| Domain | Established finding | Evidence type/sample | Quantitative detail | Confidence/limitation |
|---|---|---|---|---|
| Disease identity | Autosomal recessive nonsyndromic hearing loss 124; PKHD1L1-related deafness; DFNB124 | Curated disease-resource and peer-reviewed evidence | MONDO:0968981; OMIM phenotype 620794 | Exact identifiers supported; no disease-specific Orphanet, ICD, or MeSH identifier was established in the retrieved sources. (pqac-00000013, pqac-00000035) |
| Human phenotype | Bilateral congenital or early-onset sensorineural hearing loss ranging from mild–moderate to severe | Human series of four unrelated probands | Audiometry reported at ages 13, 9, 12, and 8 years | Foundational but very small cohort; population-level phenotype frequencies cannot be estimated. (pqac-00000003, pqac-00000014, pqac-00000015) |
| Family 1 | Slowly progressive bilateral mild–moderate SNHL in a White American female who failed newborn screening | Human longitudinal audiology | PTA increased 5 dB right and 8 dB left from ages 4.3–13.3 years; latest PTA 45.00/48.75 dB; word recognition 90%; SRT 45 dB bilaterally | Best longitudinal human evidence; episodic BPPV resolved with Epley maneuver, but association with DFNB124 is uncertain. (pqac-00000004, pqac-00000014) |
| Families 2–4 | Family 2: Iranian Lur boy with progressive moderate–severe SNHL; Family 3: Pakistani boy with severe SNHL; Family 4: Chinese boy with moderate SNHL | Human cases in the four-family series | Family 2: diagnosed at 2.5 months, SRT 60 dB, SDS 100% at 80 dB; Family 3: PTA 85 dB HL; Family 4: absent DPOAEs with normal tympanograms | Follow-up was limited; Family 3 also had a homozygous MYO7A variant, weakening attribution of severity solely to PKHD1L1. (pqac-00000015, pqac-00000017) |
| Reported genotypes | Six alleles occur in four biallelic genotypes: p.[Gly129Ser];[Gly1314Val], homozygous p.Arg3381Ter, homozygous p.His2479Gln, and p.[Gly605Arg];[Leu2818TyrfsTer5] | Human exome sequencing and segregation | Alleles: c.385G>A, c.3941G>T, c.10141C>T, c.7437C>A, c.1813G>A, and c.8452_8468del; protein reference NP_803875.2 | Only four disease-associated genotypes were reported; current ClinVar and laboratory ACMG classifications should be checked before clinical use. (pqac-00000003, pqac-00000014, pqac-00000015) |
| Population frequency | Reported alleles are rare but not uniformly ultra-rare | gnomAD frequencies reported in the discovery study | Gly129Ser 0.001471%; Gly1314Val 0.07204%; Arg3381Ter 0.02067%; His2479Gln 0.3107% | Frequencies vary by database version and ancestry; the higher His2479Gln frequency and competing MYO7A finding require caution. (pqac-00000014, pqac-00000015) |
| Functional assays | Gly129Ser and Gly1314Val destabilize recombinant PKHD1L1 fragments; Gly605Arg alters splicing | In-vitro NanoDSF and HEK293/HeLa minigene assays | Gly129Ser reduced unfolding onset by about 6 °C and melting transitions by about 4 °C; Gly1314Val reduced onset by about 7 °C and melting temperature by 9.1 °C; Gly605Arg caused exon 17 skipping and p.Val557_Arg604del | Direct molecular effects were demonstrated in protein fragments or cultured cells, not full-length protein in human cochlear tissue. (pqac-00000016, pqac-00000017, pqac-00000018) |
| Protein mechanism | PKHD1L1 is a large, predominantly extracellular, single-pass membrane component of the transient stereocilia surface coat | Mouse immunolocalization, immunogold SEM, and structural modeling | Approximately 4,249 amino acids; 14 predicted IPT repeats; enriched near stereocilia tips, especially in high-frequency cochlear regions | Coat localization is demonstrated in mice; binding partners and precise biochemical function remain unknown. (pqac-00000009, pqac-00000013, pqac-00000016) |
| Mouse models | Hair-cell-specific and constitutive Pkhd1l1 loss causes progressive stereocilia loss, bundle disorganization, and hearing impairment | Conditional Pkhd1l1 floxed/Atoh1-Cre-positive and constitutive knockout mice | High-frequency ABR and DPOAE deficits were evident by about 6 weeks and extended toward lower frequencies with age; stereocilia loss was assessed at 6 weeks, 14 weeks, and 9 months | Strong causal animal evidence, although mouse onset is delayed relative to congenital hearing loss in humans. (pqac-00000011, pqac-00000020, pqac-00000022, pqac-00000026) |
| Zebrafish model | Combined loss of the pkhd1l1 paralogs impairs auditory behavior in larvae | pkhd1l1a/pkhd1l1b double-mutant zebrafish | Reduced auditory-evoked startle at 6 days post-fertilization | Supports conserved auditory function, but startle behavior is an indirect hearing measure. (pqac-00000013, pqac-00000017, pqac-00000021) |
| Gene–environment interaction | PKHD1L1 deficiency increases susceptibility to acoustic overexposure | Controlled mouse noise-exposure experiment | Moderate octave-band exposure caused permanent threshold shifts in deficient mice but temporary shifts in controls; follow-up extended from 1 day to 8 weeks | Compelling preclinical interaction; increased human noise susceptibility remains unproven. (pqac-00000020, pqac-00000022, pqac-00000024, pqac-00000026) |
| Diagnostics | Diagnosis requires confirmation of bilateral SNHL and biallelic PKHD1L1 variants with segregation and careful variant interpretation | Human audiology and exome sequencing; general congenital-SNHL practice | Relevant tests include newborn screening, ABR or behavioral audiometry, tympanometry, OAEs, speech testing, and panel/WES/WGS analysis with CNV detection | No DFNB124-specific clinical criteria or biomarker exists; exome reanalysis identified Family 4, showing the value of periodic reinterpretation. (pqac-00000014, pqac-00000015, pqac-00000033) |
| Management | Care is phenotype-directed: hearing aids, speech-language and communication intervention, educational accommodations, serial audiology, and cochlear-implant evaluation when indicated | General congenital-SNHL care; one DFNB124 proband used bilateral hearing aids | Family 2 used bilateral hearing aids; no disease-specific response rate is available | No evidence shows that standard hearing devices perform differently in DFNB124; no therapy currently corrects PKHD1L1 dysfunction. (pqac-00000015, pqac-00000027, pqac-00000033) |
| Epidemiology | Disease-specific prevalence, incidence, penetrance, carrier frequency, sex ratio, founder effects, and geographic distribution are unknown | Four unrelated families from the United States, Iran, Pakistan, and China | Four published probands in the founding series; two came from consanguineous families | Geographic diversity suggests the disease is not confined to one population, but the sample cannot establish demographic risks or prevalence. (pqac-00000003, pqac-00000007, pqac-00000015) |
| Clinical trials | No PKHD1L1/DFNB124-specific interventional trial or targeted therapy was identified | ClinicalTrials.gov and literature searches | Zero relevant disease-specific trials among retrieved records | A search-negative finding is not proof that no unregistered or newly initiated study exists; current hereditary-hearing-loss gene-therapy trials chiefly target other genes such as OTOF. (pqac-00000027, pqac-00000031, pqac-00000033) |


*Table: Compact evidence map for PKHD1L1-related deafness, separating human, in-vitro, animal, and inferred findings. It also highlights the major epidemiologic, diagnostic, therapeutic, and clinical-trial evidence gaps.*