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; University of Washington Center for Mendelian Genomics; Jessica X Chong; Michael J Bamshad; A Micheil Innes; Tyler Mark Pierson; Joel P Mackay; Stephanie L Bielas; Donna M Martin

doi:10.1016/j.xhgg.2023.100198

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

HGG Adv. 2023 Apr 20;4(3):100198. doi: 10.1016/j.xhgg.2023.100198. eCollection 2023 Jul 13.

Authors

Elizabeth A Werren¹, Alba Guxholli^{1

2}, Natasha Jones³, Matias Wagner⁴, Iris Hannibal⁴, Jorge L Granadillo⁵, Amanda V Tyndall⁶, Amanda Moccia¹, Ryan Kuehl⁷, Kristin M Levandoski⁷, Debra L Day-Salvatore⁷, Marsha Wheeler⁸; University of Washington Center for Mendelian Genomics; Jessica X Chong^{9

10}, Michael J Bamshad^{9

10}, A Micheil Innes^{6

11}, Tyler Mark Pierson^{12

13

14

15}, Joel P Mackay³, Stephanie L Bielas^{1

2}, Donna M Martin^{1

2}

Affiliations

¹ Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
² Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
³ School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia.
⁴ Institute of Human Genetics, Technical University of Munich, 80333 Munich, Germany.
⁵ Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁶ Department of Medical Genetics, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
⁷ Saint Peter's University Hospital, New Brunswick, NJ 08901, USA.
⁸ Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
⁹ Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
¹⁰ Brotman Baty Institute, Seattle, WA 98195, USA.
¹¹ Department of Pediatrics, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
¹² Division of Pediatric Neurology, Department of Pediatrics, Guerin Children's, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹³ Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁴ Center for the Undiagnosed Patient, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁵ Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Abstract

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.

Keywords: GATAD2A; NuRD complex; NuRDopathies; neurodevelopmental disorder.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

DNA Helicases / metabolism
Humans
Mi-2 Nucleosome Remodeling and Deacetylase Complex* / genetics
Nerve Tissue Proteins
Neurodevelopmental Disorders* / genetics
Nucleosomes
Repressor Proteins* / genetics

Substances

CHD5 protein, human
DNA Helicases
Mi-2 Nucleosome Remodeling and Deacetylase Complex
Nerve Tissue Proteins
Nucleosomes
GATAD2A protein, human
Repressor Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding