NSHL is a complex disorder with highly genetic and clinical heterogeneity. Routinely, hotspot regions of four common HL-associated genes, such as
GJB2,
GJB3,
SLC26A4 and
MT-RNR1, are recommended to be initially detected for molecular diagnosis for NSHL. If results are negative, gene-panel sequencing or WES are applied for further detection. Specially, a trio-WES is quite suitable for those rare NSHL. DFNB77 is a rare NSHL with autosomal recessive inheritance, caused by homozygous mutations within
LOXHD1 gene, firstly described in 2009 [
7]. In the past ten years, about 60 variants within this gene were identified in NSHL cases. They showed different auditory characteristics, varying from stable to progressive and from mild to profound HL. The limited variant spectrum of
LOXHD1 strongly requires more studies to fill in gaps in the genotype-phenotype correlations of DFNB77. In this study, we used a trio-WES to successfully identify a novel homozygous variant, c.5948C > T (p.S1983F), within
LOXHD1 gene in a Chinese family. To the best of our knowledge, this is the second pedigree report of
LOXHD1-related NSHL in China.
LOXHD1 encodes an important protein consisting of 15 PLAT domains, which mediates protein interactions to maintain normal hair cell function [
7]. Deleterious variants within
LOXHD1 could lead to various severities and various types of NSHL including progressive and non-progressive congenital HL [
2,
7,
9‐
22]. Table
1 summarizes the published genotype-phenotype correlations of DFNB77 confirmed by segregation analysis. HL-associated variants within
LOXHD1 could occur in various races. Homozygotes (c.71delT/c.71delT, c.1588G > T/c.1588G > T, c.4212 + 1G > A/c.4212 + 1G > A, etc.) appeared to show a trend toward severe or profound HL, and compound heterozygotes showed different HL phenotypes. No overlapping genotype was reported by these studies performing segregation analysis. The quite limited information hindered to explore more genotype-phenotype correlations, requiring more studies to uncover variant spectrum of
LOXHD1 and related HL phenotype. Here, we identified a novel missense variant,
LOXHD1: c.5948C > T, was associated with non-progressive NSHL in a family under consanguineous marriage. The proband carried homozygous c.5948C > T, her parents carried heterozygous c.5948C > T, and her brother did not carry this variant, which was compatible with the autosomal recessive inheritance of DFNB77. Comprehensive analyses, including family history, trio-WES, co-segregation validation, rarity in control population, and bioinformatics prediction, strongly support that
LOXHD1: c.5948C > T could be a pathogenic factor. It makes effect on all the transcript isoforms of
LOXHD1 gene: NM_144612:exon38:c.5948C > T: p.S1983F, NM_001145473:exon7:c.851C > T:p.S284F, NM_001173129:exon7:c.851C > T:p.S284F, NM_001308013:exon19:c.2513C > T:p.S838F, and NM_001145472:exon21:c.2801C > T:p.S934F. Variants within
LOXHD1 are quite rare and recently, Hu et al. reported a first affected Chinese pedigree with progressive NSHL [
2]. Compared to the compound heterozygotes (c.1751C > T/c.5815G > A) found by Hu et al., we identified a novel homozygote, c.5948C > T/ c.5948C > T, was associated with non-progressive NSHL. In addition, c.5948C > T is located in the 14th PLAT domain of LOXHD1 protein, which harbors the most published variants to date, compared with other PLAT domains [
20]. Another five published variants (c.5869G > T, c.5885C > T, c.5934C > T, c.5944C > T and c.6162_6164delCCT) from different races are also concentrated in here [
14,
18,
20], indicating that the 14th PLAT domain could be a hotspot mutated region of
LOXHD1.
Table 1
Genotype-phenotype correlation of DFNB77 confirmed by segregation analysis
c.71delT/c.71delT | Turkish | Severe or profound | NA | |
c.442A > T/c.4217C > T | NA | NA | NA | |
c.1588G > T/c.1588G > T | Qatary | Severe to profound | Progressive | |
c.1618dup/c.1730 T > G | Dutch | Moderate to severe | Stable to progressive | |
c.1751C > T/c.5815G > A | Chinese | Severe | Progressive | |
c.1828G > T/c.2641G > A | Dutch | Mild | Stable | |
c.1904 T > C/c.4678 T > C | Dutch | Mild | Stable to progressive | |
c.2008C > T/c.2008C > T | Iranian | Mild to profound | Progressive | |
c.2696G > C/c.3834G > C | Dutch | Moderate | Stable | |
c.2696G > C/c.5934C > T | Dutch | Mild | NA | |
c.2863G > T/c.2863G > T | Turkish | NA | NA | |
c.3061C > T/c.5885C > T | Indian | Severe | Stable | |
c.3061 + 1G > A/c.6353G > A | Dutch | Moderate | NA | |
c.3076G > T/c.4375 + 1G > T | Japanese | Profound | Stable | |
c.3169C > T/c.6353G > A | Dutch | Severe | Stable | |
c.3371G > A/c.3979 T > A | Cameroonian | Profound | NA | |
c.3748 + 1G > C/c.6353G > A | Dutch | Moderate to severe | Stable to progressive | |
c.4212 + 1G > A/c.4212 + 1G > A | Japanese | Profound | Stable | |
c.4212 + 1G > A/c.5674G > T | Japanese | Mild to profound | Progressive | |
c.4480C > T/c.4480C > T | Turkish | NA | NA | |
c.4480C > T/c.5869G > T | Japanese | Moderate to severe | Stable | |
c.4623C > G/c.5545G > A | Czech | Severe | NA | |
c.4714C > T/c.4714C > T | Ashkenazi Jewish | Severe to profound | NA | |
c.5894dupG/c.5894dupG | Arab | Profound | NA | |
c.5948C > T/c.5948C > T | Chinese | Profound | Stable | This study |
Variants within
LOXHD1 were also linked to late-onset FCD, a genetic degenerative disease of corneal endothelium towards blindness. In 2012, Riazuddin, et al. first reported a heterozygous damaging variant within
LOXHD1 in a multiplex family with dominant-inherited late-onset FCD [
27]. However, subsequent studies failed to provide a strong association between
LOXHD1 variants and FCD [
20,
28‐
30]. Specially, results from a Chinese multi-generational FCD pedigree demonstrated that no pathogenic variants were identified in
LOXHD1 [
28]. In line with these previous studies, our work also did not observed any symptoms of FCD in the proband and her blood relatives within three generations. However, a limitation of our study is that the identified missense variant is lacking in animal models or in the verification of other HL patients. More functional and population studies are required to further verify our results.