Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia
Abstract
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.
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Date
2021-05
Type
Article
Subject
developmental disabilities, intellectual disability, muscle hypotonia, neurodevelopmental disorders, whole exome sequencing
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Citation
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., … Mefford, H. C. (2021). Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia. Genetics in medicine : official journal of the American College of Medical Genetics, 23(5), 881–887. https://doi.org/10.1038/s41436-020-01076-8