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

Alison M. Muir, Jennifer F. Gardner, Richard H. van Jaarsveld, Iris M. de Lange, Jasper J. van der Smagt, Golder N. Wilson, Holly Dubbs, Ethan M. Goldberg, Lia Zitano, Caleb Bupp, Jose Martinez, Myriam Srour, Andrea Accogli, Afnan Alhakeem, Meira Meltzer, Andrea Gropman, Carole Brewer, Richard C. Caswell, Tara Montgomery, Caoimhe McKennaShane McKee, Corinna Powell, Pradeep C. Vasudevan, Angela F. Brady, Shelagh Joss, Carolyn Tysoe, Grace Noh, Mark Tarnopolsky, Lauren Brady, Muhammad Zafar, Samantha A. Schrier Vergano, Brianna Murray, Lindsey Sawyer, Bryan E. Hainline, Katherine Sapp, Danielle DeMarzo, Darcy J. Huismann, Ingrid M. Wentzensen, Rhonda E. Schnur, Kristin G. Monaghan, Jane Juusola, Lindsay Rhodes, William B. Dobyns, Francois Lecoquierre, Alice Goldenberg, Tilman Polster, Susanne Axer-Schaefer, Konrad Platzer, Chiara Klöckner, Trevor L. Hoffman, Daniel G. MacArthur, Melanie C. O’Leary, Grace E. VanNoy, Eleina England, Vinod C. Varghese, Heather C. Mefford

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)881-887
Number of pages7
JournalGenetics in Medicine
Issue number5
StatePublished - May 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.


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