|Title||Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||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, Vergano, SASchrier, 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, Klöckner, C, Hoffman, TL, MacArthur, DG, O'Leary, MC, VanNoy, GE, England, E, Varghese, VC, Mefford, HC|
|Date Published||2021 05|
|Keywords||Child, Developmental Disabilities, Humans, Intellectual Disability, Muscle Hypotonia, Neurodevelopmental Disorders, Seizures, Whole Exome Sequencing|
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.
|Alternate Journal||Genet Med|
|PubMed Central ID||PMC8107131|
|Grant List||UM1 HG008900 / HG / NHGRI NIH HHS / United States |
R01 NS069605 / NS / NINDS NIH HHS / United States
/ WT / Wellcome Trust / United Kingdom
R01 HG009141 / HG / NHGRI NIH HHS / United States