Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder

Fecha de publicación: 06/05/2021 Fecha Ahead of Print: 02/04/2021

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

Latypova, Xenia
Vincent, Marie
Molle, Alice
Adebambo, Oluwadamilare A.
Fourgeux, Cynthia
Khan, Tahir N.
Caro, Alfonso
Niyazov, Dmitriy
Lederer, Damien
Deprez, Marie
Capri, Yline
Kannu, Peter
Tabet, Anne Claude
Levy, Jonathan
Aten, Emmelien
den Hollander, Nicolette
Splitt, Miranda
Walia, Jagdeep
Immken, Ladonna L.
Stankiewicz, Pawel
McWalter, Kirsty
Suchy, Sharon
Louie, Raymond J.
Bell, Shannon
Stevenson, Roger E.
Rousseau, Justine
Willem, Catherine
Retiere, Christelle
Yang, Xiang-Jiao
Campeau, Philippe M.
Rosenfeld, Jill A.
Le Caignec, Cedric
Kury, Sebastien
Mercier, Sandra
Moradkhani, Kamran
Conrad, Solene
Besnard, Thomas
Cogne, Benjamin
Katsanis, Nicholas
Bezieau, Stephane
Poschmann, Jeremie
Davis, Erica E.
Isidor, Bertrand

Grupos

Investigación Traslacional en Genética

Leader

Francisco Martínez Castellano

Abstract

Proteins involved in transcriptional regulation harbor a demonstrated enrichment of mutations in neurodevelopmental disorders. The Sin3 (Swi-independent 3)/histone deacetylase (HDAC) complex plays a central role in histone deacetylation and transcriptional repression. Among the two vertebrate paralogs encoding the Sin3 complex, SIN3A variants cause syndromic intellectual disability, but the clinical consequences of SIN3B haploinsufficiency in humans are uncharacterized. Here, we describe a syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant autism spectrum disorder, congenital malformations, corpus callosum defects, and impaired growth caused by disruptive SIN3B variants. Using chromosomal microarray or exome sequencing, and through international data sharing efforts, we identified nine individuals with heterozygous SIN3B deletion or single-nucleotide variants. Five individuals harbor heterozygous deletions encompassing SIN3B that reside within a ~230 kb minimal region of overlap on 19p13.11, two individuals have a rare nonsynonymous substitution, and two individuals have a single-nucleotide deletion that results in a frameshift and predicted premature termination codon. To test the relevance of SIN3B impairment to measurable aspects of the human phenotype, we disrupted the orthologous zebrafish locus by genome editing and transient suppression. The mutant and morphant larvae display altered craniofacial patterning, commissural axon defects, and reduced body length supportive of an essential role for Sin3 function in growth and patterning of anterior structures. To investigate further the molecular consequences of SIN3B variants, we quantified genome-wide enhancer and promoter activity states by using H3K27ac ChIP-seq. We show that, similar to SIN3A mutations, SIN3B disruption causes hyperacetylation of a subset of enhancers and promoters in peripheral blood mononuclear cells. Together, these data demonstrate that SIN3B haploinsufficiency leads to a hitherto unknown intellectual disability/autism syndrome, uncover a crucial role of SIN3B in the central nervous system, and define the epigenetic landscape associated with Sin3 complex impairment.

Datos de la publicación

ISSN/ISSNe:: 0002-9297, 1537-6605
Tipo:: Article
Páginas:: 929-941
DOI:: 10.1016/j.ajhg.2021.03.017
Factor de Impacto:: 5,042 SCImago ℠
Cuartil:: Q1 SCImago ℠

Documentos

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Métricas

Filiaciones

Latypova, Xenia:: 1Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France; Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, 44007 Nantes, France.
Vincent, Marie:: 2Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, 44007 Nantes, France.
Molle, Alice:: 3Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, 44000 Nantes, France.
Adebambo, Oluwadamilare A.:: 4Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA.
Fourgeux, Cynthia:: 3Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, 44000 Nantes, France.
Khan, Tahir N.:: 5Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA; Department of Biological Sciences, National University of Medical Sciences, 46000 Rawalpindi, Pakistan.
Caro, Alfonso:: 6Unidad de Genética, Grupo de Investigación Traslacional en Genética, Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain.
Rosello, Monica:: 6Unidad de Genética, Grupo de Investigación Traslacional en Genética, Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain.
Orellana, Carmen:: 6Unidad de Genética, Grupo de Investigación Traslacional en Genética, Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain.
Niyazov, Dmitriy:: 7Department of Pediatrics, Ochsner Clinic, New Orleans, LA 70128, USA.
Lederer, Damien:: 8Centre de Génétique Humaine, IPG, 6041 Gosselies, Belgium.
Deprez, Marie:: 9Service de Neuropédiatrie, Clinique Saint Elizabeth, 5000 Namur, Belgium.
Capri, Yline:: 10Service de Génétique Médicale, Hôpital Robert Debré, 75019 Paris, France.
Kannu, Peter:: 11Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Tabet, Anne Claude:: 12Service de Cytogénétique, Hôpital Robert Debré, 75019 Paris, France.
Levy, Jonathan:: 12Service de Cytogénétique, Hôpital Robert Debré, 75019 Paris, France.
Aten, Emmelien:: 13Department of Clinical Genetics, Leiden University Medical Center, 2333 Leiden, the Netherlands.
den Hollander, Nicolette:: 13Department of Clinical Genetics, Leiden University Medical Center, 2333 Leiden, the Netherlands.
Splitt, Miranda:: 14Northern Genetics Service, Institute of Genetic Medicine, Newcastle Upon Tyne NE1 3BZ, UK.
Walia, Jagdeep:: 15Kingston General Hospital Research Institute, 76 Stuart Street, Kingston, ON K7L 2V7, Canada.
Immken, Ladonna L.:: 16Clinical Genetics, Dell Children's Medical Group, Austin, TX 78731, USA.
Stankiewicz, Pawel:: 17Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
McWalter, Kirsty:: 18GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
Suchy, Sharon:: 18GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
Louie, Raymond J.:: 19Greenwood Genetic Center, 106 Gregor Mendel Cir, Greenwood, SC 29646, USA.
Bell, Shannon:: 19Greenwood Genetic Center, 106 Gregor Mendel Cir, Greenwood, SC 29646, USA.
Stevenson, Roger E.:: 19Greenwood Genetic Center, 106 Gregor Mendel Cir, Greenwood, SC 29646, USA.
Rousseau, Justine:: 20Sainte-Justine Hospital, 3175, Cote-Sainte-Catherine, Montreal, QC, Canada.
Willem, Catherine:: 21Etablissement Français du Sang, 44000 Nantes, France.
Retiere, Christelle:: 22Etablissement Français du Sang, 44000 Nantes, France; CRCINA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44000 Nantes, France; LabEx IGO, Nantes 44000, France.
Yang, Xiang-Jiao:: 23Rosalind & Morris Goodman Cancer Research Center and Department of Medicine, McGill University, Montreal, QC H3A 1A3, Canada.
Campeau, Philippe M.:: 20Sainte-Justine Hospital, 3175, Cote-Sainte-Catherine, Montreal, QC, Canada.
Martinez, Francisco:: 6Unidad de Genética, Grupo de Investigación Traslacional en Genética, Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain.
Rosenfeld, Jill A.:: 17Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Le Caignec, Cedric:: 2Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, 44007 Nantes, France.
Kury, Sebastien:: 2Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, 44007 Nantes, France.
Mercier, Sandra:: 2Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, 44007 Nantes, France.
Moradkhani, Kamran:: 24Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France.
Conrad, Solene:: 24Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France.
Besnard, Thomas:: 2Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, 44007 Nantes, France.
Cogne, Benjamin:: 2Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, 44007 Nantes, France.
Katsanis, Nicholas:: 25Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA; Advanced Center for Translational and Genetic Medicine, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Bezieau, Stephane:: 2Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, 44007 Nantes, France.
Poschmann, Jeremie:: 26Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, 44000 Nantes, France.
Davis, Erica E.:: 27Advanced Center for Translational and Genetic Medicine, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Isidor, Bertrand:: 28Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France; L'Institut du Thorax, INSERM, CNRS, Université de Nantes, 44007 Nantes, France.