GENETIC ANALYSIS AND PHENOTYPIC CORRELATION IN DUCTAL PLATE MALFORMATION

Background and AimsDuctal plate malformation (DPM) includes polycystic liver disease (PCLD), multiple biliary hamartomas (MBH), congenital hepatic fibrosis (CHF) and Caroli disease. We sought to identify the genetic basis of a cohort of hitherto undefined DPM.Methods34 unrelated adults with presumed congenital liver disease underwent extended genetic analysis via a clinical exome panel (PKD1, PKD2, PKHD1, SEC63, PRKCSH, GANAB, ALG8, DNAJB11, LRP5). Clinical details and phenotypic correlation were analysed.ResultsOf the 34 patients screened, genetic variants were identified in 20: Heterozygous variants in GANAB (n=4: 3 females, 1 male, mean age 56) were associated with a variety of mild PCLD phenotypes (with and without renal cysts, with Caroli’s and with MBH). Variants were pathogenic in 2 cases and were variants of unknown significance (VUS) in 2 cases (both deleterious). Heterozygous variants in PRKCSH (n=2: both female, mean age 62) were associated with PCLD without renal cysts including 1 VUS (deleterious) and 1 novel pathogenic variant in a patient considered for liver transplantation. Heterozygous variants in the SEC63 (n=4: 3 females, 1 male, mean age 60) were associated with largely asymptomatic PCLD mostly without renal cysts including 3 pathogenic (all novel) and 1 VUS (deleterious). PKD1 (n=3) and PKD2 (n=2) heterozygous gene variants (4 pathogenic including 2 novel) were associated with polycystic kidney and liver disease. All 5 were female (mean age 48) and with significant family history. Variants in PKHD1 (n=5: 4 male, 1 female, mean age 67 years) were mostly compound heterozygous and had a variety of phenotypes including CHF (n=2, both liver transplanted), CHF/MBH (n=1, portal hypertension), MBH/Caroli (n=1, kidney transplanted) and PCLD without renal cysts (n=1). In 14/34 patients, no genetic variants were identified. These included 3 CHF, 3 MBH and 8 PCLD patients.ConclusionPatients with DPM display a spectrum of disease phenotypes ranging in severity from asymptomatic, incidental diagnosis to end-stage liver disease. We identified the genetic cause in nearly 60% of a previously undefined cohort of DPM patients and discovered several novel variants. Of note, a significant proportion had meaningful variants in GANAB, PRKCSH and SEC63. PRKCSH and SEC63 variants were associated with isolated PCLD. GANAB and PKHD1 mutations were associated with mixed phenotypes, the latter found in mostly males and with a strong propensity for CHF. GANAB and SEC63 phenotypes were mild. Our findings support the use of bespoke gene panels in suspected DPM.