Abstract
Congenital deafness is prevalent among modern dog breeds, including Australian Stumpy Tail Cattle Dogs (ASCD). However, in ASCD, no causative gene has been identified so far. Therefore, we performed a genome-wide association study (GWAS) and whole genome sequencing (WGS) of affected and normal individuals. For GWAS, 3 bilateral deaf ASCDs, 43 herding dogs, and one unaffected ASCD were used, resulting in 13 significantly associated loci on 6 chromosomes, i.e., CFA3, 8, 17, 23, 28, and 37. CFA37 harbored a region with the most significant association (−log10(9.54 × 10−21) = 20.02) as well as 7 of the 13 associated loci. For whole genome sequencing, the same three affected ASCDs and one unaffected ASCD were used. The WGS data were compared with 722 canine controls and filtered for protein coding and non-synonymous variants, resulting in four missense variants present only in the affected dogs. Using effect prediction tools, two variants remained with predicted deleterious effects within the Heart development protein with EGF like domains 1 (HEG1) gene (NC_006615.3: g.28028412G>C; XP_022269716.1: p.His531Asp) and Kruppel-like factor 7 (KLF7) gene (NC_006619.3: g.15562684G>A; XP_022270984.1: p.Leu173Phe). Due to its function as a regulator in heart and vessel formation and cardiovascular development, HEG1 was excluded as a candidate gene. On the other hand, KLF7 plays a crucial role in the nervous system, is expressed in the otic placode, and is reported to be involved in inner ear development. 55 additional ASCD samples (28 deaf and 27 normal hearing dogs) were genotyped for the KLF7 variant, and the variant remained significantly associated with deafness in ASCD (p = 0.014). Furthermore, 24 dogs with heterozygous or homozygous mutations were detected, including 18 deaf dogs. The penetrance was calculated to be 0.75, which is in agreement with previous reports. In conclusion, KLF7 is a promising candidate gene causative for ASCD deafness.
Highlights
Deafness can cause several inconveniences for dogs (Canis familiaris, CFA), as more attention is required to avoid undetected danger
We identified a unique missense variant in Kruppel-like factor 7 (KLF7) gene significantly associated with deafness in Australian Stumpy Tail Cattle Dogs (ASCD)
As Kruppellike factor 7 (KLF7) plays an important role in the nervous system, is expressed in the inner ear, and seems to be involved in inner ear development [18,19], it was a convincing candidate for ASCD deafness
Summary
Deafness can cause several inconveniences for dogs (Canis familiaris, CFA), as more attention is required to avoid undetected danger. Hearing loss or deafness can be categorized mainly by five criteria in dogs: (1) Cause (genetic or nongenetic, inherited or acquired); (2) association with other diseases or phenotypes (syndromic or non-syndromic); (3) number of affected ears (unilateral or bilateral); (4) degree of loss (partial or total); and (5) site of pathology (peripheral or central) [4]. Congenital sensorineural deafness is common, resulting in total deafness in young puppies that is either unilateral or bilateral. In ASCD, congenital sensorineural deafness has been linked to a chromosomal region on CFA10 [12]. Genes 2021, 12, 467 wide association study (GWAS) reported 14 chromosomes that were significantly associated with deafness in three canine breeds, and CFA3 was significantly associated with bilateral deafness in Australian Cattle Dogs [17]. As KLF7 plays an important role in the nervous system, is expressed in the inner ear, and seems to be involved in inner ear development [18,19], it was a convincing candidate for ASCD deafness
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