Purpose

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in childhood and adolescence. We aim to identify novel monogenic causes of CAKUT.

Methods

Exome sequencing was performed in 550 CAKUT-affected families.

Results

We discovered seven FOXC1 heterozygous likely pathogenic variants within eight CAKUT families. These variants are either never reported, or present in <5 alleles in the gnomAD database with ~141,456 controls. FOXC1 is a causal gene for Axenfeld–Rieger syndrome type 3 and anterior segment dysgenesis 3. Pathogenic variants in FOXC1 have not been detected in patients with CAKUT yet. Interestingly, mouse models for Foxc1 show severe CAKUT phenotypes with incomplete penetrance and variable expressivity. The FOXC1 variants are enriched in the CAKUT cohort compared with the control. Genotype–phenotype correlations showed that Axenfeld–Rieger syndrome or anterior segment dysgenesis can be caused by both truncating and missense pathogenic variants, and the missense variants are located at the forkhead domain. In contrast, for CAKUT, there is no truncating pathogenic variant, and all variants except one are located outside the forkhead domain.

Conclusion

We thereby expanded the phenotype of FOXC1 pathogenic variants toward involvement of CAKUT, which can potentially be explained by allelism.

中文翻译：

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杂合 FOXC1 致病性变异的表型扩展，涉及先天性肾脏和泌尿道异常 (CAKUT)。

目的

先天性肾脏和泌尿道异常 (CAKUT) 是儿童和青春期慢性肾脏病的最常见原因。我们的目标是确定 CAKUT 的新的单基因原因。

方法

在 550 个受 CAKUT 影响的家庭中进行了外显子组测序。

结果

我们在 8 个 CAKUT 家族中发现了 7 个FOXC1杂合可能的致病变异。这些变体要么从未报告过，要么存在于 gnomAD 数据库中的 <5 个等位基因中，具有约 141,456 个对照。FOXC1是 Axenfeld-Rieger 综合征 3 型和眼前节发育不全 3 型的致病基因。尚未在 CAKUT 患者中检测到FOXC1的致病性变异。有趣的是，Foxc1 的小鼠模型显示出严重的CAKUT表型，具有不完全的外显率和可变的表达能力。FOXC1 _与对照相比，CAKUT 队列中的变体富集。基因型-表型相关性表明，Axenfeld-Rieger 综合征或眼前节发育不全可由截断和错义致病变异引起，并且错义变异位于叉头结构域。相比之下，对于 CAKUT，没有截断的致病变异，除一个之外的所有变异都位于叉头域之外。

结论

因此，我们将FOXC1致病变异的表型扩展到CAKUT 的参与，这可能通过等位性来解释。