| Evidence/date | Design/sample | Key finding | Implication for gene-disease validity |
|---|---|---|---|
| Delmaghani et al., 2012 | Original discovery report; 3 consanguineous Iranian siblings with profound SNHL; homozygous **TSPEAR c.1726_1728delGTCinsTT, p.Val576Leufs*38** identified by WES | Established the historical DFNB98 claim by linking biallelic TSPEAR to isolated profound hearing loss in one family; no alternative hearing-loss variants were reported in that initial study summary (pqac-00000020) | **Supportive but low-level evidence** for DFNB98 because it rests on a single family and has not been robustly replicated without confounding (pqac-00000020) |
| Bowles et al., 2021 | Cohort study of **13 newly reported individuals** with biallelic TSPEAR variants | **11/13** had tooth agenesis or ectodermal dysplasia; **3/13** had hearing loss, but **all 3** also carried variants in other hearing-loss genes (**TMPRSS3, GJB2, GJB6**). Authors concluded the evidence “creates significant doubt” that TSPEAR is a monogenic hearing-loss gene (pqac-00000007, pqac-00000000) | **Major evidence against established DFNB98 validity**; strongly shifts interpretation toward **TSPEAR-related ectodermal/dental disease** rather than isolated ARNSHL (pqac-00000007, pqac-00000000, pqac-00000001) |
| Jackson et al., 2023 | Aggregate human + mechanistic study; **30 affected individuals** analyzed across new and published cases; includes zebrafish double-knockout and mouse scRNA-seq | Human phenotype was **100% dental anomalies**; common findings included conical teeth (77%), hypodontia (50%), oligodontia (37%); **none of their cohort** had SNHL; authors state there is **“insufficient evidence to link TSPEAR variants as a cause of AR hearing loss.”** Functional work supported **ARED14** biology (enamel-knot expression, ECM/WNT-related dental model), not an auditory mechanism (pqac-00000013, pqac-00000012, pqac-00000023, pqac-00000010, pqac-00000011) | **Strongest current evidence hierarchy item**: supports **TSPEAR-related autosomal recessive ectodermal dysplasia 14 (ARED14)** as established; **DFNB98 remains disputed/insufficient** (pqac-00000013, pqac-00000012, pqac-00000023) |
| Shi et al., 2024 | Small supportive case/family report from China; compound heterozygous TSPEAR variants reported with AR hearing loss | Adds **limited supportive case-level evidence** for a hearing-loss association, but on its own does not overcome prior contradictory cohort data or the lack of replicated auditory functional evidence; details were not fully available in retrieved text (mentioned as unobtainable paper in search results) | **Weak supportive evidence only**; does **not resolve** disputed DFNB98 validity |
| Ahmadkhani et al., 2026 | Single case report; **6-year-old Iranian girl**, consanguineous family; profound bilateral SNHL; homozygous **TSPEAR c.668C>T, p.Ser223Leu** by WES | Reported isolated severe/profound bilateral SNHL with normal teeth/skin/hair/nails and absent ABR response; authors note isolated hearing presentation is rare (pqac-00000024, pqac-00000016) | **Additional anecdotal support** for possible TSPEAR-related hearing loss, but still **insufficient** to overturn Bowles/Jackson or establish DFNB98 definitively (pqac-00000024, pqac-00000016) |
| Current synthesis | Evidence hierarchy across original family reports, larger cohorts, and mechanistic studies | Hearing-loss evidence remains sparse, partly confounded, and mechanistically unvalidated for the ear; by contrast, dental/ectodermal evidence is replicated across cohorts and supported by functional data (pqac-00000007, pqac-00000013, pqac-00000023, pqac-00000006) | **Current conclusion:** **DFNB98 (TSPEAR-related ARNSHL) = disputed / insufficient evidence**; **TSPEAR-related ARED14 = established gene-disease relationship** (pqac-00000007, pqac-00000013, pqac-00000012) |


*Table: This table ranks the main published evidence bearing on the TSPEAR–DFNB98 relationship. It is useful because it distinguishes the early family-based hearing-loss claim from later larger cohort and functional studies that instead support TSPEAR-related ARED14.*