Rare Variants in PFIC-Related Genes Among Adults With Intrahepatic Cholestasis.

AIM: Biallelic pathogenic variants in progressive familial intrahepatic cholestasis (PFIC)-related genes cause severe pediatric cholestasis. However, the clinical significance of heterozygous variants in adult intrahepatic cholestasis remains unclear. We investigated the prevalence of heterozygous PFIC-related gene variants in Japanese adults with intrahepatic cholestasis.

METHODS

Whole-exome sequencing was performed in 19 adults diagnosed with intrahepatic cholestasis. Rare variants (allele frequency ≤ 0.01 in the Japanese population) predicted to be functionally damaging by in silico tools were extracted and classified according to ACMG/AMP guidelines. Allele frequencies were compared with the GEM Japan whole genome aggregation database.

RESULTS

Four heterozygous variants in PFIC-related genes were identified in four patients (21%), and all variant carriers were diagnosed with drug-induced liver injury. One patient carried a known pathogenic ABCB11 splice-site variant (c.908+1G>A), which was extremely rare in the Japanese reference population. The remaining variants were predicted to be functionally damaging by in silico analyses but were classified as variants of uncertain significance by ACMG criteria.

CONCLUSIONS

Rare variants in PFIC-related genes were identified in a subset of adults with intrahepatic cholestasis. Although all variant carriers were diagnosed with drug-induced liver injury, the clinical significance of these variants remains uncertain, particularly because most were classified as variants of uncertain significance. These findings should be considered exploratory and hypothesis-generating.