2. Academic Validation
  3. GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder

GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder

  • Genet Med. 2020 May;22(5):878-888. doi: 10.1038/s41436-019-0747-z.
Christine Shieh 1,  Natasha Jones 2,  Brigitte Vanle 3 4,  Margaret Au 5,  Alden Y Huang 6,  Ana P G Silva 2,  Hane Lee 7,  Emilie D Douine 8,  Maria G Otero 9,  Andrew Choi 9,  Katheryn Grand 10,  Ingrid P Taff 11,  Mauricio R Delgado 12,  M J Hajianpour 13,  Andrea Seeley 14,  Luis Rohena 15 16,  Hilary Vernon 17,  Karen W Gripp 18,  Samantha A Vergano 19,  Sonal Mahida 20,  Sakkubai Naidu 21 22,  Ana Berta Sousa 23,  Karen E Wain 24,  Thomas D Challman 24,  Geoffrey Beek 25,  Donald Basel 26,  Judith Ranells 27,  Rosemarie Smith 28,  Roman Yusupov 29,  Mary-Louise Freckmann 30,  Lisa Ohden 31,  Laura Davis-Keppen 32,  David Chitayat 33 34,  James J Dowling 35,  Richard Finkel 36,  Andrew Dauber 37,  Rebecca Spillmann 38,  Loren D M Pena 39 40,  Undiagnosed Diseases Network,  Kay Metcalfe 41,  Miranda Splitt 42,  Katherine Lachlan 43 44,  Shane A McKee 45,  Jane Hurst 46,  David R Fitzpatrick 47,  Jenny E V Morton 48 49 50,  Helen Cox 48 49 50,  Sunita Venkateswaran 51,  Juan I Young 52,  Eric D Marsh 53,  Stanley F Nelson 8,  Julian A Martinez 54,  John M Graham Jr 55,  Usha Kini 56,  Joel P Mackay 2,  Tyler Mark Pierson 57 58 59
Affiliations

Affiliations

  • 1 David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • 2 School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, Australia.
  • 3 Department of Psychiatry & Behavioral Neurosciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 4 Medical College of Wisconsin-Central Wisconsin, Wausau, WI, USA.
  • 5 Department of Pediatrics Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 6 Institute for Precision Health, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • 7 Department of Human Genetics and Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • 8 Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • 9 Board of Governor's Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 10 Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 11 Department of Neurology, Hofstra School of Medicine, Great Neck, NY, USA.
  • 12 Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center and Texas Scottish Rite Hospital for Children, Dallas, TX, USA.
  • 13 Department of Pediatrics, Division of Medical Genetics, East Tennessee State University, Quillen College of Medicine, Mountain Home, TN, USA.
  • 14 Geisinger Medical Center, Danville, PA, USA.
  • 15 Division of Genetics, Department of Pediatrics, Brooke Army Medical Center, Fort Sam Houston, TX, USA.
  • 16 Department of Pediatrics, UT Health San Antonio, Long School of Medicine, San Antonio, TX, USA.
  • 17 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Balitmore, MD, USA.
  • 18 Division of Medical Genetics, Al DuPont Hospital for Children, Wilmington, DE, USA.
  • 19 Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA, USA.
  • 20 Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.
  • 21 Department of Neurology and Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • 22 Hugo Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD, USA.
  • 23 Serviço de Genética Médica, Hospital Santa Maria, CHULN, Lisboa, Portugal and Faculdade de Medicina de Lisboa, Universidade de Lisboa, Lisboa, Portugal.
  • 24 Autism & Developmental Medicine Institute, Geisinger, Lewisburg, PA, USA.
  • 25 Children's Hospitals and Clinics of Minnesota Department of Genetics, Minneapolis, MN, USA.
  • 26 Department of Pediatrics, Division of Genetics; Children's Hospital of Wisconsin, Milwaukee, WI, USA.
  • 27 Division of Genetics and Metabolism, Department of Pediatrics, University of South Florida, Tampa, FL, USA.
  • 28 Department of Pediatrics, Division of Genetics, Maine Medical Center, Portland, ME, USA.
  • 29 Division of Clinical Genetics, Joe DiMaggio Children's Hospital, Hollywood, FlL, USA.
  • 30 Royal North Shore Hospital, St Leonards, NSW, Australia.
  • 31 Department of Genetic Counseling, Sanford Children's Specialty Clinic, Sioux Falls, SD, USA.
  • 32 Department of Pediatrics, Sanford School of Medicine of the University of South Dakota, Sioux Falls, SD, USA.
  • 33 The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
  • 34 Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
  • 35 Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada.
  • 36 Division of Pediatric Neurology, Department of Pediatrics, Nemours Children's Hospital, Orlando, FL, USA.
  • 37 Division of Endocrinology, Children's National Health System, Washington, DC, USA.
  • 38 Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA.
  • 39 Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 40 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
  • 41 Manchester Centre for Genomic Medicine, Manchester University NHS FT, Manchester, UK.
  • 42 Institute of Genetic Medicine, Northern Genetics Service, Newcastle upon Tyne Hospitals Trust, Newcastle, UK.
  • 43 Faculty of Medicine, University of Southampton, Southampton, UK.
  • 44 Human Development and Health Division, Wessex Clinical Genetics Service, University Hospitals of Southampton NHS Trust, Southampton, UK.
  • 45 Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK.
  • 46 Department of Clinical Genetics, NE Thames Genetics Service, Great Ormond Street Hospital, London, UK.
  • 47 Medical Research Council Human Genetics Unit, University of Edinburgh, Edinburgh, UK.
  • 48 West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham, UK.
  • 49 Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, UK.
  • 50 Birmingham Women's Hospital, Edgbaston, Birmingham, UK.
  • 51 Division of Neurology, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada.
  • 52 John P Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 53 Division of Neurology, Children's Hospital of Philadelphia and Department of Neurology and Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • 54 Department of Human Genetics; Division of Medical Genetics, Department of Pediatrics; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • 55 Department of Pediatrics, Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 56 Oxford Centre for Genomic Medicine, Oxford University Hospital NHS Foundation Trust, Oxford, UK.
  • 57 Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. [email protected].
  • 58 Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. [email protected].
  • 59 Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. [email protected].
PMID: 31949314 DOI: 10.1038/s41436-019-0747-z
Abstract

Purpose: Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND).

Methods: Fifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription-translation products were used to evaluate GATAD2B missense variants' ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex.

Results: Subjects had clinical findings that included macrocephaly, hypotonia, intellectual disability, neonatal feeding issues, polyhydramnios, apraxia of speech, epilepsy, and bicuspid aortic valves. Forty-one novelGATAD2B variants were identified with multiple variant types (nonsense, truncating frameshift, splice-site variants, deletions, and missense). Seven subjects were identified with missense variants that localized within two conserved region domains (CR1 or CR2) of the GATAD2B protein. Immunoprecipitation assays revealed several of these missense variants disrupted GATAD2B interactions with its NuRD complex binding partners.

Conclusions: A consistent GAND phenotype was caused by a range of genetic variants in GATAD2B that include loss-of-function and missense subtypes. Missense variants were present in conserved region domains that disrupted assembly of NuRD complex proteins. GAND's clinical phenotype had substantial clinical overlap with other disorders associated with the NuRD complex that involve CHD3 and CHD4, with clinical features of hypotonia, intellectual disability, cardiac defects, childhood apraxia of speech, and macrocephaly.

Keywords

GATAD2B; NuRD complex; apraxia of speech; chromatin remodeling; macrocephaly.

Figures