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Lookup NU author(s): Dr Tara Montgomery
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© 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.Purpose: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. Methods: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. Results: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. Conclusion: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.
Author(s): Muir AM, Gardner JF, van Jaarsveld RH, de Lange IM, van der Smagt JJ, Wilson GN, Dubbs H, Goldberg EM, Zitano L, Bupp C, Martinez J, Srour M, Accogli A, Alhakeem A, Meltzer M, Gropman A, Brewer C, Caswell RC, Montgomery T, McKenna C, McKee S, Powell C, Vasudevan PC, Brady AF, Joss S, Tysoe C, Noh G, Tarnopolsky M, Brady L, Zafar M, Schrier Vergano SA, Murray B, Sawyer L, Hainline BE, Sapp K, DeMarzo D, Huismann DJ, Wentzensen IM, Schnur RE, Monaghan KG, Juusola J, Rhodes L, Dobyns WB, Lecoquierre F, Goldenberg A, Polster T, Axer-Schaefer S, Platzer K, Klockner C, Hoffman TL, MacArthur DG, O'Leary MC, VanNoy GE, England E, Varghese VC, Mefford HC
Publication type: Article
Publication status: Published
Journal: Genetics in Medicine
Year: 2021
Volume: 23
Issue: 5
Pages: 881-887
Print publication date: 01/05/2021
Online publication date: 20/01/2021
Acceptance date: 15/12/2020
ISSN (print): 1098-3600
ISSN (electronic): 1530-0366
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41436-020-01076-8
DOI: 10.1038/s41436-020-01076-8
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