| Field | Evidence-based summary | Suggested ontology/identifier |
|---|---|---|
| Disease definition | DFNA76 is a very rare form of **autosomal dominant nonsyndromic hearing loss** caused by heterozygous **PLS1** variants. Human reports identify PLS1 as a deafness gene in multiple unrelated families; phenotype is isolated hearing loss without consistent syndromic findings (pqac-00000000, pqac-00000002, pqac-00000005). | Disease label: Hearing loss, autosomal dominant 76 / DFNA76; MONDO: **not confidently verified**; MeSH/ICD exact disease-specific ID: **not confidently verified** |
| Inheritance | Inheritance is **autosomal dominant** with familial segregation across reported kindreds from Hungarian Roma, Italian, US, French, Turkish, and Chinese families (pqac-00000000, pqac-00000002, pqac-00000005). Formal penetrance estimates have not been established. | HP:0000006 Autosomal dominant inheritance |
| Gene/protein | Causal gene: **PLS1** (plastin 1, fimbrin), encoding an actin-bundling protein highly expressed in inner-ear stereocilia and also detected in the cuticular plate of hair cells in mouse studies (pqac-00000000, pqac-00000007, pqac-00000010). Protein architecture includes N-terminal EF-hand calcium-binding motifs and two actin-binding domains, ABD1 and ABD2 (pqac-00000009, pqac-00000010). | HGNC: **PLS1**; NCBI Gene/Ensembl/UniProt exact IDs: **not confidently verified here**; GO suggestions: actin filament binding, actin bundling |
| Established/reported variants | Reported DFNA76-associated variants include **p.Leu363Phe** in Hungarian Roma family 6012, **p.Phe128Ser**, **p.Leu238Arg**, and recurrent **p.Glu269Lys** in European/Turkish families, plus **c.981+1G>A** splice variant in a Chinese family (pqac-00000000, pqac-00000002, pqac-00000005, pqac-00000010). Available summaries indicate these are rare/absent in population databases used in the original studies, but precise allele counts/frequencies are not fully available in current context. | Sequence Ontology suggestions: missense_variant; splice_donor_variant |
| Core phenotype | Core phenotype is **bilateral or sometimes asymmetric/unilateral nonsyndromic hearing loss**, usually sensorineural, often affecting **medium-to-high or high frequencies**; severity ranges from mild to profound across families. Mixed hearing loss was reported in some Hungarian Roma individuals (pqac-00000000, pqac-00000002, pqac-00000006). | HP:0000365 Hearing impairment; HP:0000407 Sensorineural hearing impairment; HP:0011003 Abnormality of hearing physiology |
| Onset/course | Onset appears **variable across families**: congenital/non-progressive in the Hungarian Roma cohort context, versus childhood/post-lingual to adult detection with **progressive** decline in several other families. One Italian patient was diagnosed at age 8, while an affected mother recognized loss around age 30 (pqac-00000000, pqac-00000002, pqac-00000005). | HPO suggestions: HP:0003577 Congenital onset; HP:0003596 Middle age onset; HP:0003676 Progressive hearing impairment |
| Anatomy/cell/subcellular site | Primary site is the **inner ear**, especially the **organ of Corti** and **cochlear hair-cell stereocilia**; vestibular hair-cell expression is also reported in model/mechanistic literature. Subcellular localization includes **stereocilia F-actin cores** and **cuticular plate** (pqac-00000007, pqac-00000009). | UBERON: inner ear / cochlea / organ of Corti / stereocilium (**exact IDs not confidently verified**); CL: auditory hair cell (**exact ID not confidently verified**); GO CC: stereocilium, actin cytoskeleton |
| Mechanism | Best-supported mechanism is disruption of **actin bundling/crosslinking in stereocilia**, impairing stereocilia architecture and long-term maintenance. Human missense variants are modeled to destabilize **ABD1** and weaken F-actin interaction; splice variant **c.981+1G>A** causes exon 8 skipping or partial deletion in ABD1. **PI3K-AKT upregulation is provisional**, supported by the **2022 preprint / later 2023 publication stream** and cell/zebrafish work, but not yet established as the definitive human disease mechanism (pqac-00000000, pqac-00000001, pqac-00000009, pqac-00000010, pqac-00000011). | GO suggestions: actin filament bundle assembly, stereocilium organization, sensory perception of sound |
| Models | **Pls1 knockout mice** develop moderate progressive hearing loss with shortened/thinner inner-hair-cell stereocilia and later degeneration, supporting a maintenance role for plastin 1. **Zebrafish** expressing/perturbed for the splice-variant context show abnormal otolith/cochlear morphometry and reduced swimming behavior (pqac-00000007, pqac-00000008, pqac-00000010). | Model systems: mouse knockout; zebrafish transient model |
| Diagnosis | Diagnosis currently relies on **audiologic phenotyping plus molecular testing**. Reported methods include next-generation sequencing or whole-exome sequencing with segregation testing, Sanger confirmation, and for splice variants, **minigene assays** to demonstrate aberrant splicing (pqac-00000000, pqac-00000004, pqac-00000011). | NCIT suggestions: Genetic Testing; Audiometry; Sanger Sequencing; Whole Exome Sequencing |
| Treatment | No **PLS1-specific molecular therapy** or genotype-directed clinical trial was identified. Current care is standard hereditary hearing-loss management: longitudinal audiologic follow-up, **hearing aids**, and **cochlear implantation** when indicated by severity/function, extrapolating from broader DFNA practice (pqac-00000000, pqac-00000002). | NCIT suggestions: Hearing Aid Device; Cochlear Implantation; Genetic Counseling |
| Epidemiology | DFNA76 is **ultra-rare**; evidence is limited to a small number of reported families from several ancestries. No robust prevalence, incidence, sex ratio, or carrier-frequency estimates are available (pqac-00000000, pqac-00000002, pqac-00000005). | Orphanet/MONDO prevalence term: **not confidently verified** |
| Key evidence gaps | Major gaps include lack of validated disease-specific identifiers in readily available context, no firm penetrance estimates, sparse natural-history data, minimal variant-level population frequency detail, no disease-specific QoL/outcome studies, no established modifier genes, no confirmed epigenetic mechanism, and no approved targeted therapy. The **PI3K-AKT** link remains **hypothesis-generating/provisional** rather than clinically established (pqac-00000001, pqac-00000010, pqac-00000011). | Knowledge-gap annotation; MONDO/HPO/UBERON exact IDs to be added after manual verification |


*Table: This table summarizes the current evidence base for PLS1-related autosomal dominant nonsyndromic hearing loss (DFNA76), including clinical features, variants, mechanism, models, and gaps. It is designed as a compact artifact for knowledge-base population while clearly flagging uncertain identifiers and provisional mechanistic claims.*