Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract
Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract
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DOI：
10.1681/asn.2017121265
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发表时间：
2018-09-01
影响因子：
13.6
通讯作者：
Hildebrandt, Friedhelm
中科院分区：
文献类型：
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作者：
van der Ven, Amelie T.;Connaughton, Dervla M.;Hildebrandt, Friedhelm
背景先天性肾脏和泌尿道异常（CAKUT）是生命最初30年中最常见的肾脏疾病原因。以前的基因面板的研究表明，高达12%的CAKUT.Methods患者单基因的因果关系，我们应用全外显子组测序分析的基因型的个人从232个家庭与CAKUT，评估已知的单基因突变引起人类CAKUT和基因引起小鼠CAKUT。在血缘或多重家庭，我们另外进行了搜索新的单基因CAKUT.Results原因在29个家庭（13%），我们检测到一个致病突变的已知基因的孤立或综合征CAKUT，充分解释了病人的CAKUT表型。在三个家庭（1%），我们检测到一个基因突变，导致CAKUT的表型。在155个孤立CAKUT的家庭中，我们检测到综合征CAKUT基因的有害突变。我们额外的搜索新的单基因CAKUT的原因，在血缘和多重家庭发现一个潜在的单一的，新的单基因CAKUT基因在19 232家庭（8%）。结论我们确定了单基因突变在一个已知的人类CAKUT基因或CAKUT表型基因的疾病的原因，在本研究中的CAKUT家庭的14%。全外显子组测序为大部分CAKUT患者提供了病因学诊断，并将为CAKUT的机制理解提供新的基础。
Background Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT.Methods We applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT.Results In 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient's CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%).Conclusions We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.