Rising of LOXHD1 as a signature causative gene of down-sloping hearing loss in people in their teens and 20s

Background Down-sloping sensorineural hearing loss (SNHL) in people in their teens and 20s hampers efficient learning and communication and in-depth social interactions. Nonetheless, its aetiology remains largely unclear, with the exception of some potential causative genes, none of which stands out especially in people in their teens and 20s. Here, we examined the role and genotype-phenotype correlation of lipoxygenase homology domain 1 (LOXHD1) in down-sloping SNHL through a cohort study. Methods Based on the Seoul National University Bundang Hospital (SNUBH) genetic deafness cohort, in which the patients show varying degrees of deafness and different onset ages (n=1055), we have established the 'SNUBH Teenager-Young Adult Down-sloping SNHL' cohort (10-35 years old) (n=47), all of whom underwent exome sequencing. Three-dimensional molecular modelling, minigene splicing assay and short tandem repeat marker genotyping were performed, and medical records were reviewed. Results LOXHD1 accounted for 33.3% of all genetically diagnosed cases of down-sloping SNHL (n=18) and 12.8% of cases in the whole down-sloping SNHL cohort (n=47) of young adults. We identified a potential common founder allele, as well as an interesting genotype-phenotype correlation. We also showed that transcript 6 is necessary and probably sufficient for normal hearing. Conclusions LOXHD1 exceeds other genes in its contribution to down-sloping SNHL in young adults, rising as a signature causative gene, and shows a potential but interesting genotype-phenotype correlation.

Automated summary

The study examined the role and genotype-phenotype correlation of LOXHD1 in down-sloping sensorineural hearing loss (SNHL) in teenagers and young adults, revealing that LOXHD1 accounts for a significant proportion of genetically diagnosed cases in this age group. The findings suggest that LOXHD1 may play a signature causative role in down-sloping SNHL in young adults, with potential interesting genotype-phenotype correlations.