Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA.
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Hum Genet. 2021 Jun;140(6):957-967. doi: 10.1007/s00439-021-02263-6. Epub 2021 Mar 21.
While newborns and children with hearing loss are routinely offered genetic testing, adults are rarely clinically tested for a genetic etiology. One clinically actionable result from genetic testing in children is the discovery of variants in syndromic hearing loss genes. EYA4 is a known hearing loss gene which is also involved in important pathways in cardiac tissue. The pleiotropic effects of rare EYA4 variants are poorly understood and their prevalence in a large cohort has not been previously reported. We investigated cardio-auditory phenotypes in 11,451 individuals in a large biobank using a rare variant, genome-first approach to EYA4. We filtered 256 EYA4 variants carried by 6737 participants to 26 rare and predicted deleterious variants carried by 42 heterozygotes. We aggregated predicted deleterious EYA4 gene variants into a combined variable (i.e. "gene burden") and performed association studies across phenotypes compared to wildtype controls. We validated findings with replication in three independent cohorts and human tissue expression data. EYA4 gene burden was significantly associated with audiometric-proven HL (p = [Formula: see text], Mobitz Type II AV block (p = [Formula: see text]) and the syndromic presentation of HL and primary cardiomyopathy (p = 0.0194). Analyses on audiogram, echocardiogram, and electrocardiogram data validated these associations. Prior reports have focused on identifying variants in families with severe or syndromic phenotypes. In contrast, we found, using a genotype-first approach, that gene burden in EYA4 is associated with more subtle cardio-auditory phenotypes in an adult medical biobank population, including cardiac conduction disorders which have not been previously reported. We show the value of using a focused approach to uncover human disease related to pleiotropic gene variants and suggest a role for genetic testing in adults presenting with hearing loss.
虽然新生儿和听力损失儿童通常会接受基因检测，但成年人很少接受针对遗传病因的临床检测。儿童基因检测的一个临床可操作结果是发现综合征性听力损失基因的变异。EYA4 是已知的听力损失基因，它也参与心脏组织中的重要途径。罕见 EYA4 变异的多效性影响尚未得到充分理解，其在大样本中的患病率以前也没有报道过。我们使用罕见变异体、全基因组优先的方法对 EYA4 进行了一项大型生物库中的 11451 个人的心脏-听觉表型研究。我们筛选了 6737 名参与者携带的 256 种 EYA4 变异体，得到了 42 名杂合子携带的 26 种罕见和预测有害的变异体。我们将预测有害的 EYA4 基因变异体聚合为一个组合变量（即“基因负担”），并将其与野生型对照进行表型关联研究。我们使用三个独立队列和人类组织表达数据进行了验证。EYA4 基因负担与经听力证实的 HL（p = [公式]，Mobitz 型 II AV 阻滞（p = [公式]）和 HL 及原发性心肌病的综合征表现（p = 0.0194）显著相关。对听力图、超声心动图和心电图数据的分析验证了这些关联。以前的报告主要集中在识别具有严重或综合征表型的家族中的变异体。相比之下，我们使用基因优先的方法发现，EYA4 中的基因负担与成人医疗生物库人群中更微妙的心脏-听觉表型相关，包括以前未报道过的心脏传导障碍。我们展示了使用集中方法揭示与多效性基因变异体相关的人类疾病的价值，并建议对出现听力损失的成年人进行遗传检测。
