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

Child Female Male Developmental Disabilities / genetics Haploinsufficiency / genetics Intellectual Disability / pathology Mutation, Missense / genetics Neurodevelopmental Disorders / genetics Phenotype Humans
Drosophila SRSF1 epigenetic signature haploinsufficiency neurodevelopmental disorder splicing

Journal

American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475

Informations de publication

Date de publication:
04 05 2023
Historique:
received: 14 12 2022
accepted: 23 03 2023
medline: 8 5 2023
pubmed: 19 4 2023
entrez: 18 4 2023
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ajhg.2023.03.016 PMID: 37071997 PMC: PMC10183470
pubmed: 37071997
pii: S0002-9297(23)00100-3
doi: 10.1016/j.ajhg.2023.03.016
pmc: PMC10183470
pii:
doi:

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

790-808

Subventions

Organisme : NHGRI NIH HHS
ID : R01 HG009141
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS105078
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States

Informations de copyright

Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests I.M.W. is an employee of GeneDx, LLC. J.R.L. has stock ownership in 23andMe, is a paid consultant for the Regeneron Genetics Center, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics (BG) Laboratories. J.R.L. serves on the Scientific Advisory Board of BG.

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Auteurs

Elke Bogaert (E)

Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium; Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium.

Aurore Garde (A)

UMR1231 GAD, Inserm - Université de Bourgogne, Dijon, France; Centre de Référence Maladies Rares "Anomalies du Développement et Syndromes Malformatifs", Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, 21000 Dijon, France.

Thierry Gautier (T)

University Grenoble Alpes, Inserm U1209, CNRS UMR 5309, Institute for Advanced Biosciences (IAB), 38000 Grenoble, France.

Kathleen Rooney (K)

Department of Pathology and Laboratory Medicine, Western University, London, ON N5A 3K7, Canada; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON N6A 5W9, Canada.

Yannis Duffourd (Y)

UMR1231 GAD, Inserm - Université de Bourgogne, Dijon, France; Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, 21000 Dijon, France.

Pontus LeBlanc (P)

Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium; Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium.

Emma van Reempts (E)

Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium; Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium.

Frederic Tran Mau-Them (F)

UMR1231 GAD, Inserm - Université de Bourgogne, Dijon, France; Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, 21000 Dijon, France.

Ingrid M Wentzensen (IM)

GeneDx, Gaithersburg, MD, USA.

Kit Sing Au (KS)

Division of Medical Genetics, Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX, USA; Children's Memorial Hermann Hospital, Houston, TX, USA.

Kate Richardson (K)

Division of Medical Genetics, Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX, USA; Children's Memorial Hermann Hospital, Houston, TX, USA.

Hope Northrup (H)

Division of Medical Genetics, Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX, USA; Children's Memorial Hermann Hospital, Houston, TX, USA.

Vincent Gatinois (V)

Unité de Génétique Chromosomique, CHU Montpellier, Montpellier, France.

David Geneviève (D)

Montpellier University, Inserm U1183, Montpellier, France; Reference center for rare disease developmental anomaly malformative syndrome, Department of Medical Genetics, Montpellier Hospital, Montpellier, France.

Raymond J Louie (RJ)

Greenwood Genetic Center, Greenwood, SC, USA.

Michael J Lyons (MJ)

Greenwood Genetic Center, Greenwood, SC, USA.

Lone Walentin Laulund (LW)

Department of Paediatrics, Odense University Hospital, Odense, Denmark.

Charlotte Brasch-Andersen (C)

Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark; Human Genetics, Department of Clinical Research, Health Faculty, University of Southern Denmark, 5000 Odense, Denmark.

Trine Maxel Juul (T)

Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark.

Fatima El It (F)

UMR1231 GAD, Inserm - Université de Bourgogne, Dijon, France.

Nathalie Marle (N)

Laboratoire de Génétique Chromosomique et Moléculaire, Pôle de Biologie, CHU de Dijon, Dijon, France.

Patrick Callier (P)

UMR1231 GAD, Inserm - Université de Bourgogne, Dijon, France; Laboratoire de Génétique Chromosomique et Moléculaire, Pôle de Biologie, CHU de Dijon, Dijon, France.

Raissa Relator (R)

Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON N6A 5W9, Canada.

Sadegheh Haghshenas (S)

Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON N6A 5W9, Canada.

Haley McConkey (H)

Department of Pathology and Laboratory Medicine, Western University, London, ON N5A 3K7, Canada; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON N6A 5W9, Canada.

Jennifer Kerkhof (J)

Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON N6A 5W9, Canada.

Claudia Cesario (C)

Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Antonio Novelli (A)

Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Nicola Brunetti-Pierri (N)

Telethon Institute of Genetics and Medicine, Pozzuoli, Italy; Department of Translational Medicine, University of Naples Federico II, Naples, Italy.

Michele Pinelli (M)

Telethon Institute of Genetics and Medicine, Pozzuoli, Italy; Department of Translational Medicine, University of Naples Federico II, Naples, Italy.

Perrine Pennamen (P)

Medical Genetics Department, CHU Bordeaux, Bordeaux, France.

Sophie Naudion (S)

Medical Genetics Department, CHU Bordeaux, Bordeaux, France.

Marine Legendre (M)

Medical Genetics Department, CHU Bordeaux, Bordeaux, France.

Cécile Courdier (C)

Medical Genetics Department, CHU Bordeaux, Bordeaux, France.

Aurelien Trimouille (A)

INSERM U1211, Laboratoire MRGM, Bordeaux University, Bordeaux, France; Pathology Department, CHU Bordeaux, Bordeaux, France.

Martine Doco Fenzy (MD)

Service de génétique, CHU de Reims, Reims, France; Service de génétique médicale, CHU de Nantes, Nantes, France; L'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU de Nantes, Nantes, France.

Lynn Pais (L)

Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Alison Yeung (A)

Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, Australia.

Kimberly Nugent (K)

Department of Pediatrics, Baylor College of Medicine, San Antonio, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Elizabeth R Roeder (ER)

Department of Pediatrics, Baylor College of Medicine, San Antonio, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Tadahiro Mitani (T)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Jennifer E Posey (JE)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Daniel Calame (D)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA.

Hagith Yonath (H)

Internal Medicine A, Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Jill A Rosenfeld (JA)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Baylor Genetics Laboratories, Houston, TX, USA.

Luciana Musante (L)

Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy.

Flavio Faletra (F)

Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy.

Francesca Montanari (F)

UO Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

Giovanna Sartor (G)

UO Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

Alessandra Vancini (A)

Neonatal Intensive Care Unit, Maggiore Hospital, Bologna, Italy.

Marco Seri (M)

UO Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

Claude Besmond (C)

Université Paris Cité, Imagine Institute, INSERM UMR1163, Paris 75015, France.

Karine Poirier (K)

Université Paris Cité, Imagine Institute, INSERM UMR1163, Paris 75015, France.

Laurence Hubert (L)

Université Paris Cité, Imagine Institute, INSERM UMR1163, Paris 75015, France.

Dimitri Hemelsoet (D)

Department of Neurology, Ghent University Hospital, 9000 Ghent, Belgium.

Arnold Munnich (A)

Université Paris Cité, Imagine Institute, INSERM UMR1163, Paris 75015, France.

James R Lupski (JR)

Department of Pediatrics, Baylor College of Medicine, San Antonio, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.

Christophe Philippe (C)

UMR1231 GAD, Inserm - Université de Bourgogne, Dijon, France; Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, 21000 Dijon, France.

Christel Thauvin-Robinet (C)

UMR1231 GAD, Inserm - Université de Bourgogne, Dijon, France; Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, 21000 Dijon, France; Centre de Référence Maladies Rares « Déficiences intellectuelles de causes rares », Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.

Laurence Faivre (L)

UMR1231 GAD, Inserm - Université de Bourgogne, Dijon, France; Centre de Référence Maladies Rares "Anomalies du Développement et Syndromes Malformatifs", Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, 21000 Dijon, France.

Bekim Sadikovic (B)

Department of Pathology and Laboratory Medicine, Western University, London, ON N5A 3K7, Canada; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON N6A 5W9, Canada.

Jérôme Govin (J)

University Grenoble Alpes, Inserm U1209, CNRS UMR 5309, Institute for Advanced Biosciences (IAB), 38000 Grenoble, France.

Bart Dermaut (B)

Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium; Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium. Electronic address: bart.dermaut@ugent.be.

Antonio Vitobello (A)

UMR1231 GAD, Inserm - Université de Bourgogne, Dijon, France; Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, 21000 Dijon, France. Electronic address: antonio.vitobello@u-bourgogne.fr.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › SRSF1 haploinsufficiency is responsible for a...
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Incapacités de développement › SRSF1 haploinsufficiency is responsible for a...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Dosage génique › Haploinsuffisance › SRSF1 haploinsufficiency is responsible for a...
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Déficience intellectuelle › SRSF1 haploinsufficiency is responsible for a...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation faux-sens › SRSF1 haploinsufficiency is responsible for a...
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › SRSF1 haploinsufficiency is responsible for a...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › SRSF1 haploinsufficiency is responsible for a...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › SRSF1 haploinsufficiency is responsible for a...