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

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; National Birth Defects Prevention Study

doi:10.1002/ajmg.a.63185

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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

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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

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, …

American journal of medical genetics. Part A, Vol.191(6), pp.1546-1556

06/2023

DOI: 10.1002/ajmg.a.63185

PMCID: PMC10947986

PMID: 36942736

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https://pmc.ncbi.nlm.nih.gov/articles/PMC10947986/pdf/nihms-1964254.pdfView

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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.

rare variants

biliary atresia

birth defect

NBDPS

whole exome sequencing

Details

Title: Subtitle: 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
Creators: Pagna Sok - Baylor College of Medicine
Aniko Sabo - Baylor College of Medicine
Lynn M Almli - National Center on Birth Defects and Developmental Disabilities
Mary M Jenkins - National Center on Birth Defects and Developmental Disabilities
Wendy N Nembhard - University of Arkansas for Medical Sciences
A J Agopian - Department of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas School of Public Health, Houston, Texas, USA
Michael J Bamshad - Brotman Baty Institute
Elizabeth E Blue - University of Washington
Lawrence C Brody - National Human Genome Research Institute
Austin L Brown - Baylor College of Medicine
Marilyn L Browne - University at Albany, State University of New York
Mark A Canfield - Birth Defects Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, Texas, USA
Suzan L Carmichael - Stanford University School of Medicine
Jessica X Chong - Brotman Baty Institute
Shannon Dugan-Perez - Baylor College of Medicine
Marcia L Feldkamp - University of Utah
Richard H Finnell - Baylor College of Medicine
Richard A Gibbs - Baylor College of Medicine
Denise M Kay - Wadsworth Center
Yunping Lei - Baylor College of Medicine
Qingchang Meng - Baylor College of Medicine
Cynthia A Moore - National Center on Birth Defects and Developmental Disabilities
James C Mullikin - National Human Genome Research Institute
Donna Muzny - Baylor College of Medicine
Andrew F Olshan - Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
Faith Pangilinan - National Human Genome Research Institute
Jennita Reefhuis - National Center on Birth Defects and Developmental Disabilities
Paul A Romitti - Department of Epidemiology, University of Iowa College of Public Health, Iowa City, Iowa, USA
Jeremy M Schraw - Baylor College of Medicine
Gary M Shaw - Stanford University School of Medicine
Martha M Werler - Boston University
Sanjiv Harpavat - Gastroenterology, Hepatology and Nutrition, Texas Children's Hospital, Houston, Texas, USA
Philip J Lupo - Baylor College of Medicine
University of Washington Center for Mendelian Genomics
NISC Comparative Sequencing Program
National Birth Defects Prevention Study
Resource Type: Journal article
Publication Details: American journal of medical genetics. Part A, Vol.191(6), pp.1546-1556
DOI: 10.1002/ajmg.a.63185
PMID: 36942736
PMCID: PMC10947986
NLM abbreviation: Am J Med Genet A
ISSN: 1552-4825
eISSN: 1552-4833
Grant note: Birth Defects Study To Evaluate Pregnancy exposureS CDC HHS National Birth Defects Prevention Study NHLBI NIH HHS NHGRI NIH HHS NIH HHS
Language: English
Electronic publication date: 03/21/2023
Date published: 06/2023
Academic Unit: Epidemiology; Biostatistics
Record Identifier: 9984380367602771

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