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 - Publisher Copyright:
© 2020, American College of Medical Genetics and Genomics.
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
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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
SN - 1098-3600
VL - 22
SP - 878
EP - 888
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 5
ER -