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.

背景先天性肾脏和尿路异常 (CAKUT) 是生命前三十年肾脏疾病的最常见原因。之前的基因组研究表明，高达 12% 的 CAKUT 患者存在单基因因果关系。

方法我们应用全外显子组测序来分析 232 个 CAKUT 家族个体的基因型，评估已知导致人类 CAKUT 的单个基因和已知导致小鼠 CAKUT 的基因的突变。在近亲或多重家族中，我们还对 CAKUT 的新单基因原因进行了搜索。

结果在 29 个家庭 (13%) 中，我们检测到孤立性或综合征性 CAKUT 的已知基因中存在致病突变，该突变足以解释患者的 CAKUT 表型。在三个家族 (1%) 中，我们检测到据报告导致 CAKUT 表型的基因突变。在 155 个患有孤立 CAKUT 的家庭中的 15 个中，我们检测到了综合征 CAKUT 基因的有害突变。我们对近亲和多重家族中 CAKUT 的新单基因原因进行的额外搜索揭示了 232 个家族中的 19 个家族 (8%) 中存在一个潜在的单一、新单基因 CAKUT 基因。

结论在本研究中，我们确定已知人类 CAKUT 基因或 CAKUT 表型基因的单基因突变是 14% CAKUT 家族的疾病原因。全外显子组测序为大部分 CAKUT 患者提供了病因诊断，并将为 CAKUT 机制的理解提供新的基础。