Exome-Wide Assessment of Isolated Biliary Atresia: A Report From the National Birth Defects Prevention Study Using Child-Parent Trios and a Case-Control Design To Identify Novel Rare Variants

Authors

Pagna Sok
Aniko Sabo
Lynn M Almli
Mary M Jenkins
Wendy N Nembhard
A J Agopian
Michael J Bamshad
Elizabeth E Blue
Lawrence C Brody
Austin L Brown
Marilyn L Browne
Mark A Canfield
Suzan L Carmichael
Jessica X Chong
Shannon Dugan-Perez
Marcia L Feldkamp
Richard H Finnell
Richard A Gibbs
Denise M Kay
Yunping Lei
Qingchang Meng
Cynthia A Moore
James C Mullikin
Donna Muzny
Andrew F Olshan
Faith Pangilinan
Jennita Reefhuis
Paul A Romitti
Jeremy M Schraw
Gary M Shaw
Martha M Werler
Sanjiv Harpavat
Philip J Lupo
University of Washington Center for Mendelian Genomics, NISC Comparative Sequencing Program, the National Birth Defects Prevention Study

Publication Date

6-1-2023

Journal

American Journal of Medical Genetics Part A

DOI

10.1002/ajmg.a.63185

PMID

36942736

PMCID

PMC10947986

PubMedCentral® Posted Date

6-1-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Biliary Atresia, Exome, Homozygote, Parents, Case-Control Studies, Membrane Proteins

Abstract

The etiology of biliary atresia (BA) is unknown, but recent studies suggest a role for rare protein-altering variants (PAVs). Exome sequencing data from the National Birth Defects Prevention Study on 54 child-parent trios, one child-mother duo, and 1513 parents of children with other birth defects were analyzed. Most (91%) cases were isolated BA. We performed (1) a trio-based analysis to identify rare de novo, homozygous, and compound heterozygous PAVs and (2) a case-control analysis using a sequence kernel-based association test to identify genes enriched with rare PAVs. While we replicated previous findings on PKD1L1, our results do not suggest that recurrent de novo PAVs play important roles in BA susceptibility. In fact, our finding in NOTCH2, a disease gene associated with Alagille syndrome, highlights the difficulty in BA diagnosis. Notably, IFRD2 has been implicated in other gastrointestinal conditions and warrants additional study. Overall, our findings strengthen the hypothesis that the etiology of BA is complex.

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