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

Genet Med. 2021 May;23(5):881-887. doi: 10.1038/s41436-020-01076-8. Epub 2021 Jan 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child
  • Developmental Disabilities / genetics
  • Humans
  • Intellectual Disability* / diagnosis
  • Intellectual Disability* / genetics
  • Muscle Hypotonia / diagnosis
  • Muscle Hypotonia / genetics
  • Neurodevelopmental Disorders* / diagnosis
  • Neurodevelopmental Disorders* / genetics
  • Seizures / genetics
  • Whole Exome Sequencing