TY - JOUR
T1 - GATAD2B-associated neurodevelopmental disorder (GAND)
T2 - clinical and molecular insights into a NuRD-related disorder
AU - The Undiagnosed Diseases Network
AU - Shieh, Christine
AU - Jones, Natasha
AU - Vanle, Brigitte
AU - Au, Margaret
AU - Huang, Alden Y.
AU - Silva, Ana P.G.
AU - Lee, Hane
AU - Douine, Emilie D.
AU - Otero, Maria G.
AU - Choi, Andrew
AU - Grand, Katheryn
AU - Taff, Ingrid P.
AU - Delgado, Mauricio R.
AU - Hajianpour, M. J.
AU - Seeley, Andrea
AU - Rohena, Luis
AU - Vernon, Hilary
AU - Gripp, Karen W.
AU - Vergano, Samantha A.
AU - Mahida, Sonal
AU - Naidu, Sakkubai
AU - Sousa, Ana Berta
AU - Wain, Karen E.
AU - Challman, Thomas D.
AU - Beek, Geoffrey
AU - Basel, Donald
AU - Ranells, Judith
AU - Smith, Rosemarie
AU - Yusupov, Roman
AU - Freckmann, Mary Louise
AU - Ohden, Lisa
AU - Davis-Keppen, Laura
AU - Chitayat, David
AU - Dowling, James J.
AU - Finkel, Richard
AU - Dauber, Andrew
AU - Spillmann, Rebecca
AU - Pena, Loren D.M.
AU - Metcalfe, Kay
AU - Splitt, Miranda
AU - Lachlan, Katherine
AU - McKee, Shane A.
AU - Hurst, Jane
AU - Fitzpatrick, David R.
AU - Morton, Jenny E.V.
AU - Cox, Helen
AU - Venkateswaran, Sunita
AU - Young, Juan I.
AU - Marsh, Eric D.
AU - Nelson, Stanley F.
N1 - Funding Information:
We thank the subjects and their families for their help, for their providing medical information, and providing consent to include photographs in this article. We also would like to extend special thanks to the Helping Hands for GAND Foundation for their assistance and continued cooperation. We are grateful to Charles Simmons and Clive Svendsen for mentorship and Kelli Dejohn, Roxana Ramirez, Joanne Baez, and Carmela Brito for clinical and technical assistance. We acknowledge Jaemin Kim and Yogesh Kushwaha for their contribution to the work. We also thank Barrington Burnett for their critical review of the manuscript. Research reported in this paper was supported by the National Institutes of Health (NIH) Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under award number U01HG007672. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. GAND50’s seq+ analysis was supported by NIH National Center for Advancing Translational Science (NCATS) UCLA Clinical and Translational Science Institute (CTSI) grant number UL1TR001881. J.P.M. received funding from the National Health and Medical Research Council (APP1012161, APP1063301, APP1126357, APP1058916). T.M.P. and this research was supported by the Cedars-Sinai institutional funding program and the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular and the Fashion Industries Guild Endowed Fellowship for the Undiagnosed Diseases Program. T.M.P. is especially grateful for the wonderful and continued support from the Cedars-Sinai Fashion Industries Guild.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - Purpose: Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder(GAND). Methods: Fifty GAND subjects were evaluated to determine consistentgenotypic/phenotypic features. Immunoprecipitation assays utilizing in vitrotranscription–translation products were used to evaluate GATAD2B missensevariants’ ability to interact with binding partners within the nucleosomeremodeling 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 withmultiple variant types (nonsense, truncating frameshift, splice-site variants,deletions, and missense). Seven subjects were identified with missense variantsthat localized within two conserved region domains (CR1 or CR2) of the GATAD2Bprotein. Immunoprecipitation assays revealed several of these missense variantsdisrupted GATAD2B interactions with its NuRD complex binding partners. Conclusions: A consistent GAND phenotype was caused by a range of geneticvariants in GATAD2B that includeloss-of-function and missense subtypes. Missense variants were present inconserved region domains that disrupted assembly of NuRD complex proteins.GAND’s clinical phenotype had substantial clinical overlap with other disordersassociated with the NuRD complex that involve CHD3 and CHD4, with clinicalfeatures of hypotonia, intellectual disability, cardiac defects, childhoodapraxia of speech, and macrocephaly.
AB - Purpose: Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder(GAND). Methods: Fifty GAND subjects were evaluated to determine consistentgenotypic/phenotypic features. Immunoprecipitation assays utilizing in vitrotranscription–translation products were used to evaluate GATAD2B missensevariants’ ability to interact with binding partners within the nucleosomeremodeling 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 withmultiple variant types (nonsense, truncating frameshift, splice-site variants,deletions, and missense). Seven subjects were identified with missense variantsthat localized within two conserved region domains (CR1 or CR2) of the GATAD2Bprotein. Immunoprecipitation assays revealed several of these missense variantsdisrupted GATAD2B interactions with its NuRD complex binding partners. Conclusions: A consistent GAND phenotype was caused by a range of geneticvariants in GATAD2B that includeloss-of-function and missense subtypes. Missense variants were present inconserved region domains that disrupted assembly of NuRD complex proteins.GAND’s clinical phenotype had substantial clinical overlap with other disordersassociated with the NuRD complex that involve CHD3 and CHD4, with clinicalfeatures of hypotonia, intellectual disability, cardiac defects, childhoodapraxia of speech, and macrocephaly.
KW - GATAD2B; NuRD complex; apraxia of speech; chromatin remodeling;macrocephaly
UR - http://www.scopus.com/inward/record.url?scp=85078297373&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078297373&partnerID=8YFLogxK
U2 - 10.1038/s41436-019-0747-z
DO - 10.1038/s41436-019-0747-z
M3 - Article
C2 - 31949314
AN - SCOPUS:85078297373
VL - 22
SP - 878
EP - 888
JO - Genetics in Medicine
JF - Genetics in Medicine
SN - 1098-3600
IS - 5
ER -