loss of SRSF1 splicing activity in Drosophila, correlating with a detectable and specific DNA methylation episignature. In addition, our orthogonal in silico, in vivo, and epigenetics analyses enabled the separation of clearly pathogenic missense variants from those with uncertain significance. Overall, these results indicated that haploinsufficiency of SRSF1 is responsible for a syndromic NDD with ID due to a partial loss of SRSF1-mediated splicing activity.

Alternate JournalAm J Hum Genet
PubMed ID37071997
PubMed Central IDPMC10183470
Grant ListR01 HG009141 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
UM1 HG008900 / HG / NHGRI NIH HHS / United States

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