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Genetic Analysis of Progressive Familial Intrahepatic Cholestasis: A Novel Insight into Hepatorenal Ciliopathy

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Mohammad Shagrani

KÁROLY RÁCZ CONSERVATIVE MEDICINE PROGRAM

Dr. Fekete Andrea

Semmelweis Egyetem I. sz. Gyermekgyógyászati Klinika Koós Aurél terem

2026-11-17 13:00:00

Gyermekkori betegségek klinikuma, élettana és prevenciója

Dr. Dr. Szabó Attila

Dr. Antal Dezsőfi-Gottl

Dr. Szűcs Dániel

Dr. Arató András

Dr. Szabó Miklós

Dr. Hagymási Krisztina

Dr. Lásztity Natália

Progressive Familial Intrahepatic Cholestasis (PFIC) represents a heterogeneous group of autosomal-recessive, monogenic liver disorders characterized by impaired bile flow, chronic cholestasis, and progressive hepatic injury. The condition manifests clinically with varying biochemical profiles either normal gamma-glutamyl transferase (γ-GT) cholestasis, typical of transporter defects such as BSEP or ATP8B1, or high-γ-GT cholestasis, usually associated with canalicular or ductal abnormalities involving MDR3 (ABCB4) or tight-junction proteins. Due to major genetic and diagnostic advances, the molecular spectrum of PFIC continues to expand, what has underlined its biological complexity and regional genetic diversity. This thesis explored the genetic basis of PFIC and related pediatric cholestatic diseases in a population characterized by high consanguinity, where homozygous variants are frequent. Using large-scale genomic analyses combining whole-exome sequencing, autozygosity mapping, and functional studies one of the highest molecular diagnostic yields reported worldwide was achieved for pediatric cholestasis. The profiling identified a broad range of pathogenic variants across known PFIC genes, based on two different patient cohorts, revealing both severe and moderate allelic variants. Recurrent founder variants and extended runs of homozygosity were major contributors to the genetic burden in Saudi Arabia. Building on this foundation, this thesis identified and functionally characterized a novel hepato-renal ciliopathy caused by variants in PSKH1, now recognized as a new PFIC subtype (provisionally PFIC13). Functional analyses using patient-derived fibroblasts and a Pskh1 knockout mouse model showed that loss of PSKH1 disrupts ciliary structure and signaling, linking bile-acid regulation to hepatocellular ciliary integrity. These findings establish PSKH1 as a key regulator of biliary and renal epithelial homeostasis and uncover a new pathophysiological mechanism in cholestatic liver disease. Finally, this work underscores the impact of consanguinity on amplifying rare recessive variants and sets a foundation for regional genomic medicine initiatives. The findings advocate for genotype-based treatment strategies and reinforce the emerging paradigm that precision hepatology grounded in molecular discovery and functional validation can markedly improve outcomes for children with PFIC and related disorders.