METHODS: In a cohort of 299 pediatric participants (279 families) with intrahepatic cholestasis, we performed exome sequencing as a first-tier diagnostic test.
RESULTS: A likely causal variant was identified in 135 families (48.56%). These comprise 135 families that harbor variants spanning 37 genes with established or tentative links to cholestasis. In addition, we propose a novel candidate gene (PSKH1) (HGNC:9529) in 4 families. PSKH1 was particularly compelling because of strong linkage in three consanguineous families who shared a novel hepatorenal ciliopathy phenotype. Two of the four families shared a founder homozygous variant while the third had a different homozygous variant in PSKH1. PSKH1 encodes a putative protein serine kinase of unknown function. Patient fibroblasts displayed abnormal cilia that are long and show abnormal transport. A homozygous Pskh1 mutant mouse faithfully recapitulated the human phenotype and displayed abnormally long cilia. The phenotype could be rationalized by the loss of catalytic activity observed for each recombinant PSKH1 variant using in vitro kinase assays.
CONCLUSIONS: Our results support the use of genomics in the workup of pediatric cholestasis and reveal PSKH1-related hepatorenal ciliopathy as a novel candidate monogenic form.
方法:在299名患有肝内胆汁淤积的儿科参与者(279个家庭)的队列中,我们将外显子组测序作为一级诊断试验.
结果:在135个家庭中发现了一个可能的因果变异(48.56%)。这些家族包括135个家族,这些家族包含跨越37个基因的变体,这些基因与胆汁淤积有既定或暂时的联系。此外,我们在4个家族中提出了一个新的候选基因(PSKH1)(HGNC:9529)。PSKH1特别引人注目,因为三个近亲家族具有一种新的肝肾纤毛病表型。四个家族中的两个家族共享一个创始人纯合变体,而第三个家族在PSKH1中具有不同的纯合变体。PSKH1编码功能未知的推定蛋白丝氨酸激酶。患者成纤维细胞显示出长的异常纤毛并显示异常转运。纯合Pskh1突变小鼠忠实地概括了人类表型,并显示出异常长的纤毛。表型可以通过使用体外激酶测定观察到的每个重组PSKH1变体的催化活性损失来合理化。
结论:我们的结果支持基因组学在小儿胆汁淤积检查中的应用,并揭示了PSKH1相关的肝肾纤毛病是一种新的候选单基因形式。