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Congenital aural atresia (CAA) is characterized by absence or severe narrowing of the external auditory canal, often leading to conductive hearing loss. Recent cytogenetic and sequencing studies have implicated haploinsufficiency of the homeobox gene TSHZ1 in isolated CAA. CAA can present as an isolated malformation or within complex syndromes such as 18q deletion syndrome, but disruption of TSHZ1 alone is sufficient to produce the ear phenotype.
Initial evidence arose from two unrelated families: four individuals from two pedigrees with CAA and additional 18q22.3 deletions all shared overlapping microdeletions that encompassed only TSHZ1 ([PMID:22152683]). Follow-up sequencing in a cohort of 11 unrelated patients with isolated bilateral CAA identified two additional loss-of-function alleles, c.858G>A (p.Trp286Ter) and c.1081_1082insA (p.Pro361fs), both predicted to truncate TSHZ1 ([PMID:22152683]). Together, these six probands across four families demonstrate recurrent heterozygous deletions or truncating variants in TSHZ1 consistent with an autosomal dominant, haploinsufficiency mechanism.
Segregation analysis showed that each familial microdeletion co-segregated with CAA in first-degree relatives (two additional affected relatives total) and no unaffected carriers were observed ([PMID:22152683]). The variant spectrum includes two large hemizygous deletions and two distinct truncating mutations, supporting a loss-of-function paradigm without evidence for missense or hypomorphic alleles to date.
Functional studies in mouse have shown that Tshz1 is required for middle-ear morphogenesis: Tshz1 knockout mice recapitulate external auditory canal atresia and malformation of ossicles, and expression of TSHZ1 is enriched in embryonic otic epithelium, confirming concordant developmental pathways ([PMID:22152683]). No conflicting data have been reported.
Integration of genetic and experimental data yields a Strong ClinGen classification for TSHZ1 in congenital aural atresia, with robust segregation, multiple unrelated probands carrying loss-of-function alleles, and a concordant animal model. Key take-home: heterozygous truncating or deletion variants in TSHZ1 should be included in diagnostic panels for congenital aural atresia.
Gene–Disease AssociationStrongSix probands across four families with heterozygous TSHZ1 deletions or truncating variants, plus murine model concordance Genetic EvidenceStrongFour individuals with 18q22.3 microdeletions and two with distinct truncating alleles in TSHZ1 in unrelated CAA cases Functional EvidenceModerateTshz1 knockout mice recapitulate external auditory canal atresia and display developmental expression in otic epithelium |