Large-scale genomic investigation of pediatric cholestasis reveals a novel hepatorenal ciliopathy caused by PSKH1 mutations

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

Author(s): 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;
Details: Publication Year 2024-11,Volume 26,Issue #11,Page 101231
Journal Title: Genetics in Medicine
Abstract: PURPOSE: 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. 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 3 consanguineous families who shared a novel hepatorenal ciliopathy phenotype. Two of the 4 families shared a founder homozygous variant, whereas the third and fourth had different homozygous variants 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. CONCLUSION: 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.
Publisher: Elsevier
Keywords: Humans; *Ciliopathies/genetics/pathology; Male; Female; *Mutation/genetics; Mice; *Exome Sequencing; Animals; Child; *Cholestasis/genetics/pathology; *Pedigree; Child, Preschool; Infant; Genomics/methods; Homozygote; Cholestasis, Intrahepatic/genetics/pathology/diagnosis; Phenotype; Cilia/pathology/genetics; Autozygosity; Exome sequencing; Hepatorenal ciliopathy; Pediatric cholestasis; Primary cilium
Research Division(s): Inflammation
PubMed ID: 39132680
Publisher's Version: https://doi.org/10.1016/j.gim.2024.101231
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-08-14 09:49:40

Last Modified: 2024-12-05 10:33:39