Submission Details

P2RX2 was first reported in relation to autosomal dominant nonsyndromic hearing loss in 2013 (Yan et al. 2013, PMID: 23345450). Three missense variants that have been reported in four probands in four publications are included in this curation (PMIDs: 23345450, 24211385, 29986705, 34425661). The hearing loss in these families had a postlingual onset, was progressive, and co-occurred with tinnitus in one family. An additional family was reported in which hearing loss co occurred with a mitochondrial disorder, however there wasn't strong evidence in support of pathogenicity of the P2RX2 variant for this phenotype and the variant was present in gnomAD (25788561). Functional evidence suggests a dominant negative mechanism (23345450). Substantial experimental evidence suggests that the P2RX2 receptor modulates a temporary threshold shift that protects the cochlea from overstimulation by loud noise exposure (23592720). This gene-disease relationship is also supported by animal models, expression studies, and in vitro functional assays (PMIDs: 23345450, 33791800, 23592720, 18491132). Loss of the P2RX2 receptor in mice increases susceptibility to noise-induced hearing loss, and a significant correlation was found in a large Chinese family between noise exposure during adolescence and severity of hearing loss (PMIDs: 23345450, 33791800). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the Hearing Loss GCEP on 02/20/2018. It was reevaluated on 09/21/2022. Although a new case with hearing loss (29986705) and a new knock-in mouse model with progressive hearing loss (33791800) were scored, the classification did not change (SOP Version 9).