Submission Details

TJP2 was FIRST reported in relation to autosomal dominant nonsyndromic hearing loss (NSHL) in 2008 (Hilgert et al., PMID: 18616530). Of note, this gene has also been implicated in autosomal recessive cholestasis and autosomal recessive hypercholanemia. These will be assessed separately by the Syndromic GCEP. At least 11 variants (missense, nonsense, large inverted duplication) have been reported in humans. None of the sequence variants showed autosomal dominant inheritance. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Summary of Case Level Data: 1.7 POINTS. Variants in this gene have been reported in at least 11 probands in 7 publications (PMIDs:18616530, 24752540, 24853665, 26667150, 31486067, 33162339, 34912366). However, due to inconsistent inheritance, allele frequency in gnomAD, inconsistent phenotypes, or lack of evidence for pathogenicity, only 2 variants were scored. The inverted duplication impacting TJP2 and another gene (FAM189A2) segregated with disease in 27 additional family members from one family and was proposed to overexpress TJP2 in affected patients (PMID: 20602916). The mechanism for disease is unknown. This gene-disease association is supported by expression and functional alteration studies (PMIDs: 20602916, 22671599). Of note, a homozygous null mouse model has also demonstrated that absence of this gene's product is embryonic lethal (PMID: 18172007). 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 gene-disease pair was originally evaluated by the Hearing Loss GCEP on 12/19/2017 (SOP v6). It was reevaluated on 1/19/2022 (SOP v8) with the addition of PMIDs: 31486067, 33162339, 34912366; however, none of them contained any scorable evidence. As a result of this reevaluation, the classification did not change.