Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Nephrology & Transplantation, Beaumont Hospital, Dublin, Ireland; Trinity Health Kidney Centre, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
Department of Nephrology & Transplantation, Beaumont Hospital, Dublin, Ireland.
Kidney Int. 2019 Apr;95(4):914-928. doi: 10.1016/j.kint.2018.10.031. Epub 2019 Feb 14.
Approximately 500 monogenic causes of chronic kidney disease (CKD) have been identified, mainly in pediatric populations. The frequency of monogenic causes among adults with CKD has been less extensively studied. To determine the likelihood of detecting monogenic causes of CKD in adults presenting to nephrology services in Ireland, we conducted whole exome sequencing (WES) in a multi-centre cohort of 114 families including 138 affected individuals with CKD. Affected adults were recruited from 78 families with a positive family history, 16 families with extra-renal features, and 20 families with neither a family history nor extra-renal features. We detected a pathogenic mutation in a known CKD gene in 42 of 114 families (37%). A monogenic cause was identified in 36% of affected families with a positive family history of CKD, 69% of those with extra-renal features, and only 15% of those without a family history or extra-renal features. There was no difference in the rate of genetic diagnosis in individuals with childhood versus adult onset CKD. Among the 42 families in whom a monogenic cause was identified, WES confirmed the clinical diagnosis in 17 (40%), corrected the clinical diagnosis in 9 (22%), and established a diagnosis for the first time in 16 families referred with CKD of unknown etiology (38%). In this multi-centre study of adults with CKD, a molecular genetic diagnosis was established in over one-third of families. In the evolving era of precision medicine, WES may be an important tool to identify the cause of CKD in adults.
已经确定了大约 500 种导致慢性肾脏病 (CKD) 的单基因病因，主要是在儿科人群中。成人 CKD 中单基因病因的频率尚未得到广泛研究。为了确定在爱尔兰肾病科就诊的成人中检测到 CKD 的单基因病因的可能性，我们对包括 138 名 CKD 患者在内的 114 个多中心家族进行了全外显子组测序 (WES)。受影响的成年人是从 78 个有阳性家族史的家庭、16 个有肾脏外特征的家庭和 20 个既没有家族史也没有肾脏外特征的家庭中招募的。我们在 114 个家庭中的 42 个家庭中检测到一个已知 CKD 基因的致病性突变 (37%)。在有 CKD 阳性家族史的受影响家庭中，36%的家庭确定了单基因病因，69%的有肾脏外特征的家庭，只有 15%的没有家族史或肾脏外特征的家庭。在有儿童期和成年期发病 CKD 的个体中，遗传诊断的比率没有差异。在确定单基因病因的 42 个家庭中，WES 证实了 17 个 (40%)的临床诊断，纠正了 9 个 (22%)的临床诊断，并首次为 16 个家族建立了病因诊断，这些家族被转诊为原因不明的 CKD (38%)。在这项针对成人 CKD 的多中心研究中，超过三分之一的家庭确定了分子遗传诊断。在精准医学的时代，WES 可能是识别成人 CKD 病因的重要工具。
