Early onset of adult deafness in the Rhodesian Ridgeback is associated with in-frame deletion in the EPS8L2 gene

Domestic dogs exhibit diverse types of both congenital and non-congenital hearing losses. Rhodesian Ridgebacks can suffer from a progressive hearing loss in the early stage of their life, a condition known as early onset of adult deafness (EOAD), where they lose their hearing ability within 1-2 years after birth. In order to investigate the genetic basis of this hereditary hearing disorders, we performed a genome-wide association study (GWAS) by using a sample of 23 affected and 162 control Rhodesian Ridgebacks. We identified a genomic region on canine chromosome 18 (CFA18) that is strongly associated with EOAD, and our subsequent targeted Sanger sequencing analysis identified a 12-bp inframe deletion in EPS8L2 (CFA18:25,868,739-25,868,751 in the UMICH_Zoey_3.1/canFam5 reference genome build). Additional genotyping confirmed a strong association between the 12-bp deletion and EOAD, where all affected dogs were homozygous for the deletion, while none of the control dogs was a deletion homozygote. A segregation pattern of this deletion in a 2-generation nuclear family indicated an autosomal recessive mode of inheritance. Since EPS8L2 plays a critical role in the maintenance and integrity of the inner ear hair cells in humans and other mammals, the inframe deletion found in this study represents a strong candidate causal mutation for EOAD in Rhodesian Ridgebacks. Genetic and clinical similarities between childhood deafness in humans and EOAD in Rhodesian Ridgebacks emphasizes the potential value of this dog breed in translational research in hereditary hearing disorders.

家犬存在多种类型的先天性与非先天性听力损失。罗得西亚脊背犬（Rhodesian Ridgebacks）会在生命早期出现进行性听力损失，这一病症被称为成年期早发性耳聋（early onset of adult deafness, EOAD），患病犬仅会在出生后1~2年内丧失听力。为探究该遗传性听力障碍的遗传基础，本研究以23例患病罗得西亚脊背犬与162例健康对照个体为样本，开展了全基因组关联分析（genome-wide association study, GWAS）。我们在犬18号染色体（canine chromosome 18, CFA18）上鉴定到一个与EOAD显著相关的基因组区域；后续靶向桑格测序（Sanger sequencing）分析则在EPS8L2基因中鉴定到一段12 bp的框内缺失（UMICH_Zoey_3.1/canFam5参考基因组组装版本中的坐标为CFA18:25,868,739-25,868,751）。额外的基因分型实验证实，该12 bp缺失与EOAD存在强关联：所有患病犬均为该缺失的纯合子，而对照个体中无任何个体为该缺失纯合子。对一个两代核心家系的分离模式分析显示，该缺失遵循常染色体隐性遗传模式。由于EPS8L2在人类及其他哺乳动物的内耳毛细胞维持与结构完整性中发挥关键作用，本研究发现的框内缺失可作为罗得西亚脊背犬EOAD的强候选致病变异。人类儿童期耳聋与罗得西亚脊背犬EOAD之间存在的遗传与临床相似性，凸显了该犬种在遗传性听力障碍转化研究中的潜在应用价值。