Journal article
De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas
American journal of human genetics, Vol.106(6), pp.830-845
06/04/2020
DOI: 10.1016/j.ajhg.2020.04.015
PMID: 32442410
Abstract
SOX6 belongs to a family of 20 SRY-related HMG-box-containing (SOX) genes that encode transcription factors controlling cell fate and differentiation in many developmental and adult processes. For SOX6, these processes include, but are not limited to, neurogenesis and skeletogenesis. Variants in half of the SOX genes have been shown to cause severe developmental and adult syndromes, referred to as SOXopathies. We here provide evidence that SOX6 variants also cause a SOXopathy. Using clinical and genetic data, we identify 19 individuals harboring various types of SOX6 alterations and exhibiting developmental delay and/or intellectual disability; the individuals are from 17 unrelated families. Additional, inconstant features include attention-deficit/hyperactivity disorder (ADHD), autism, mild facial dysmorphism, craniosynostosis, and multiple osteochondromas. All variants are heterozygous. Fourteen are de novo, one is inherited from a mosaic father, and four offspring from two families have a paternally inherited variant. Intragenic microdeletions, balanced structural rearrangements, frameshifts, and nonsense variants are predicted to inactivate the SOX6 variant allele. Four missense variants occur in residues and protein regions highly conserved evolutionarily. These variants are not detected in the gnomAD control cohort, and the amino acid substitutions are predicted to be damaging. Two of these variants are located in the HMG domain and abolish SOX6 transcriptional activity in vitro. No clear genotype-phenotype correlations are found. Taken together, these findings concur that SOX6 haploinsufficiency leads to a neurodevelopmental SOXopathy that often includes ADHD and abnormal skeletal and other features.
Details
- Title: Subtitle
- De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas
- Creators
- Dara Tolchin - Department of Surgery, Division of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USAH.E StevensJessica P Yeager - Department of Surgery, Division of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USAPriya Prasad - Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201, USANaghmeh Dorrani - Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USAAlvaro Serrano Russi - Division of Medical Genetics, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USAJulian A Martinez-Agosto - Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USAAbdul Haseeb - Department of Surgery, Division of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USAMarco Angelozzi - Department of Surgery, Division of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USAG.W.E Santen - Department of Clinical Genetics, Leiden University Medical Centre, 2300 LC Leiden, the NetherlandsClaudia Ruivenkamp - Department of Clinical Genetics, Leiden University Medical Centre, 2300 LC Leiden, the NetherlandsSaadet Mercimek-Andrews - Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, CanadaChristel Depienne - Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, GermanyAlma Kuechler - Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, GermanyBarbara Mikat - Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, GermanyHermann-Josef Ludecke - Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, GermanyFrederic Bilan - Neurovascular Unit and Cognitive Disorders (EA-3808 NEUVACOD), Université de Poitiers, 86073 Poitiers, FranceGwenael Le Guyader - Neurovascular Unit and Cognitive Disorders (EA-3808 NEUVACOD), Université de Poitiers, 86073 Poitiers, FranceBrigitte Gilbert-Dussardier - Neurovascular Unit and Cognitive Disorders (EA-3808 NEUVACOD), Université de Poitiers, 86073 Poitiers, FranceBoris Keren - Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique, 75013 Paris, FranceSolveig Heide - Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique, 75013 Paris, FranceDamien Haye - Service de Génétique, Centre Hospitalier Universitaire de Nice Hôpital de l’Archet 2,151 route Saint Antoine de la Ginestière, 062002 Nice, FranceHilde Van Esch - Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, BelgiumLiesbeth Keldermans - Laboratory for Molecular Diagnosis, Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, BelgiumDamara Ortiz - University of Pittsburgh Medical Center, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USAEmily Lancaster - University of Pittsburgh Medical Center, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USAIan D Krantz - Roberts Individualized Medical Genetics Center, Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USABryan L Krock - Division of Genomic Diagnostics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USAKieran B Pechter - Division of Genomic Diagnostics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USAAlexandre Arkader - Department of Surgery, Division of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USALivija Medne - Roberts Individualized Medical Genetics Center, Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USAElizabeth T DeChene - Division of Genomic Diagnostics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USAEduardo Calpena - MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UKGiada Melistaccio - MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UKAndrew O.M Wilkie - MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UKMohnish Suri - Clinical Genetics Service, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham NG5 1PB, UKNicola Foulds - Wessex Clinical Genetics Services, University Hospital Southampton NHS Foundation Trust, Southampton SO16 5YA, UKJ.C AmbroseM BledaF Boardman-PrettyJ.M BoissiereC.R BoustredM.J CaulfieldG.C ChanC.E.H CraigL.C DaughertyA de BurcaA DevereauG ElgarR.E FoulgerT FowlerP Furió-TaríJ.M HackettD HalaiJ.E HolmanT.J.P HubbardD KasperaviciuteM KayikciL LahnsteinK LawsonS.E.A LeighI.U.S LeongF.J LopezF Maleady-CroweJ MasonE.M McDonaghL MoutsianasM MuellerA.C NeedC.A OdhamsC PatchD Perez-GilD PolychronopoulosJ PullingerT RahimA RendonT RogersM RytenK SavageR.H ScottA SiddiqA SieghartD SmedleyK.R SmithA SosinskyW SpoonerA StuckeyE R A ThomasS.R ThompsonC TregidgoA TucciE WalshS.A WattersM.J WellandE WilliamsK WitkowskaS.M WoodM ZarowieckiAmber Begtrup - GeneDx, Gaithersburg, MD 20877, USALindsay B Henderson - GeneDx, Gaithersburg, MD 20877, USACara Forster - GeneDx, Gaithersburg, MD 20877, USAPatrick Reed - GeneDx, Gaithersburg, MD 20877, USAMarie T McDonald - Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, NC 27707, USAAllyn McConkie-Rosell - Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, NC 27707, USAJulien Thevenon - Service de Génétique, Génomique, et Procréation, Centre Hospitalier Universitaire Grenoble Alpes, 38700 La Tronche, FrancePauline Le Tanno - Service de Génétique, Génomique, et Procréation, Centre Hospitalier Universitaire Grenoble Alpes, 38700 La Tronche, FranceCharles Coutton - Service de Génétique, Génomique, et Procréation, Centre Hospitalier Universitaire Grenoble Alpes, 38700 La Tronche, FranceAnne C.H Tsai - Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO 80045, USASarah Stewart - Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO 80045, USAAles Maver - Clinical Institute of Medical Genetics, University Medical Centre Ljubljana, 1000 Ljubljana, SloveniaRudolf Gorazd - Clinical Institute of Medical Genetics, University Medical Centre Ljubljana, 1000 Ljubljana, SloveniaOlivier Pichon - Centre Hospitalier Universitaire Nantes, Service de Génétique Médicale, 44000 Nantes, FranceMathilde Nizon - Centre Hospitalier Universitaire Nantes, Service de Génétique Médicale, 44000 Nantes, FranceBenjamin Cogné - Centre Hospitalier Universitaire Nantes, Service de Génétique Médicale, 44000 Nantes, FranceBertrand Isidor - Centre Hospitalier Universitaire Nantes, Service de Génétique Médicale, 44000 Nantes, FranceDominique Martin-Coignard - Service de Cytogénétique, Centre Hospitalier Universitaire de Le Mans, 72037 Le Mans, FranceRadka Stoeva - Service de Cytogénétique, Centre Hospitalier Universitaire de Le Mans, 72037 Le Mans, FranceVéronique Lefebvre - Department of Surgery, Division of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USACédric Le Caignec - Centre Hospitalier Universitaire Nantes, Service de Génétique Médicale, 44000 Nantes, France
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.106(6), pp.830-845
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.ajhg.2020.04.015
- PMID
- 32442410
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Grant note
- name: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme; DOI: 10.13039/100010269, name: Wellcome Trust; DOI: 10.13039/501100000289, name: Cancer Research UK; DOI: 10.13039/501100000265, name: Medical Research Council; DOI: 10.13039/100006458, name: Children's Hospital of Philadelphia
- Language
- English
- Date published
- 06/04/2020
- Academic Unit
- Psychiatry; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984071953602771
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