Assessment of Autosomal Dominant Polycystic Liver Disease (ADPLD) in Clinical and Population Cohorts

Background: ADPLD (major genes PRKCSH and SEC63) usually presents with multiple liver cysts, similar to ADPKD (major genes PKD1 and PKD2), but with minimal kidney cysts. Minor ADPLD genes include ALG8 and GANAB, but many ADPLD individuals remain unresolved. Here we evaluated the genetic basis in clinical and population ADPLD cohorts, determined the penetrance of PRKCSH and SEC63, and examined overlap between ADPLD and ADPKD. Methods: We analyzed 2,287 individuals from the Mayo PKD/PLD Center (MTPC) to identify those with an ADPLD-like phenotype employing liver and kidney volume, cyst number, and genetic data. Separately, we evaluated 56,862 exome sequenced participants from Mayo Clinic Biobank (MCBB) for monoallelic pathogenic PRKCSH or SEC63 variants and for relevant PLD ICD codes. Liver and kidney phenotypes were assessed and compared between MCBB PRKCSH/SEC63 carriers and age and sex matched controls, as well as between the MTPC and MCBB carriers. Results: Among MTPC participants, 126 had an ADPLD-like phenotype: 38% PRKCSH, 17% SEC63, 6% PKD1, 6% ALG8, 3% GANAB, 3% PKD2, 1% ALG6 and 26% remained unresolved. In the MCBB cohort, we identified 13 PRKCSH and 19 SEC63 carriers, plus 20 PLD ICD defined cases. MCBB PRKCSH/SEC63 carriers had significantly more liver cysts (p=0.0001) than controls, although fewer than corresponding MTPC subjects (p=0.0001). The proportion meeting a clinical threshold for PLD (>10 cysts) was 54% for PRKCSH and 80% for SEC63; 39% and 46%, respectively, had >100 cysts—indicating moderate penetrance. Kidney cyst burden did not differ significantly between MCBB cases and controls (p=0.123). However, kidney cysts were more common in MTPC-defined SEC63 and unresolved cases compared to their MCBB counterparts (p=0.0005). eGFR adjusted for age did not differ between MCBB ADPLD cases and controls (p=0.272), nor between MTPC and MCBB (p=0.714). Conclusion: ADPLD is genetically complicated with phenotypic overlap with the major ADPKD genes, PKD1 and PKD2, while the major ADPLD genes (PRKCSH, SEC63) demonstrate incomplete penetrance. Genetic diversity and variable penetrance underscore the need for broad genetic testing in individuals with suspected ADPLD. Funding: NIDDK Support