{Reference Type}: Journal Article
{Title}: Large Scale Genomic Investigation of Pediatric Cholestasis Reveals a Novel Hepatorenal Ciliopathy Caused by PSKH1 Mutations.
{Author}: Maddirevula S;Shagrani M;Ji AR;Horne CR;Young SN;Mather LJ;Alqahtani M;McKerlie C;Wood G;Potter PK;Abdulwahab F;AlSheddi T;van der Woerd WL;van Gassen KLI;AlBogami D;Kumar K;Muhammad Akhtar AS;Binomar H;Almanea H;Faqeih E;Fuchs SA;Scott JW;Murphy JM;Alkuraya FS;
{Journal}: Genet Med
{Volume}: 0
{Issue}: 0
{Year}: 2024 Aug 9
{Factor}: 8.864
{DOI}: 10.1016/j.gim.2024.101231
{Abstract}: <B>OBJECTIVE: </B>Pediatric cholestasis is the phenotypic expression of clinically and genetically heterogeneous disorders of bile acid synthesis and flow. Although a growing number of monogenic causes of pediatric cholestasis have been identified, the majority of cases remain undiagnosed molecularly.<BR><B>METHODS: </B>In a cohort of 299 pediatric participants (279 families) with intrahepatic cholestasis, we performed exome sequencing as a first-tier diagnostic test.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.