GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder
| Autor: | Shieh, Christine, Jones, Natasha, Vanle, Brigitte, Au, Margaret, Huang, Alden Y, Silva, Ana PG, Lee, Hane, Douine, Emilie D, Otero, Maria G, Choi, Andrew, Grand, Katheryn, Taff, Ingrid P, Delgado, Mauricio R, Hajianpour, MJ, Seeley, Andrea, Rohena, Luis, Vernon, Hilary, Gripp, Karen W, Vergano, Samantha A, Mahida, Sonal, Naidu, Sakkubai, Sousa, Ana Berta, Wain, Karen E, Challman, Thomas D, Beek, Geoffrey, Basel, Donald, Ranells, Judith, Smith, Rosemarie, Yusupov, Roman, Freckmann, Mary-Louise, Ohden, Lisa, Davis-Keppen, Laura, Chitayat, David, Dowling, James J, Finkel, Richard, Dauber, Andrew, Spillmann, Rebecca, Pena, Loren DM, Undiagnosed Diseases Network, Metcalfe, Kay, Splitt, Miranda, Lachlan, Katherine, McKee, Shane A, Hurst, Jane, Fitzpatrick, David R, Morton, Jenny EV, Cox, Helen, Venkateswaran, Sunita, Young, Juan I, Marsh, Eric D, Nelson, Stanley F, Martinez, Julian A, Graham, John M, Kini, Usha, Mackay, Joel P, Pierson, Tyler Mark |
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| Rok vydání: | 2020 |
| Předmět: |
Intellectual and Developmental Disabilities (IDD)
Clinical Sciences apraxia of speech NuRD complex macrocephaly GATA Transcription Factors chromatin remodeling GATAD2B Pregnancy Clinical Research Intellectual Disability Genetics Humans 2.1 Biological and endogenous factors Aetiology Child Pediatric Genetics & Heredity Undiagnosed Diseases Network Megalencephaly Nucleosomes Brain Disorders Repressor Proteins Phenotype Neurodevelopmental Disorders Congenital Structural Anomalies Female |
| Zdroj: | Genetics in medicine : official journal of the American College of Medical Genetics, vol 22, iss 5 |
| Popis: | PurposeDetermination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND).MethodsFifty 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.ResultsSubjects 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.ConclusionsA 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. |
| Databáze: | OpenAIRE |
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