Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 613079 (trait) , 613072 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2021

Species-specific name: Nonsyndromic hearing loss

Inheritance: Hytönen et al. (2021): "To validate the LOXHD1 variant, we genotyped it in a cohort of 585 Rottweilers, including the four affected siblings and 581 unaffected dogs. We observed complete segregation of the variant with hearing loss, as all four affected dogs were homozygous for the variant. The unaffected dogs were either heterozygous (n = 33) or wild-type (n = 548). The six unaffected littermates of the probands were either wild-type or heterozygous for the variant."

Molecular basis: Using "a combined approach of homozygosity mapping and genome sequencing to dissect the genetic background of the disorder . . . . [Hytönen et al. (2021)] identified a fully segregating missense variant [chr7:44,806,821G>C; p.(G1914A)] 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."

Clinical features: Hytönen et al. (2021): "Sensorineural bilateral deafness was diagnosed in four Rottweiler siblings (one female and three males) in a litter of ten puppies using brainstem auditory evoked response (BAER) testing. BAER testing was performed either at 4 (n = 2), 5, or 19 months of age, and no auditory response was detected in any of them. However, owners’ observations suggested that the puppies had already been affected by hearing impairment at a few weeks of age. No other clinical signs were observed."

Prevalence: Hytönen et al. (2021): "The allele frequency in the population [of Rottweilers], excluding the affected family, was 2.6% and carrier frequency 5.3%. An additional sample of dogs submitted for commercial genetic testing was screened for the LOXHD1 variant to explore its distribution across breeds. All 28,116 tested dogs representing 374 breeds, breed varieties or designer dog mixes were found homozygous for the wild-type allele (Online Resource 7). Finally, the variant was also screened in a larger study sample of 771,864 dogs submitted to genetic testing, including breed detection assessment. A variant carrier frequency of 0.08% and allele frequency of 0.04% were observed in this dataset. Interestingly, six dogs were found homozygous for the LOXHD1 variant. We were able to contact the owners of 4/6 of the homozygous dogs and the owners reported profound hearing loss or deafness in all of them. One of the deaf dogs did not show any immediate Rottweiler ancestry, while one was a purebred Rottweiler and two were mixed-breed with Rottweiler ancestry. Altogether, of the dogs carrying at least one copy of the deafness candidate variant, 63.4% showed evidence of Rottweiler ancestry in their immediate three-generation pedigree going back to great-grandparents, providing further support for a link between this specific breed background and the presence of the variant."

Breed: Rottweiler.

Associated gene: