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

Autor:	Maddirevula S; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Shagrani M; Pediatric Transplant Gastro & Hepatology, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia., Ji AR; Translational Medicine Research Program, The Hospital for Sick Children, Toronto, ON, Canada; The Centre for Phenogenomics, Toronto, ON, Canada., Horne CR; Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia., Young SN; Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia., Mather LJ; Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia., Alqahtani M; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., McKerlie C; Translational Medicine Research Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada., Wood G; Department of Pathobiology, University of Guelph, Guelph, ON, Canada., Potter PK; Department of Biomedical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, United Kingdom., Abdulwahab F; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., AlSheddi T; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., van der Woerd WL; Department of Pediatric Gastroenterology, Hepatology and Nutrition, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands., van Gassen KLI; Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands., AlBogami D; Pediatric Transplant Gastro & Hepatology, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia., Kumar K; Pediatric Transplant Gastro & Hepatology, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia., Muhammad Akhtar AS; Pediatric Transplant Gastro & Hepatology, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia., Binomar H; Pediatric Transplant Gastro & Hepatology, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia., Almanea H; Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Faqeih E; Section of Medical Genetics, Department of Pediatric Subspecialties, Children Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., Fuchs SA; Department of Pediatric Gastroenterology, Hepatology and Nutrition, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands., Scott JW; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia; The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia; St Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia., Murphy JM; Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia., Alkuraya FS; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. Electronic address: falkuraya@kfshrc.edu.sa.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2024 Nov; Vol. 26 (11), pp. 101231. Date of Electronic Publication: 2024 Aug 09.
DOI:	10.1016/j.gim.2024.101231
Abstrakt:	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. Competing Interests: Conflict of Interest The authors declare no conflicts of interest. (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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