Monogenic causes of chronic kidney disease in adults
Monogenic causes of chronic kidney disease in adults
复制标题
DOI：
10.1016/j.kint.2018.10.031
复制
发表时间：
2019-04-01
影响因子：
19.6
通讯作者：
Hildebrandt, Friedhelm
中科院分区：
文献类型：
--
作者：
Connaughton, Deryla M.;Kennedy, Claire;Hildebrandt, Friedhelm
已确定约500种慢性肾脏病（CKD）的单基因病因，主要发生在儿科人群中。成人CKD患者中单基因病因的频率研究较少。为了确定在爱尔兰接受肾脏病服务的成人中检测到CKD单基因病因的可能性，我们对114个家庭（包括138名CKD患者）的多中心队列进行了全外显子组测序（WES）。受影响的成年人从78个具有阳性家族史的家庭，16个具有肾外特征的家庭和20个既没有家族史也没有肾外特征的家庭中招募。我们在114个家族中的42个（37%）中检测到已知CKD基因的致病性突变。在36%有CKD阳性家族史的受影响家族中确定了单基因原因，69%有肾外特征，只有15%没有家族史或肾外特征。儿童期和成人期CKD患者的基因诊断率无差异。在确定单基因病因的42个家庭中，WES确认了17个（40%）的临床诊断，纠正了9个（22%）的临床诊断，并在16个病因不明的CKD家庭中首次建立了诊断（38%）。在这项对CKD成人的多中心研究中，在超过三分之一的家庭中建立了分子遗传学诊断。在不断发展的精准医学时代，WES可能是识别成人CKD病因的重要工具。
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 multicentre 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.