De novo variants in GATAD2A in individuals with a neurodevelopmental disorder: GATAD2A-related neurodevelopmental disorder

Elizabeth A. Werren; Alba Guxholli; Natasha Jones; Matias Wagner; Iris Hannibal; Jorge L. Granadillo; Amanda V. Tyndall; Amanda Moccia; Ryan Kuehl; Kristin M. Levandoski; Debra L. Day-Salvatore; Marsha Wheeler; Jessica X. Chong; Michael J. Bamshad; A. Micheil Innes; Tyler Mark Pierson; Joel P. Mackay; Stephanie L. Bielas; Donna M. Martin

HGG Advances (Jul 2023)

De novo variants in GATAD2A in individuals with a neurodevelopmental disorder: GATAD2A-related neurodevelopmental disorder

Elizabeth A. Werren,
Alba Guxholli,
Natasha Jones,
Matias Wagner,
Iris Hannibal,
Jorge L. Granadillo,
Amanda V. Tyndall,
Amanda Moccia,
Ryan Kuehl,
Kristin M. Levandoski,
Debra L. Day-Salvatore,
Marsha Wheeler,
Jessica X. Chong,
Michael J. Bamshad,
A. Micheil Innes,
Tyler Mark Pierson,
Joel P. Mackay,
Stephanie L. Bielas,
Donna M. Martin

Affiliations

Elizabeth A. Werren: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Alba Guxholli: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Natasha Jones: School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia
Matias Wagner: Institute of Human Genetics, Technical University of Munich, 80333 Munich, Germany
Iris Hannibal: Institute of Human Genetics, Technical University of Munich, 80333 Munich, Germany
Jorge L. Granadillo: Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
Amanda V. Tyndall: Department of Medical Genetics, Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
Amanda Moccia: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Ryan Kuehl: Saint Peter’s University Hospital, New Brunswick, NJ 08901, USA
Kristin M. Levandoski: Saint Peter’s University Hospital, New Brunswick, NJ 08901, USA
Debra L. Day-Salvatore: Saint Peter’s University Hospital, New Brunswick, NJ 08901, USA
Marsha Wheeler: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
Jessica X. Chong: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Brotman Baty Institute, Seattle, WA 98195, USA
Michael J. Bamshad: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Brotman Baty Institute, Seattle, WA 98195, USA
A. Micheil Innes: Department of Medical Genetics, Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Pediatrics, Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
Tyler Mark Pierson: Division of Pediatric Neurology, Department of Pediatrics, Guerin Children’s, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Center for the Undiagnosed Patient, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Joel P. Mackay: School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia
Stephanie L. Bielas: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Donna M. Martin: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Corresponding author

Journal volume & issue: Vol. 4, no. 3
p. 100198

Abstract

Read online

Summary: GATA zinc finger domain containing 2A (GATAD2A) is a subunit of the nucleosome remodeling and deacetylase (NuRD) complex. NuRD is known to regulate gene expression during neural development and other processes. The NuRD complex modulates chromatin status through histone deacetylation and ATP-dependent chromatin remodeling activities. Several neurodevelopmental disorders (NDDs) have been previously linked to variants in other components of NuRD’s chromatin remodeling subcomplex (NuRDopathies). We identified five individuals with features of an NDD that possessed de novo autosomal dominant variants in GATAD2A. Core features in affected individuals include global developmental delay, structural brain defects, and craniofacial dysmorphology. These GATAD2A variants are predicted to affect protein dosage and/or interactions with other NuRD chromatin remodeling subunits. We provide evidence that a GATAD2A missense variant disrupts interactions of GATAD2A with CHD3, CHD4, and CHD5. Our findings expand the list of NuRDopathies and provide evidence that GATAD2A variants are the genetic basis of a previously uncharacterized developmental disorder.

Published in HGG Advances

ISSN: 2666-2477 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Biology (General): Genetics
Website: https://www.cell.com/hgg-advances/home

About the journal

Abstract

Keywords