Genetic Analysis of Severe Polycystic Liver Disease in Japan.

Key Points: Among patients with severe polycystic liver disease (PLD) (height-adjusted total liver volume of <1800 ml/m), variants were found in 34%. Three patients with or variants are reported with severe PLD but normal-sized kidneys (hTKV of < 250 ml/m).

Background: Polycystic liver disease (PLD) is present in most patients with autosomal dominant polycystic kidney disease (ADPKD). PLD can alternatively be found with few, if any, kidney cysts as a diagnosis of isolated PLD (autosomal dominant PLD [ADPLD]). Several genes are identified as causative for this spectrum of phenotypes; however, the relative incidence of genetic etiologies among patients with severe PLD is unknown.

Methods: Patients with ADPKD or ADPLD having severe PLD defined as height-adjusted total liver volume (hTLV) >1800 ml/m were recruited. Subsequent clinical care was followed. Genetic analysis was performed using whole exome sequencing.

Results: We enrolled and sequenced 49 patients (38 women, 11 men). Pathogenic or suspected pathogenic variants in polycystic disease genes were found in 44 of 49 patients (90%). The disease gene was in 20 of 44 patients (45%), in 15 of 44 patients (34%), in 5 of 44 patients (11%), in 2 of 44 patients (5%), in 1 of 44 patients (2%), and in 1 of 44 patients (2%). The median hTLV was no different between genetically defined ADPKD and ADPLD groups (4431 [range, 1817–9148] versus 3437 [range, 1860–8211]) ml, = 0.77), whereas height-adjusted kidney volume was larger as expected in ADPKD than in ADPLD (607 [range, 190–2842] versus 179 [range, 138–234] ml/m, < 0.01). Of the clinically defined ADPKD patients, 20 of 38 patients (53%) were , 15 of 38 (39%) were , and 3 (8%) remained genetically unsolved. Among patients with a pathogenic or variant, we found three patients with a liver-dominant ADPKD (severe PLD with height-adjusted total kidney volume <250 ml/m).

Conclusions: ADPLD-related genes represent 20% of patients with severe PLD in our cohort. Of those enrolled with ADPKD, we observed a higher frequency of carriers than in any previously reported ADPKD cohorts. Although there was no significant difference in the hTLV between patients with and in this cohort, our data suggest that enrollment on the basis of severe PLD may enrich for patients with .