Genetic Analysis of Isolated Hepatic Ductal Plate Malformation Reveals Novel Variants and Insights into Phenotypic...

Polycystic liver disease and other manifestations of ductal plate malformation (DPM) may be incidental or indeed develop significant complications. The genetic basis of 'isolated' DPM differs from that associated with polycystic kidney disease and remains incompletely understood.

We sought to genetically characterize a sizeable single-center cohort of patients with 'isolated' DPM, defined as absence of polycystic kidney disease.

55 consecutive patients with isolated DPM were analyzed retrospectively with next-generation sequencing used to identify genetic variants.

54/55 completed genetic characterization. 40 patients had polycystic liver disease (PCLD) as the primary phenotype, 9 had congenital hepatic fibrosis (CHF), 1 had Caroli disease and 5 had multiple biliary hamartomas. 10 patients had mixed phenotype. The majority were female (78%) and mean age at presentation was 47 years. Of patients with PCLD, previous estrogen exposure was associated with cyst complications. Of the 54 genetically analyzed patients, pathogenic or likely pathogenic variants were identified in 31. PCLD was mainly associated with SEC63, PRKCSH and GANAB heterozygous variants with a minor contribution from PKHD1 and ALG8. PRKCSH followed by GANAB was associated with the most severe PCLD presentation. CHF was represented solely by PKHD1 variants half of which were missense, as opposed to truncating in all but one of the other genotypes. Importantly, 5 novel variants were identified (4 SEC63, 1 PRKCSH).

We have shown that current genetic testing methods are often revealing in isolated DPM. Future broadening of genetic analysis will enhance diagnosis and understanding within this heterogeneous disease spectrum.