The TSHZ1 gene was first reported in relation to autosomal dominant congenital aural atresia/deafness in 2011 (Feenstra et al., PMID 22152683). 7 variants (missense, nonsense, frameshift) that have been reported in at least 11 probands in 3 publications (PMIDs: 22152683, 35487415, 36597107) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse models, expression-level evidence; PMIDs: 17586487, 24487590). Temporal and spatial expression of TSHZ1 mRNA during development of the middle ear is consistent with the phenotype (PMID: 17586487). The homozygous TSHZ1 null mouse model showed a middle ear malformation, as well as neonatal lethality. A conditional nervous system-specific TSHZ1 knock out mouse model demonstrated hyposmia (PMIDs: 17586487, 24487590). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This GDR was originally evaluated by the Syndromic Disorders GCEP on June 19, 2020. It was reevaluated on July 23, 2024. A new phenotype, congenital vertical talus, was reported in probands, in addition to more cases of deafness (PMIDs: 35487415, 36597107). An additional two missense variants were added to the curation from two probands in one publication (PMID: 36597107). Despite new genetic evidence, as a result of this reevaluation, the classification did not change (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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