TY - JOUR
T1 - De novo variants in GATAD2A in individuals with a neurodevelopmental disorder
T2 - GATAD2A-related neurodevelopmental disorder
AU - University of Washington Center for Mendelian Genomics
AU - Werren, Elizabeth A.
AU - Guxholli, Alba
AU - Jones, Natasha
AU - Wagner, Matias
AU - Hannibal, Iris
AU - Granadillo, Jorge L.
AU - Tyndall, Amanda V.
AU - Moccia, Amanda
AU - Kuehl, Ryan
AU - Levandoski, Kristin M.
AU - Day-Salvatore, Debra L.
AU - Wheeler, Marsha
AU - Chong, Jessica X.
AU - Bamshad, Michael J.
AU - Innes, A. Micheil
AU - Pierson, Tyler Mark
AU - Mackay, Joel P.
AU - Bielas, Stephanie L.
AU - Martin, Donna M.
N1 - Funding Information:
The authors thank all individuals with GATAD2A variants and their families for their participation in this work. A.M.I. and A.V.T. wish to thank Julia Tagoe for clinical support, and acknowledge work done under the Care4Rare Canada Consortium funded by Genome Canada and the Ontario Genomics Institute , the Canadian Institutes of Health Research , Ontario Research Foundation , Genome Alberta , Genome British Columbia , Génome Québec , Children's Hospital of Eastern Ontario Foundation , and the Alberta Children's Hospital Foundation . We would like to thank Dr. Steven Leber for interpretation of brain MRI findings. We would like to thank the contributors to GeneMatcher, MyGene2, and The University of Washington Center for Mendelian Genomics and GeneDx for use of data. Sequencing provided by the University of Washington Center for Mendelian Genomics (UW-CMG) was funded by NHGRI and NHLBI grants UM1 HG006493 and U24 HG008956 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This research was supported by NIH R01 DC018404 and the Ravitz Foundation Professorship granted to D.M.M., as well as the Fashion Industries Guild Endowed Fellowship for the Undiagnosed Diseases Program, the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases, and the Cedars-Sinai institutional funding program awarded to T.M.P.
Funding Information:
The authors thank all individuals with GATAD2A variants and their families for their participation in this work. A.M.I. and A.V.T. wish to thank Julia Tagoe for clinical support, and acknowledge work done under the Care4Rare Canada Consortium funded by Genome Canada and the Ontario Genomics Institute, the Canadian Institutes of Health Research, Ontario Research Foundation, Genome Alberta, Genome British Columbia, Génome Québec, Children's Hospital of Eastern Ontario Foundation, and the Alberta Children's Hospital Foundation. We would like to thank Dr. Steven Leber for interpretation of brain MRI findings. We would like to thank the contributors to GeneMatcher, MyGene2, and The University of Washington Center for Mendelian Genomics and GeneDx for use of data. Sequencing provided by the University of Washington Center for Mendelian Genomics (UW-CMG) was funded by NHGRI and NHLBI grants UM1 HG006493 and U24 HG008956. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This research was supported by NIH R01 DC018404 and the Ravitz Foundation Professorship granted to D.M.M. as well as the Fashion Industries Guild Endowed Fellowship for the Undiagnosed Diseases Program, the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases, and the Cedars-Sinai institutional funding program awarded to T.M.P. A.M.I. M.J.B. and J.X.C. serve in a voluntary capacity as members of the Human Genetics and Genomics Advances (HGG-A) Editorial Board.
Publisher Copyright:
© 2023 The Author(s)
PY - 2023/7/13
Y1 - 2023/7/13
N2 - 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.
AB - 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.
KW - GATAD2A
KW - NuRD complex
KW - NuRDopathies
KW - neurodevelopmental disorder
UR - http://www.scopus.com/inward/record.url?scp=85153857217&partnerID=8YFLogxK
U2 - 10.1016/j.xhgg.2023.100198
DO - 10.1016/j.xhgg.2023.100198
M3 - Article
C2 - 37181331
AN - SCOPUS:85153857217
SN - 2666-2477
VL - 4
JO - Human Genetics and Genomics Advances
JF - Human Genetics and Genomics Advances
IS - 3
M1 - 100198
ER -