Further audiovestibular characterization of DFNB77, caused by deleterious variants in LOXHD1, and investigation into the involvement of Fuchs corneal dystrophy

Abstract

This study focuses on further characterization of the audiovestibular phenotype and on genotype-phenotype correlations of DFNB77, an autosomal recessive type of hearing impairment (HI). DFNB77 is associated with disease-causing variants in LOXHD1, and is genetically and phenotypically highly heterogeneous. Heterozygous deleterious missense variants in LOXHD1 have been associated with late-onset Fuchs corneal dystrophy (FCD). However, up to now screening for FCD of heterozygous carriers in DFNB77 families has not been reported. This study describes the genotype and audiovestibular phenotype of 9 families with DFNB77. In addition, carriers within the families were screened for FCD. Fifteen pathogenic missense and truncating variants were identified, of which 12 were novel. The hearing phenotype showed high inter- and intrafamilial variation in severity and progression. There was no evidence for involvement of the vestibular system. None of the carriers showed (pre-clinical) symptoms of FCD. Our findings expand the genotypic and phenotypic spectrum of DFNB77, but a clear correlation between the type or location of the variant and the severity or progression of HI could not be established. We hypothesize that environmental factors or genetic modifiers are responsible for phenotypic differences. No association was found between heterozygous LOXHD1 variants and the occurrence of FCD in carriers.

Five Novel Mutations in LOXHD1 Gene Were Identified to Cause Autosomal Recessive Nonsyndromic Hearing Loss in Four Chinese Families

“…However, in the four families we have studied, all the patients and the family members with normal hearing but carrying a single heterozygous mutation in the LOXHD1 gene showed no corneal abnormalities. Other studies also reported no symptoms of FCD were observed in the probands and their blood-related relatives [7,10,33]. Although the relationship of LOXHD1-related hearing loss and FCD is still unclear, we suggest that ophthalmologic examinations should be performed in patients with ARNSHL when LOXHD1 is suspected to be the pathogenic gene.…”

“…Moreover, studies suggested that a single heterozygous mutation of LOXHD1 was also associated with another hereditary disease, Fuchs corneal dystrophy (FCD) [9]. Other studies demonstrated conflicting conclusions that there was no association between LOXHD1 mutations and FCD [9,10].…”

Recessive LOXHD1 Variants Cause a Milder Prelingual Hearing Loss: Genotype-Phenotype Correlation and Three Additional Patients With Novel Variants

“…A murine study has demonstrated that the first damaged part of cochlear hair cells was the stereocilia in the basal cochlear turn, which respond to the highest frequencies [5], indicating low frequencies should have relative milder damage. A milder HL was also reported in some patients with LOXHD1 variants [5] [8]. However, studies reported that some LOXHD1 variants are associated with a more severe HL [23] [18] [9] [19].…”

“…To date, about 100 cases with DFNB77 have been reported [8] [9] [10] [11] [5]. However, the acoustic characteristics are heterogeneous.…”

A novel LOXHD1 variant in a Chinese couple with hearing loss

“…They show different auditory characteristics and audiometric phenotypes, varying from mild to profound and from stable to progressive sensorineural HL. 5,[7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Animal c.5869G>T Nonsense Het Moderate-severe Non-progressive Japanese 3 5 c.4480C>T Nonsense Het Moderate-severe Non-progressive Japanese 4 7 c.884C>T Missense Het Moderate-severe Progressive -5 7 c.2825_2827delAGA Frameshift Het Moderate-severe Progressive -6 7 c.2797C>T Nonsense Het Profound Non-progressive -7 7 c.1730T>G Frameshift Het Profound Non-progressive -8 7 c.2722G>A Missense Het Profound Non-progressive -9 7 c. 13 However, Wesdorp et al 4 found that the type of variant (nonsense or missense) did not associate with HL severity, and that the combination of a nonsense and missense variant could cause different audiometric phenotypes. Such research is limited, so correlations between LOXHD1 variants and phenotypic characteristics of HL remain unclear.…”