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Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia


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 Galphai1 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.

Type Journal
ISBN 1530-0366 (Electronic) 1098-3600 (Linking)
Authors Muir, A. M.; Gardner, J. F.; van Jaarsveld, R. H.; de Lange, I. M.; van der Smagt, J. J.; Wilson, G. N.; Dubbs, H.; Goldberg, E. M.; Zitano, L.; Bupp, C.; Martinez, J.; Srour, M.; Accogli, A.; Alhakeem, A.; Meltzer, M.; Gropman, A.; Brewer, C.; Caswell, R. C.; Montgomery, T.; McKenna, C.; McKee, S.; Powell, C.; Vasudevan, P. C.; Brady, A. F.; Joss, S.; Tysoe, C.; Noh, G.; Tarnopolsky, M.; Brady, L.; Zafar, M.; Schrier Vergano, S. A.; Murray, B.; Sawyer, L.; Hainline, B. E.; Sapp, K.; DeMarzo, D.; Huismann, D. J.; Wentzensen, I. M.; Schnur, R. E.; Monaghan, K. G.; Juusola, J.; Rhodes, L.; Dobyns, W. B.; Lecoquierre, F.; Goldenberg, A.; Polster, T.; Axer-Schaefer, S.; Platzer, K.; Klockner, C.; Hoffman, T. L.; MacArthur, D. G.; O'Leary, M. C.; VanNoy, G. E.; England, E.; Varghese, V. C.; Mefford, H. C.
Published Date 2021-05-31
Published Volume 23
Published Issue 5
Published Pages 881-887
Status Published in-print
DOI 10.1038/s41436-020-01076-8
URL link to publisher's version