Submission Details

PIK3R5 was first reported in relation to autosomal recessive ataxia-oculomotor apraxia in 2012 in a consanguineous family of which four siblings harbored the same homozygous variant in PIK3R5 (c.1885C>T, p.P629S) and were affected by ataxia, oculomotor apraxia, sensory axonal neuropathy, progressive distal muscular atrophy, and cerebellar atrophy (Al Tassan et al., PMID: 22065524). However, this variant has a total minor allele frequency of 0.001525 in the general population, is particularly common among the African/African American alleles, with a Grpmax Filtering Allele Frequency of 0.02622, and is observed in thirty homozygotes (Genome Aggregation Database v4.1). To date, no additional PIK3R5 variants have been reported in relation to autosomal recessive ataxia-oculomotor apraxia. Additional human cases of PIK3R5-related ataxia have not been found in the literature. A recent cohort study of 52 patients affected by autosomal recessive cerebellar ataxia with oculomotor apraxia did not detect any variants in PIK3R5 (PMID: 35426160). This gene-disease relationship is supported by expression studies by Al Tassan et al. who demonstrated ubiquitous expression of the PIK3R5 gene in human tissues with high expression in the brain (PMID: 22065524). To date, no publications in scientific literature can be found indicating protein function studies or non-human models showing the ocular motility or coordination and movement deficient phenotype observed in human patients with ataxia-oculomotor apraxia. In summary, the evidence supporting the relationship between PIK3R5 and autosomal recessive ataxia-oculomotor apraxia has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role PIK3R5 plays in this disease. This classification was approved by the ClinGen Cerebellar Ataxia GCEP on the meeting date April 9, 2025 (SOP Version 11).