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 one 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.

Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of GNAO1 and GNAI1 for the Dominant Disease

“…As both parents do not harbor the mutation (Supplementary Figure S2B,C), the GNAO1c.155A > G (Gln52Arg) is concluded to be a de novo mutation. The clinical manifestations of this hitherto undescribed de novo Gln52Arg mutation in GNAO1 are reminiscent of the previously observed Gln52Pro mutations in GNAO1 and in GNAI1 [23,24]. Table 1 provides a comparison of the clinical features of the three patients with mutation in the codon Gln52.…”

“…Recently, a number of mutations in a related gene GNAI1, many of them identical to those in the GNAO1-encephalopathy (Supplementary Figure S1), have been described to cause similar clinical manifestations in children [23]. Among the amino acids found mutated both in the GNAO1and GNAI1-encephalopathy, the Gln52Pro mutations have been identified [23,24].…”

“…For the GNAO1 Gln52Pro variant, the patient had DEE with normal brain MRI [24]. For the GNAI1 Gln52Pro variant patient, DEE was similarly reported [23] (see Table 1). In our work, we here describe another Gln52 mutant GNAO1 patient, harboring a hitherto unknown Gln52Arg substitution.…”

“…Similarly to Gαo, another Gαi/o protein, Gαi1 (encoded by the gene GNAI1, see Supplementary Figure S1 for the amino acid alignment showing high homology between the two Gα-subunits) shows prominent central nervous system expression; its genetic ablation reveals important neurological functions such as involvement in long-term potentiation [22]. In a further similarity to Gαo, de novo point mutations in GNAI1, some of them-in the same positions as those found in GNAO1 mutant patients, have recently been described to cause dominant infantile neurological disorders with variable degrees of developmental delay, seizures, and hypotonia [23].…”

“…Among the amino acid found mutated both in GNAO1 and GNAI1 patients, de novo Gln52Pro substitutions have been described [23,24]. For the GNAO1 Gln52Pro variant, the patient had DEE with normal brain MRI [24].…”