Document Type

Article

Publication Date

12-2026

Identifier

DOI: 10.1002/ajmg.a.70250

Abstract

Progressive familial intrahepatic cholestasis (PFIC) is classically caused by biallelic pathogenic variants, yet monoallelic variants of uncertain significance (VUS) in PFIC-associated genes are increasingly identified in children with cholestasis, creating diagnostic uncertainty. We conducted a multicenter cohort study of children with liver disease and/or cholestasis harboring monoallelic VUS in ATP8B1, ABCB11, ABCB4, TJP2, or NR1H4. Clinical and longitudinal data were analyzed, and variant frequencies were compared with population data from gnomAD. Twenty-six children with 37 monoallelic PFIC-gene VUS met inclusion criteria, and multigenic variant burden was common (73.1%). PFIC-like biochemical patterns were observed in 42.3% but were frequently transient, and no patient met criteria for monogenic PFIC on longitudinal follow-up. Severe liver outcomes, including transplantation in two patients, occurred in a subset of patients with ABCB4 and/or ATP8B1 VUS and multigenic burden, along with competing clinical factors. Among 22 variants with population data, 11 (50%) demonstrated significant enrichment after multiple-testing correction, most commonly involving ABCB4. These findings suggest that monoallelic PFIC-associated variants currently classified as VUS are unlikely to represent monogenic disease drivers in isolation and may instead contribute within multigenic or susceptibility-based contexts. Population-level enrichment, particularly involving ABCB4, further supports careful phenotype-anchored, longitudinal interpretation in pediatric liver disease.

Journal Title

American journal of medical genetics. Part A

Volume

200

Issue

12

First Page

2692

Last Page

2707

MeSH Keywords

Humans; Cholestasis, Intrahepatic; Female; Genetic Association Studies; Male; Child, Preschool; Infant; Child; ATP Binding Cassette Transporter, Subfamily B, Member 11; Retrospective Studies; ATP Binding Cassette Transporter, Subfamily B; Alleles; Liver Diseases; Mutation; Adenosine Triphosphatases; Adolescent; Genetic Predisposition to Disease; Phenotype

PubMed ID

42477309

Keywords

ABCB4; VUS; cholestasis; genetic susceptibility; multigenic inheritance; progressive familial intrahepatic cholestasis; variant of uncertain significance

Comments

Grants and funding

This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Publisher's Link: https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.70250

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