Hepatic manifestations of ciliopathies: genetic causes and clinical update.

Ciliopathies are genetically heterogeneous disorders of primary cilia that frequently involve the liver in childhood, producing a spectrum of hepatobiliary pathology. Primary cilia on cholangiocytes and hepatic progenitors are mechano-, chemo-, and osmo-sensors essential for remodelling of the ductal plate, the embryologic precursor of the liver's intrahepatic bile duct system. Disruption of the components of primary cilia (basal body, intraflagellar transport (IFT), transition-zone, trafficking, and endoplasmic reticulum (ER)/Golgi protein homeostasis components) leads to ductal plate malformation, aberrant biliary branching, and progressive periductal fibrosis. Classical loci (PKHD1, PKD1, PKD2) more commonly associated with cystic kidney disease remain central to aetiology, while ER/glycosylation protein homeostasis genes (GANAB, ALG8, PRKCSH, SEC63, DNAJB11), trafficking/IFT-A and WDR/dynein-2 components (TULP3, WDR family) are increasingly recognised. Liver disease most often appears from childhood to adolescence in autosomal recessive polycystic kidney disease (ARPKD), Bardet-Biedl syndrome, Joubert syndrome, and WDR-related disorders, while autosomal dominant polycystic kidney and liver disease (ADPKD and ADPLD) usually presents in adulthood. The main disease patterns also vary: congenital hepatic fibrosis and portal hypertension in ARPKD, hepatic cysts in ADPKD, steatotic liver disease in Bardet-Biedl syndrome, and transaminitis or fibrocystic liver disease in Joubert and WDR-related disorders. Emerging contributors such as DCDC2 and PKD1L1 implicate microtubule-cilium interactions and mechanosensory dysfunction in neonatal cholestasis and biliary atresia. Diagnosis increasingly relies on broad multigene panels or exome/genome sequencing, with functional assays guiding interpretation of novel alleles.

conclusionThis narrative review synthesises contemporary knowledge on ciliary roles in biliary development, the clinical hepatic phenotypes observed in children and adults, and the evolving genetic landscape with emphasis on discoveries from recent sequencing cohorts and functional studies. WHAT IS KNOWN: • Ciliopathies are genetically heterogeneous disorders in which primary cilia dysfunction disrupts cholangiocyte signalling and ductal plate remodelling, leading to a spectrum of paediatric hepatobiliary disease ranging from congenital hepatic fibrosis and portal hypertension to cystic liver disease, steatotic liver disease, and neonatal cholestasis. WHAT IS NEW: • Recent genomic and functional studies have broadened the spectrum of ciliopathy-associated genes implicated in paediatric hepatic disease. Clinicians caring for these children should maintain a high index of suspicion as the range of reported phenotypes continues to expand.