Novel TECTA Variants Reveal Distinct Molecular Mechanisms in Dominant and Recessive Hearing Loss

Variants in TECTA , encoding the glycoprotein \((α)\)-tectorin, a critical component of the cochlear tectorial membrane, have been linked to both autosomal dominant (DFNA8/12) and recessive (DFNB21) non-syndromic hearing loss (HL), depending on the affected protein domain. In this study, we identified and characterized five novel TECTA variants in seven families (five Iranian, two German), using whole exome sequencing, segregation analysis, and functional assays. We identified three autosomal recessive variants: two variants in the +5 position and one missense variant. Aberrant splicing was confirmed for variants at the +5 position: c.5272+5G C (resulting in r.3544_4105del, p.(Val1182Leufs*14)) and c.4105+5G C (leading to r.4977_5272del, p.(Arg1659Serfs5)), both associated with autosomal recessive inheritance. We also identified the autosomal recessive c.5942A G p.(Tyr1981Cys) variant, located in the vital zona pellucida domain. In the German families, we identified two autosomal dominant missense variants: c.2858T A p.(Leu953His), and c.4437C G p.(Cys1479Trp), both located in the zonadhesin-like domain. Established genotype-phenotype correlations are consistent with our identified variants. Our findings expand the mutational spectrum of TECTA and clarify the molecular mechanisms underlying HL. Our results support domain-specific mechanisms, splicing defects in recessive cases and predicted structural destabilization in dominant cases. These insights advance our understanding of TECTA -related HL, enabling precision diagnostics and potential therapeutic strategies for genetic HL.