| Evidence category | Finding | Quantitative/detail | Evidence type/source |
|---|---|---|---|
| Core monogenic report | ATP2B2 loss-of-function variants define ATP2B2-related autosomal dominant hearing loss (DFNA82) | Five heterozygous variants across five families: c.397+1G>A, c.955delG p.Ala319fs, c.1963G>T p.Glu655*, c.1998C>A p.Cys666*, c.2329C>T p.Arg777* (pqac-00000018, pqac-00000020) | Human clinical genetics, WES/segregation; Smits et al. 2019 (pqac-00000018, pqac-00000020) |
| Inheritance | Mixed de novo and familial autosomal dominant transmission | Two variants de novo (c.955delG, c.1963G>T); three in families with autosomal dominant inheritance (pqac-00000018, pqac-00000020) | Human pedigree/segregation (pqac-00000018, pqac-00000020) |
| Cohort size | Clinically characterized affected subjects | 11 clinically evaluated affected individuals; ages 6-68 years in analyzed cohort (pqac-00000019, pqac-00000007) | Human clinical series (pqac-00000019, pqac-00000007) |
| Onset/screening | Early childhood onset despite normal newborn screening | All four screened subjects passed newborn screening; diagnosis typically followed at ~2-6 years, with most onset in first decade; one outlier reported onset at 55 years (pqac-00000018, pqac-00000019, pqac-00000021) | Human audiology/natural history (pqac-00000018, pqac-00000019, pqac-00000021) |
| Audiometric phenotype | Nonsyndromic progressive SNHL with characteristic configuration | Bilateral, sensorineural, symmetric, mild-to-profound loss; audiograms typically (steeply) downsloping with high frequencies most affected (pqac-00000019, pqac-00000021) | Human audiometry (pqac-00000019, pqac-00000021) |
| Progression | Quantified annual deterioration | Average annual threshold deterioration ages 10-70 years: 0.5 dB/year low frequencies, 1.1 dB/year middle, 0.7 dB/year high (pqac-00000019) | Cross-sectional ARTA analysis in human cohort (pqac-00000019) |
| Imaging | No structural inner-ear or retrocochlear abnormality | CT/MRI in five subjects showed normal temporal bone/cochlear anatomy and no retrocochlear pathology (except unrelated operated ear findings) (pqac-00000018, pqac-00000019) | Human radiology/clinical workup (pqac-00000018, pqac-00000019) |
| Vestibular findings | Vestibular function essentially normal in heterozygotes | No balance complaints overall; extensive testing showed only minor/nonspecific abnormalities, with no clear ATP2B2-related vestibular dysfunction (pqac-00000018, pqac-00000017) | Human vestibular phenotyping (pqac-00000018, pqac-00000017) |
| Population frequency | Variants are ultra-rare/absent in reference datasets | None of the five variants present in gnomAD v2.02 or an in-house database of ~20,000 exomes (pqac-00000020, pqac-00000007) | Human population genetics/filtering (pqac-00000020, pqac-00000007) |
| Molecular mechanism | Loss of PMCA2 function is the likely disease mechanism | Variants affect exons/splice sites encoding the PMCA2 w/a ortholog; 4/5 predicted to trigger nonsense-mediated decay; distribution supports haploinsufficiency (pqac-00000018, pqac-00000021) | Human molecular interpretation supported by model-organism biology (pqac-00000018, pqac-00000021) |
| Cochlear biology | PMCA2 is a stereociliary Ca2+ pump required for hair-cell ion homeostasis | PMCA2 extrudes Ca2+ from stereocilia to endolymph; w/a isoform is highly abundant in OHC stereocilia and present apically in IHCs (pqac-00000018, pqac-00000017) | Mechanistic synthesis from human report citing prior auditory biology (pqac-00000018, pqac-00000017) |
| Model support | Mouse dosage effects mirror the human phenotype | Heterozygous Atp2b2 loss-of-function mice show rapidly progressive early-onset high-frequency hearing loss; homozygotes typically have severe hearing and vestibular/ataxic phenotypes (pqac-00000018, pqac-00000021, pqac-00000012) | Model-organism evidence (mouse) (pqac-00000018, pqac-00000021, pqac-00000012) |
| Genetic interaction context | Distinguish monogenic DFNA82 from earlier modifier evidence | ATP2B2 p.Val586Met is a hypofunctional PMCA2 allele reported as a modifier/digenic contributor with CDH23-related hearing loss, not the core monogenic DFNA82 mechanism established by ATP2B2 loss-of-function alleles (pqac-00000004, pqac-00000001, pqac-00000018) | Human modifier study vs later monogenic clinical-genetic study (pqac-00000004, pqac-00000001, pqac-00000018) |


*Table: This table condenses the key human and supporting model evidence defining ATP2B2-related autosomal dominant hearing loss (DFNA82). It separates the core monogenic loss-of-function evidence from the earlier ATP2B2 p.Val586Met modifier/digenic report.*