LOXHD1 – Autosomal Recessive Nonsyndromic Hearing Loss 77

LOXHD1 encodes a multi-PLAT domain protein expressed in cochlear hair cells and is causally linked to DFNB77, a progressive nonsyndromic sensorineural hearing loss. Initial case reports identified a novel homozygous missense LOXHD1 variant c.2696G>C (p.Arg899Pro) in a consanguineous Chinese family, co-segregating with profound bilateral hearing loss (PMID:30760222). Subsequent cohort studies across diverse populations have confirmed biallelic LOXHD1 variants in 9 families (PMID:29676012), 28 Japanese patients with a recurrent splice-site founder allele c.4212+1G>A in 18 individuals (PMID:31547530), and three additional unrelated children with novel missense and splice variants (PMID:33892339). A large Chinese NSHL panel study found LOXHD1 causative variants in 21 of 2,901 patients (~0.72%), identifying 20 novel alleles and six recurrent hotspots (PMID:35711932). Compound heterozygous LOXHD1 missense and truncating mutations were also reported in a Pakistani family with prelingual DFNB77 (PMID:36472766).

Inheritance is autosomal recessive; affected individuals carry biallelic missense, splice-site, and frameshift variants, with clear co-segregation in multiplex families and consanguineous pedigrees. Segregation analysis has demonstrated at least two additional affected relatives sharing these variants in independent families (PMID:26973026). The variant spectrum encompasses 15 distinct missense and truncating alleles in 9 families, 21 alleles in 28 patients, splice-site changes (e.g., c.4212+1G>A), frameshifts (e.g., c.6425_6428del), and founder mutations specific to Japanese and Chinese populations. Audiovestibular phenotyping reveals a down-sloping audiogram often presenting before age five, with high inter- and intrafamilial variability but no vestibular involvement.

Functional data are limited. Molecular modeling of the PLAT domain predicts that missense variants such as p.Val1892Phe and p.Arg899Pro disrupt protein folding and lipid-binding interfaces in hair cells (PMID:26973026). Expression studies confirm LOXHD1 transcript and protein localization in murine and human cochlear hair cells, consistent with a hair-cell–intrinsic mechanism. No animal models fully recapitulating DFNB77 have been published, and rescue assays remain unexplored.

No convincing conflicting evidence has been reported for DFNB77. Heterozygous carriers show no vestibular or corneal dystrophy phenotypes related to LOXHD1. The association is specific to autosomal recessive sensorineural hearing loss.

In summary, biallelic LOXHD1 variants cause DFNB77 through presumed loss of function in cochlear hair cells. This gene–disease relationship is replicated across multiple cohorts and populations, with consistent segregation and variant pathogenicity. LOXHD1 testing should be incorporated into diagnostic panels for early-onset progressive hearing loss, and variant interpretation should consider missense hotspots and splice-site founder alleles.

Key Take-home: LOXHD1 is a definitive autosomal recessive deafness gene; genetic screening enables accurate diagnosis and carrier counseling for DFNB77.

References

• BMC medical genetics • 2019 • Whole-exome sequencing identifies a novel missense variant within LOXHD1 causing rare hearing loss in a Chinese family. PMID:30760222
• Clinical genetics • 2018 • Further audiovestibular characterization of DFNB77, caused by deleterious variants in LOXHD1, and investigation into the involvement of Fuchs corneal dystrophy. PMID:29676012
• Genes • 2019 • Mutational Spectrum and Clinical Features of Patients with LOXHD1 Variants Identified in an 8074 Hearing Loss Patient Cohort. PMID:31547530
• International journal of pediatric otorhinolaryngology • 2021 • Recessive LOXHD1 variants cause a prelingual down-sloping hearing loss: genotype-phenotype correlation and three additional children with novel variants. PMID:33892339
• Auris, nasus, larynx • 2016 • Clinical characteristics of a Japanese family with hearing loss accompanied by compound heterozygous mutations in LOXHD1. PMID:26973026
• Frontiers in genetics • 2022 • Genetic Analysis of the LOXHD1 Gene in Chinese Patients With Non-Syndromic Hearing Loss. PMID:35711932
• Genes & genomics • 2023 • Biallelic mutations in pakistani families with autosomal recessive prelingual nonsyndromic hearing loss. PMID:36472766

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