Submission Details

Variants in GNAI1 were first reported in individuals with neurodevelopmental disorders between 2014 and 2017, when several large exome sequencing studies in autism or developmental disorders reported de novo GNAI1 variants in multiple probands without detailed clinical information (PMIDs: 25363760, 25363768, 28135719). GNAI1 encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. In 2021, Muir et al. described 16 unique GNAI1 variants in 24 individuals with neurodevelopmental disorders, some of whom had been described in previous publications (PMID: 33473207). Core clinical features include global developmental delay, intellectual disability, hypotonia, and epilepsy; some individuals also have autism and variable mild dysmorphic features. While the pLI and LOEUF scores for GNAI1 in gnomAD (v2.1.1) suggest intolerance to loss-of-function variation (0.91 and 0.38, respectively), most reported variants are missense or in-frame deletions, and functional studies have not been performed to assess the mechanism by which they impact gene function. However, many of the de novo missense variants identified in affected individuals are located at recurrent amino acid positions. This pattern of variation is characteristic of pathogenic missense variants in other G proteins, and suggests that the mechanism of pathogenicity could be antimorphic (or dominant-interfering). Homozygous knockout mice exhibit deficits in learning and memory (PMIDs: 14715142), but since most of the variants in humans are heterozygous missense/in-frame variants, this experimental evidence was not scored. In summary, there is definitive evidence to support the relationship between GNAI1 and complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability/Autism Gene Curation Expert Panel on 3/17/2021.