Expanding the Early Childhood Manifestations of ITPR1 Heterozygous Variants Beyond Congenital Ataxia and Gillespie Syndrome.

Background and Objectives: Heterozygous ITPR1 variants have been previously linked to multiple human disease phenotypes, including congenital ataxia and Gillespie syndrome. Previous reports have described potential genotype-phenotype correlations, yet at a functional level, the mechanisms underlying the clinical variability remain unclear. The aim of this study was to expand the known phenotypic spectrum of ITPR1 variants by describing a case series of pediatric patients with clinical presentations distinct from those previously reported. We also functionally tested the effects of a novel ITPR1 missense variant on calcium cellular dynamics. Methods: Clinical data were collected by retrospective chart review at a single center. Functional studies to test the effect of the p.Gly2539Trp novel missense variant were performed in vitro to assess the subcellular distribution of the encoded IP3R type 1 protein, as well as the channel's calcium activity. Results: We identified 3 pediatric patients with heterozygous ITPR1 variants [c.7615G>T (p.Gly2539Trp), a 7.116-Mb deletion of 3p26.1p26.3 including ITPR1, and c.7900T>C (p.Tyr2634His)] without evidence of congenital ophthalmologic abnormalities or ataxia. Patients exhibited a range of symptoms, including language delays, autism spectrum disorder, and exercise intolerance. Functionally, we show that although the p.Gly2539Trp variant does not affect the subcellular distribution of the channel, it does abolish agonist-induced calcium release. Discussion: Our data support an expansion of the clinical phenotype of the pediatric presentation of ITPR1 variants, highlighting cognitive difficulties, autism, and a later onset of ataxia in childhood. We also provide evidence for the pathogenicity of the novel heterozygous p.Gly2539Trp variant by a loss-of-function mechanism.