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
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.
