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Exome sequencing in patient‐parent trios suggests new candidate genes for early‐onset primary sclerosing cholangitis
Author(s) -
Haisma SjoukjeMarije,
Weersma Rinse K.,
Joosse Maria E.,
Koning Barbara A. E.,
Meij Tim,
Koot Bart G. P.,
V. M. Wolters,
Norbruis Obbe,
Daly Mark J.,
Stevens Christine,
Xavier Ramnik J.,
Koskela Jukka,
Rivas Manuel A.,
Visschedijk Marijn C.,
Verkade Henkjan J.,
Barbieri Ruggero,
Jansen Dianne B. H.,
Festen Eleonora A. M.,
Rheenen Patrick F.,
Diemen Cleo C.
Publication year - 2021
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.14831
Subject(s) - primary sclerosing cholangitis , exome sequencing , candidate gene , gene , genetics , biology , compound heterozygosity , allele , exome , disease , mutation , medicine
BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) is a rare bile duct disease strongly associated with inflammatory bowel disease (IBD). Whole‐exome sequencing (WES) has contributed to understanding the molecular basis of very early‐onset IBD, but rare protein‐altering genetic variants have not been identified for early‐onset PSC. We performed WES in patients diagnosed with PSC ≤ 12 years to investigate the contribution of rare genetic variants to early‐onset PSC. METHODS In this multicentre study, WES was performed on 87 DNA samples from 29 patient‐parent trios with early‐onset PSC. We selected rare (minor allele frequency < 2%) coding and splice‐site variants that matched recessive (homozygous and compound heterozygous variants) and dominant (de novo) inheritance in the index patients. Variant pathogenicity was predicted by an in‐house developed algorithm (GAVIN), and PSC‐relevant variants were selected using gene expression data and gene function. RESULTS In 22 of 29 trios we identified at least 1 possibly pathogenic variant. We prioritized 36 genes, harbouring a total of 54 variants with predicted pathogenic effects. In 18 genes, we identified 36 compound heterozygous variants, whereas in the other 18 genes we identified 18 de novo variants. Twelve of 36 candidate risk genes are known to play a role in transmembrane transport, adaptive and innate immunity, and epithelial barrier function. CONCLUSIONS The 36 candidate genes for early‐onset PSC need further verification in other patient cohorts and evaluation of gene function before a causal role can be attributed to its variants.