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. 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 recessive Gillespie syndrome. Variants in ITPR1 have also been implicated in two types of autosomal dominant spinocerebellar ataxia (SCA), in which iris development is normal: infantile-onset SCA29 and adult-onset SCA15. The relationship between ITPR1 and spinocerebellar ataxia will be curated separately.

Six homozygous or compound heterozygous truncating variants (nonsense, frameshift, and splice) that have been reported in five probands in three publications (PMIDs: 27108797, 29169895, 29663667) are included in this curation. The mechanism of pathogenicity appears to be partial loss of function. The recessive alleles are predicted to generate premature termination codons that appear to act as partial rather than full loss-of-function variants, possibly via exon skipping mechanisms (PMID: 27108797). ITPR1 haploinsufficiency causes adult-onset SCA15; because carrier parents of individuals with recessive Gillespie syndrome are unaffected, there is no apparent haploinsufficient effect associated with these hypomorphic alleles. A single homozygous missense variant, located in the C-terminal channel domain, has been reported in a girl with features of Gillespie syndrome (PMID: 35574166); in the absence of functional evidence of pathogenicity, the significance of this variant is unclear.

This gene-disease relationship is also supported by mouse models partially recapitulating the human phenotype (PMIDs: 8538767, 34338282).

In summary, there is definitive evidence supporting the relationship between ITPR1 and autosomal recessive Gillespie syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on January 23, 2025 (SOP Version 11).