GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder

GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder. Shieh, C., Jones, N., Vanle, B., Au, M., Huang, A., Y., Silva, A., P., G., Lee, H., Douine, E., D., Otero, M., G., Choi, A., Grand, K., Taff, I., P., Delgado, M., R., Hajianpour, M., J., Seeley, A., Rohena, L., Vernon, H., Gripp, K., W., Vergano, S., A., Mahida, S., Naidu, S., Sousa, A., B., Wain, K., E., Challman, T., D., Beek, G., Basel, D., Ranells, J., Smith, R., Yusupov, R., Freckmann, M., Ohden, L., Davis-Keppen, L., Chitayat, D., Dowling, J., J., Finkel, R., Dauber, A., Spillmann, R., Pena, L., D., M., Metcalfe, K., Splitt, M., Lachlan, K., McKee, S., A., Hurst, J., Fitzpatrick, D., R., Morton, J., E., V., Cox, H., Venkateswaran, S., Young, J., I., Marsh, E., D., Nelson, S., F., Martinez, J., A., Graham, J., M., Kini, U., Mackay, J., P., & Pierson, T., M. Genetics in Medicine, 22(5):878-888, 5, 2020.

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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.

@article{
 title = {GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder},
 type = {article},
 year = {2020},
 keywords = {GATAD2B,NuRD complex,apraxia of speech,chromati},
 pages = {878-888},
 volume = {22},
 websites = {http://doi.org/10.1038/s41436-019-0747-z},
 month = {5},
 day = {17},
 id = {6308af4d-95ba-3986-b5f1-b8362afa6d89},
 created = {2020-12-17T05:29:53.237Z},
 file_attached = {false},
 profile_id = {a5a2ab6f-a8b5-3db6-97bc-618752ee4386},
 group_id = {bc1ab1d4-9e57-37e6-9fb5-435fca0ee9d2},
 last_modified = {2020-12-17T05:29:53.237Z},
 read = {false},
 starred = {false},
 authored = {false},
 confirmed = {true},
 hidden = {false},
 citation_key = {Shieh2020},
 source_type = {article},
 private_publication = {false},
 abstract = {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.},
 bibtype = {article},
 author = {Shieh, Christine and Jones, Natasha and Vanle, Brigitte and Au, Margaret and Huang, Alden Y. and Silva, Ana P. G. and Lee, Hane and Douine, Emilie D. and Otero, Maria G. and Choi, Andrew and Grand, Katheryn and Taff, Ingrid P. and Delgado, Mauricio R. and Hajianpour, M. J. and Seeley, Andrea and Rohena, Luis and Vernon, Hilary and Gripp, Karen W. and Vergano, Samantha A. and Mahida, Sonal and Naidu, Sakkubai and Sousa, Ana Berta and Wain, Karen E. and Challman, Thomas D. and Beek, Geoffrey and Basel, Donald and Ranells, Judith and Smith, Rosemarie and Yusupov, Roman and Freckmann, Mary-Louise and Ohden, Lisa and Davis-Keppen, Laura and Chitayat, David and Dowling, James J. and Finkel, Richard and Dauber, Andrew and Spillmann, Rebecca and Pena, Loren D. M. and Metcalfe, Kay and Splitt, Miranda and Lachlan, Katherine and McKee, Shane A. and Hurst, Jane and Fitzpatrick, David R. and Morton, Jenny E. V. and Cox, Helen and Venkateswaran, Sunita and Young, Juan I. and Marsh, Eric D. and Nelson, Stanley F. and Martinez, Julian A. and Graham, John M. and Kini, Usha and Mackay, Joel P. and Pierson, Tyler Mark},
 doi = {10.1038/s41436-019-0747-z},
 journal = {Genetics in Medicine},
 number = {5}
}

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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.","bibtype":"article","author":"Shieh, Christine and Jones, Natasha and Vanle, Brigitte and Au, Margaret and Huang, Alden Y. and Silva, Ana P. G. and Lee, Hane and Douine, Emilie D. and Otero, Maria G. and Choi, Andrew and Grand, Katheryn and Taff, Ingrid P. and Delgado, Mauricio R. and Hajianpour, M. 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