Genetics of Fibrocystic Diseases of the Liver and Molecular Approaches to Therapy

Abstract

Congenital hepatic fibrosis (CHF), Caroli’s disease (CD), and polycystic liver disease (PLD) are the three major descriptive categories of fibrocystic liver disease. Caroli’s syndrome (CS) and CD probably represent different presentations of the same continuum. CS refers to CD in association with CHF. CHF/CS and PLD are often part of multisystem disorders associated with fibrocystic renal involvement. These are collectively referred to as “ciliopathies,” since the abnormal proteins involved function on the primary cilium or its basal body. The inheritance pattern of CHF/CS is autosomal recessive, with rare exceptions such as the CHF associated with X-linked oral-facial-digital syndrome type 1. The inheritance pattern of PLD is autosomal dominant; the majority of patients have autosomal dominant polycystic kidney disease (ADPKD) caused by mutations in the PKD1 or PKD2 genes. Autosomal dominant polycystic liver disease (ADPLD), in which PLD is not associated with renal cysts, refers to a genetically distinct entity caused by mutations in the PRKCSH or SEC63 genes. CHF/CS most commonly presents in association with autosomal recessive polycystic kidney disease (ARPKD) caused by mutations in the PKHD1 gene. Multisystem syndromes associated with CHF/CS include Meckel, Bardet–Biedl, and Joubert syndromes and related cerebello-hepatorenal syndromes, renal-hepatic-pancreatic-dysplasia, and ciliary skeletal dysplasias such as Jeune’s chondrodysplasia. Many syndromic ciliopathies display marked genotypic heterogeneity with multiple different genes causing the same disease. This chapter will review the molecular genetic bases of these disorders and provide an overview of novel targeted therapies.