ANO10 was first reported in relation to autosomal recessive cerebellar ataxia in 2010 (Vermeer et al., PMID: 21092923). The ANO10 gene is a member of the anoctamin family and encodes a transmembrane protein that has various functions including phospholipid scrambling, chloride channel activity, and calcium signaling (PMID: 35648332). Autosomal recessive cerebellar ataxia due to variants in ANO10 is characterized by gait and limb ataxia, dysarthria, nystagmus, and cerebellar atrophy on brain imaging (PMID: 21092923). Other features may be present as well and age of onset is variable (PMID: 36698452).
Six variants (2 nonsense, 2 frameshift, 1 missense, 1 canonical splice-site) that have been reported in 5 probands in 3 publications (PMIDs: 21092923, 23551081, 25133958) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism of pathogenicity is unknown.
This gene-disease relationship is also supported by experimental evidence including alteration of calcium signaling in mouse intestinal epithelial cells (PMID: 27838374), alteration of endosomal retrograde transport in mouse embryonic fibroblasts (PMID: 32620747), and a knockout mouse model displaying impairment of neuromuscular function (PMID: 32620747).
In summary, there is definitive evidence supporting the relationship between ANO10 and autosomal recessive cerebellar ataxia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cerebellar Ataxia GCEP on the meeting date December 11, 2024 (SOP Version 10).
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