A Novel Missense Variant in LMX1A Leads to Autosomal Dominant Nonsyndromic Hearing Loss

Hereditary nonsyndromic hearing loss (NSHL) is a prevalent entity associated with over 150 known causative genes, including LMX1A, which has fewer than 10 reported pathogenic variants. Here we present a novel missense variant in LMX1A in a family of European descent with hereditary hearing loss. Clinical and family histories were obtained, and genetic testing was performed on two affected members using the BMGDL Hearing Loss Panel. Allelic frequencies were explored across population databases, and in silico predictors were used to assess pathogenicity. Genetic testing revealed a variant of uncertain significance (p.Val241Ala) in LMX1A in a 56-year-old male with hearing loss since adolescence and his 12-year-old son, who failed newborn hearing screening. Family history exhibited an autosomal dominant inheritance pattern, supported by the segregation of this variant in both affected individuals. The p.Val241Ala variant was absent in GnomAD, indicating the variant's rarity, and in silico predictors reported strong pathogenic potential. Other pathogenic missense variants have previously been reported at the same Val241 site, suggesting that this location may be a hotspot for pathogenic variants contributing to NSHL, although further research is needed. This study expands the current understanding of how LMX1A relates to autosomal dominant hearing loss.