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Published on: August 15, 2019
Rare Variants in PFIC-Related Genes Among Adults With Intrahepatic Cholestasis
Shunji Hirose1, Kota Tsuruya1, Yusuke Mishima1
1Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
Summary
Rare heterozygous variants in progressive familial intrahepatic cholestasis (PFIC) genes were found in Japanese adults with intrahepatic cholestasis. The clinical significance of these variants, often linked to drug-induced liver injury, remains uncertain.
Area of Science:
- Genetics
- Hepatology
- Genomics
Background:
- Biallelic pathogenic variants in progressive familial intrahepatic cholestasis (PFIC) genes cause severe pediatric cholestasis.
- The role of heterozygous variants in adult intrahepatic cholestasis is not well understood.
Purpose of the Study:
- To investigate the prevalence of heterozygous PFIC-related gene variants in Japanese adults with intrahepatic cholestasis.
- To explore the potential clinical significance of these variants.
Main Methods:
- Whole-exome sequencing was performed on 19 adult patients with intrahepatic cholestasis.
- Rare, predicted functionally damaging variants were identified and classified using ACMG/AMP guidelines.
- Variant allele frequencies were compared to the GEM Japan database.
Main Results:
- Four heterozygous variants in PFIC-related genes were found in 21% of patients.
- All variant carriers had drug-induced liver injury.
- One patient had a known pathogenic ABCB11 variant; others were classified as variants of uncertain significance.
Conclusions:
- Rare heterozygous variants in PFIC-related genes were detected in a subset of adult intrahepatic cholestasis patients.
- While associated with drug-induced liver injury, their clinical significance is uncertain.
- Findings are exploratory and hypothesis-generating.
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