Submission Details

ITPR1 encodes a calcium channel that releases calcium from the endoplasmic reticulum upon stimulation by inositol 1,4,5-trisphosphate (IP3). ITPR1 was first reported in relation to both autosomal dominant and recessive Gillespie syndrome (also known as aniridia-cerebellar ataxia-intellectual disability syndrome) in 2016 (Gerber et al., PMID: 27108797; McEntagart et al., PMID: 27108798). Clinical features include aniridia or iris hypoplasia, hypotonia, non-progressive cerebellar ataxia, cerebellar atrophy, and variable intellectual disability. Affected individuals are usually diagnosed within the first year of life. The syndrome is caused by heterozygous dominant-negative missense variants or biallelic truncating variants in ITPR1 that appear to act as partial rather than full loss-of-function variants (PMID: 27108797). Based on the ClinGen Lumping and Splitting guidance, there are differences in inheritance pattern and molecular mechanism and therefore, the autosomal dominant and recessive forms of Gillespie syndrome were assessed separately. This curation concerns autosomal dominant Gillespie syndrome.

Seven unique heterozygous ITPR1 variants (6 missense and 1 in-frame deletion) identified in 12 unrelated individuals in four publications (PMIDs: 27108797, 27108798, 28698159, 31340402) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The variants are often de novo but may also be inherited from an affected parent. All the missense or in-frame deletion variants in autosomal dominant Gillespie syndrome reported so far are located in the C-terminal region of ITPR1, mainly in the transmembrane channel domain, and affect a restricted number of residues (PMID: 37964426). The mechanism of pathogenicity appears to be dominant negative (PMIDs: 27108797, 27108798).

Mice heterozygous for Itpr1 null variants exhibit mild coordination deficits (PMID: 11334652), but do not replicate the ataxia or eye phenotype seen in Gillespie syndrome (PMIDs: 8538767, 27108798).

Of note, variants in ITPR1 have also been implicated in two types of autosomal dominant spinocerebellar ataxia, in which iris development is normal: infantile-onset spinocerebellar ataxia type 29, caused by heterozygous missense variants in ITPR1, and adult-onset spinocerebellar ataxia type 15, caused by heterozygous loss-of-function variants. The relationship between ITPR1 and spinocerebellar ataxia will be curated separately. No obvious genotype-phenotype correlations have been observed for the Gillespie syndrome and spinocerebellar ataxia type 29 variants clustered in the C-terminal domain (PMID: 37964426).

In summary, there is definitive evidence supporting the relationship between ITPR1 and autosomal dominant Gillespie syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the Intellectual Disability and Autism Gene Curation Expert Panel on November 3, 2021 and classified as Definitive. It was reevaluated on January 23, 2025 (SOP Version 11). Although additional evidence was curated, the classification did not change.