Submission Details

TSPEAR was first reported in relation to autosomal recessive nonsyndromic hearing loss in 2012 (Delmaghani et al., PMID: 22678063). At least 5 unique variants (3 frameshift, 1 nonsense, 1 silent variant in splice consensus sequence) have been reported in at least 4 probands in 4 publications (PMIDs: 22678063, 26969326, 34795337, 37561809). A frameshift variant that was reported in 2 probands and segregated in 2 additional family members (PMID: 22678063, 37561809) has also been reported in 2 families with ectodermal dysplasia and normal hearing (PMID: 27736875). Another nonsense variant that was observed as a homozygous variant in a proband was found to be heterozygous in the proband’s affected sibling and unaffected mother (PMID: 34795337). Moreover, a heterozygous missense variant with no second variant was reported in 1 proband (PMID: 30733538). This gene-disease relationship is supported by expression studies in murine cochlear tissue as well as functional alteration studies of null variants in non-patient cells (PMID: 22678063). Additionally, a TSPEAR K14-Cre knockdown revealed effects of Tspear knockdown in mice hair follicles and NOTCH1 signaling but was not assessed for hearing loss (PMID: 27736875). In summary, the relationship between TSPEAR and autosomal recessive nonsyndromic hearing loss has been disputed. More evidence is needed to either support or refute the role TSPEAR plays in this disease. This gene-disease pair was originally evaluated by the ClinGen Hearing Loss GCEP on 09/26/2017 as per SOP v6. It was reevaluated on 10/31/2024 using SOP v11. As a result of this reevaluation, this record underwent a review to be consistent with SOP v11. New case level evidence has been reviewed, but the classification did not change (PMIDs: 30733538, 34795337, 37561809).