GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder
Christine Shieh, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Natasha Jones, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, Australia.
Brigitte Vanle, Department of Psychiatry & Behavioral Neurosciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Margaret Au, Department of Pediatrics Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Alden Y. Huang, Institute for Precision Health, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
Ana P. Silva, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, Australia.
Hane Lee, Department of Human Genetics and Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
Emilie D. Douine, Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
Maria G. Otero, Board of Governor's Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Andrew Choi, Board of Governor's Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Katheryn Grand, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Ingrid P. Taff, Department of Neurology, Hofstra School of Medicine, Great Neck, NY, USA.
Mauricio R. Delgado, Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center and Texas Scottish Rite Hospital for Children, Dallas, TX, USA.
M J. Hajianpour, Department of Pediatrics, Division of Medical Genetics, East Tennessee State University, Quillen College of Medicine, Mountain Home, TN, USA.
Andrea Seeley, Geisinger Medical Center, Danville, PA, USA.
Luis Rohena, Division of Genetics, Department of Pediatrics, Brooke Army Medical Center, Fort Sam Houston, TX, USA.
Hilary Vernon, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Balitmore, MD, USA.
Karen W. Gripp, Division of Medical Genetics, Al DuPont Hospital for Children, Wilmington, DE, USA.
Samantha A. Vergano, Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA, USA.
Sonal Mahida, Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.
Sakkubai Naidu, Department of Neurology and Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Ana Berta Sousa, Serviço de Genética Médica, Hospital Santa Maria, CHULN, Lisboa, Portugal and Faculdade de Medicina de Lisboa, Universidade de Lisboa, Lisboa, Portugal.
Karen E. Wain, Autism & Developmental Medicine Institute, Geisinger, Lewisburg, PA, USA.
Thomas D. Challman, Autism & Developmental Medicine Institute, Geisinger, Lewisburg, PA, USA.
Geoffrey Beek, Children's Hospitals and Clinics of Minnesota Department of Genetics, Minneapolis, MN, USA.
Donald Basel, Department of Pediatrics, Division of Genetics; Children's Hospital of Wisconsin, Milwaukee, WI, USA.
Judith Ranells, Division of Genetics and Metabolism, Department of Pediatrics, University of South Florida, Tampa, FL, USA.
Rosemarie Smith, Department of Pediatrics, Division of Genetics, Maine Medical Center, Portland, ME, USA.
Roman Yusupov, Division of Clinical Genetics, Joe DiMaggio Children's Hospital, Hollywood, FlL, USA.
Mary-Louise Freckmann, Royal North Shore Hospital, St Leonards, NSW, Australia.
Lisa Ohden, Department of Genetic Counseling, Sanford Children's Specialty Clinic, Sioux Falls, SD, USA.
Laura Davis-Keppen, Department of Pediatrics, Sanford School of Medicine of the University of South Dakota, Sioux Falls, SD, USA.
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.