Missense variant in LOXHD1 is associated with canine nonsyndromic hearing loss

Abstract

Hearing loss is a common sensory deficit in both humans and dogs. In canines, the genetic basis is largely unknown, as genetic variants have only been identified for a syndromic form of hearing impairment. We observed a congenital or early-onset sensorineural hearing loss in a Rottweiler litter. Assuming an autosomal recessive inheritance, we used a combined approach of homozygosity mapping and genome sequencing to dissect the genetic background of the disorder. We identified a fully segregating missense variant in LOXHD1, a gene that is known to be essential for cochlear hair cell function and associated with nonsyndromic hearing loss in humans and mice. The canine LOXHD1 variant was specific to the Rottweiler breed in our study cohorts of pure-bred dogs. However, it also was present in some mixed-breed dogs, of which the majority showed Rottweiler ancestry. Low allele frequencies in these populations, 2.6% and 0.04%, indicate a rare variant. To summarize, our study describes the first genetic variant for canine nonsyndromic hearing loss, which is clinically and genetically similar to human LOXHD1-related hearing disorder, and therefore, provides a new large animal model for hearing loss. Equally important, the affected breed will benefit from a genetic test to eradicate this LOXHD1-related hearing disorder from the population.

Fig. 1

Results of homozygosity mapping in three affected and three unaffected dogs. Case-specific, allelically matching ROH are indicated in blue

Fig. 2

a Example chromatograms from Sanger sequencing of the chr7:44,806,821G>C variant. b Genotypes of four cases and three controls at a ROH at chr7:41.0–45.7 Mb. A distinct case-specific homozygous haplotype can be observed at 41.2–45.5 Mb. The bottommost case was not included in ROH detection due to a poor call rate. c Schematic illustration of the domain structure of LOXHD1 (J9PAE4)