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Updated: Aug 6, 2026

Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information
09:37

Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information

Published on: August 15, 2019

Genotype-Phenotype Correlations of Monoallelic PFIC Variants in Pediatric Liver Disease: A Multicenter Retrospective

Brett J Hoskins1, Tiziano Pramparo2, Chaowapong Jarasvaraparn1

  • 1Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana, USA.

American Journal of Medical Genetics. Part A
|July 20, 2026
PubMed

Insights

Monoallelic variants of uncertain significance (VUS) in progressive familial intrahepatic cholestasis (PFIC) genes are unlikely to cause disease alone in children. These variants may contribute to liver disease in combination with other genetic factors or environmental influences.

Area of Science:

  • Pediatric Hepatology
  • Genetic Liver Diseases
  • Genomics

Background:

  • Progressive familial intrahepatic cholestasis (PFIC) is typically caused by biallelic pathogenic variants.
  • Monoallelic variants of uncertain significance (VUS) in PFIC-associated genes are increasingly found in children with cholestasis, causing diagnostic challenges.

Purpose of the Study:

  • To investigate the clinical significance of monoallelic VUS in PFIC-associated genes in pediatric liver disease.
  • To determine if these monoallelic VUS act as sole disease drivers or contribute to disease in other contexts.

Main Methods:

  • Multicenter cohort study of children with liver disease and/or cholestasis.
  • Analysis of clinical and longitudinal data for patients with monoallelic VUS in ATP8B1, ABCB11, ABCB4, TJP2, or NR1H4.
  • Comparison of variant frequencies with population data from gnomAD.

Main Results:

  • Twenty-six children with 37 monoallelic PFIC-gene VUS were included; multigenic variant burden was common (73.1%).
  • PFIC-like biochemical patterns were transient in 42.3% of patients; none met criteria for monogenic PFIC longitudinally.
  • Severe liver outcomes occurred in a subset with ABCB4 and/or ATP8B1 VUS and multigenic burden, alongside other clinical factors.

Conclusions:

  • Monoallelic PFIC-gene VUS are unlikely to be monogenic drivers in isolation but may contribute in multigenic or susceptibility contexts.
  • Population enrichment of certain VUS (e.g., ABCB4) supports careful, phenotype-anchored, longitudinal interpretation in pediatric liver disease.

Keywords:
ABCB4VUScholestasisgenetic susceptibilitymultigenic inheritanceprogressive familial intrahepatic cholestasisvariant of uncertain significance

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