Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature.

Abnormalities, Multiple / genetics Adenosine Triphosphatases / genetics Case-Control Studies Cohort Studies Craniofacial Abnormalities / genetics DNA Methylation Epigenesis, Genetic Female Genetic Predisposition to Disease Growth Disorders / genetics Heart Septal Defects, Ventricular / genetics Humans Infant, Newborn Male Mutation Neurodevelopmental Disorders / genetics Phenotype
DNA methylation signature Floating-Harbor syndrome SRCAP epigenomics genotype-phenotype correlation intellectual disability neurodevelopmental disorders non-FLHS SRCAP-related NDD nonsense-mediated decay speech delay

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:
03 06 2021
Historique:
received: 20 01 2021
accepted: 31 03 2021
pubmed: 29 4 2021
medline: 29 6 2021
entrez: 28 4 2021
Statut: ppublish

Résumé

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.

Identifiants

DOI: 10.1016/j.ajhg.2021.04.008 PMID: 33909990 PMC: PMC8206150
pubmed: 33909990
pii: S0002-9297(21)00139-7
doi: 10.1016/j.ajhg.2021.04.008
pmc: PMC8206150
pii:
doi:

Substances chimiques

Adenosine Triphosphatases EC 3.6.1.-
SRCAP protein, human EC 3.6.4.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1053-1068

Subventions

Organisme : CIHR
ID : IGH-155182
Pays : Canada
Organisme : CIHR
ID : MOP-126054
Pays : Canada

Informations de copyright

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

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Auteurs

Dmitrijs Rots (D)

Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands.

Eric Chater-Diehl (E)

Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.

Alexander J M Dingemans (AJM)

Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands.

Sarah J Goodman (SJ)

Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.

Michelle T Siu (MT)

Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.

Cheryl Cytrynbaum (C)

Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada.

Sanaa Choufani (S)

Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.

Ny Hoang (N)

Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada; Department of Genetic Counselling, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.

Susan Walker (S)

Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.

Zain Awamleh (Z)

Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.

Joshua Charkow (J)

Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.

Stephen Meyn (S)

Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.

Rolph Pfundt (R)

Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.

Tuula Rinne (T)

Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.

Thatjana Gardeitchik (T)

Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.

Bert B A de Vries (BBA)

Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands.

A Chantal Deden (AC)

Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.

Erika Leenders (E)

Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.

Michael Kwint (M)

Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.

Constance T R M Stumpel (CTRM)

Department of Clinical Genetics and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, 6229 HX Maastricht, the Netherlands.

Servi J C Stevens (SJC)

Maastricht University Medical Center, 6229 HX Maastricht, the Netherlands.

Jeroen R Vermeulen (JR)

Maastricht University Medical Center, 6229 HX Maastricht, the Netherlands.

Jeske V T van Harssel (JVT)

Department of Genetics, University Medical Center 3584 CX Utrecht, Utrecht, the Netherlands.

Danielle G M Bosch (DGM)

Department of Genetics, University Medical Center 3584 CX Utrecht, Utrecht, the Netherlands.

Koen L I van Gassen (KLI)

Department of Genetics, University Medical Center 3584 CX Utrecht, Utrecht, the Netherlands.

Ellen van Binsbergen (E)

Department of Genetics, University Medical Center 3584 CX Utrecht, Utrecht, the Netherlands.

Christa M de Geus (CM)

University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands.

Hein Brackel (H)

Catharina Hospital, 5623 EJ Eindhoven, the Netherlands.

Maja Hempel (M)

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.

Davor Lessel (D)

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.

Jonas Denecke (J)

Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.

Anne Slavotinek (A)

Division of Genetics, Department of Pediatrics, UCSF, San Francisco, CA 94143, USA.

Jonathan Strober (J)

Division of Child Neurology, Department of Neurology & Pediatrics, UCSF, San Francisco, CA 94143, USA.

Amy Crunk (A)

GeneDx, Gaithersburg, MD 20877, USA.

Leandra Folk (L)

GeneDx, Gaithersburg, MD 20877, USA.

Ingrid M Wentzensen (IM)

GeneDx, Gaithersburg, MD 20877, USA.

Hui Yang (H)

GeneDx, Gaithersburg, MD 20877, USA.

Fanggeng Zou (F)

GeneDx, Gaithersburg, MD 20877, USA.

Francisca Millan (F)

GeneDx, Gaithersburg, MD 20877, USA.

Richard Person (R)

GeneDx, Gaithersburg, MD 20877, USA.

Yili Xie (Y)

GeneDx, Gaithersburg, MD 20877, USA.

Shuxi Liu (S)

GeneDx, Gaithersburg, MD 20877, USA.

Lilian B Ousager (LB)

Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark; Department of Clinical Research, Clinical Genetics, University of Southern Denmark, 5230 Odense, Denmark.

Martin Larsen (M)

Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark; Department of Clinical Research, Clinical Genetics, University of Southern Denmark, 5230 Odense, Denmark.

Laura Schultz-Rogers (L)

Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55902, USA.

Eva Morava (E)

Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55902, USA.

Eric W Klee (EW)

Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55902, USA; Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55902, USA.

Ian R Berry (IR)

Yorkshire and North East Genomic Laboratory Hub Central Laboratory, Leeds LS1 3EX, UK.

Jennifer Campbell (J)

Department of Clinical Genetics, Chapel Allerton Hospital, Leeds LS7 4SA, UK.

Kristin Lindstrom (K)

Phoenix Children's Hospital, Phoenix, AZ 85016 USA.

Brianna Pruniski (B)

Phoenix Children's Hospital, Phoenix, AZ 85016 USA.

Ann M Neumeyer (AM)

Massachusetts General Hospital for Children, Harvard Medical School, Boston, MA 02114, USA.

Jessica A Radley (JA)

Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham B15 2TG, UK; Clinical Genetics, London North West University Healthcare Foundation Trust, London HA1 3UJ, UK.

Chanika Phornphutkul (C)

Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.

Berkley Schmidt (B)

University of Virginia School of Medicine, Charlottesville, VA 22903, USA.

William G Wilson (WG)

University of Virginia School of Medicine, Charlottesville, VA 22903, USA.

Katrin Õunap (K)

Department of Clinical Genetics, United Laboratories, Tartu University Hospital, 50406 Tartu, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, 50090 Tartu, Estonia.

Karit Reinson (K)

Department of Clinical Genetics, United Laboratories, Tartu University Hospital, 50406 Tartu, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, 50090 Tartu, Estonia.

Sander Pajusalu (S)

Department of Clinical Genetics, United Laboratories, Tartu University Hospital, 50406 Tartu, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, 50090 Tartu, Estonia.

Arie van Haeringen (A)

Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.

Claudia Ruivenkamp (C)

Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.

Roos Cuperus (R)

Department of Paediatrics, Juliana Children's Hospital HAGA, 2545 AA the Hague, the Netherlands.

Fernando Santos-Simarro (F)

Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, 28029 Madrid, Spain.

María Palomares-Bralo (M)

Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, 28029 Madrid, Spain.

Marta Pacio-Míguez (M)

Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, 28029 Madrid, Spain.

Alyssa Ritter (A)

Division of Human Genetics, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA.

Elizabeth Bhoj (E)

Division of Human Genetics, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA.

Elin Tønne (E)

Department of Medical Genetics, Oslo University Hospital, 0450 Oslo, Norway.

Kristian Tveten (K)

Department of Medical genetics, Telemark Hospital Trust, 3710 Skien, Norway.

Gerarda Cappuccio (G)

Department of Translational Medicine, University of Naples "Federico II," 80138 Naples, Italy; Telethon Institute of Genetics and Medicine, 20129 Pozzuoli, Italy.

Nicola Brunetti-Pierri (N)

Department of Translational Medicine, University of Naples "Federico II," 80138 Naples, Italy; Telethon Institute of Genetics and Medicine, 20129 Pozzuoli, Italy.

Leah Rowe (L)

University of Colorado School of Medicine, Aurora, CO 13001, USA.

Jason Bunn (J)

University of Colorado School of Medicine, Aurora, CO 13001, USA.

Margarita Saenz (M)

University of Colorado School of Medicine, Aurora, CO 13001, USA.

Konrad Platzer (K)

Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany.

Mareike Mertens (M)

Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany.

Oana Caluseriu (O)

Department of Medical Genetics in the Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada.

Małgorzata J M Nowaczyk (MJM)

Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.

Ronald D Cohn (RD)

Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5G 1V7, Canada.

Peter Kannu (P)

Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2R3, Canada.

Ebba Alkhunaizi (E)

Genetics Program, North York General Hospital, Toronto, ON M2K 1E1, Canada.

David Chitayat (D)

Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada; Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.

Stephen W Scherer (SW)

Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada.

Han G Brunner (HG)

Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands; Maastricht University Medical Center, 6229 HX Maastricht, the Netherlands.

Lisenka E L M Vissers (LELM)

Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands.

Tjitske Kleefstra (T)

Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands.

David A Koolen (DA)

Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands. Electronic address: david.koolen@radboudumc.nl.

Rosanna Weksberg (R)

Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5G 1V7, Canada; Institute of Medical Science, School of Graduate Studies, University of Toronto, Toronto, ON M5S 2Z9, Canada. Electronic address: rweksb@sickkids.ca.

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Classifications MeSH

questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Malformations › Malformations multiples › Truncating SRCAP variants outside the...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Acid anhydride hydrolases › Adenosine triphosphatases › Truncating SRCAP variants outside the...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études cas-témoins › Truncating SRCAP variants outside the...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Truncating SRCAP variants outside the...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Malformations › Malformations de l'appareil locomoteur › Malformations crâniofaciales › Truncating SRCAP variants outside the...
questionsmedicales.fr › Phénomènes génétiques › Méthylation de l'ADN › Truncating SRCAP variants outside the...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Truncating SRCAP variants outside the...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Truncating SRCAP variants outside the...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Troubles de la croissance › Truncating SRCAP variants outside the...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Malformations › Malformations cardiovasculaires › Cardiopathies congénitales › Malformations des cloisons cardiaques › Communications interventriculaires › Truncating SRCAP variants outside the...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Truncating SRCAP variants outside the...
questionsmedicales.fr › Personnes › Tranches d'âge › Nourrisson › Nouveau-né › Truncating SRCAP variants outside the...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Truncating SRCAP variants outside the...
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Truncating SRCAP variants outside the...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Truncating SRCAP variants outside the...