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

Details

• Alternative Title:
  Am J Med Genet A
• Personal Author:
  Sok, Pagna ; Sabo, Aniko ; Almli, Lynn M. ; Jenkins, Mary M. ; Nembhard, Wendy N. ; Agopian, A. J. ; Bamshad, Michael J. ; Blue, Elizabeth E. ; Brody, Lawrence C. ; Brown, Austin L. ; Browne, Marilyn L. ; Canfield, Mark A. ; Carmichael, Suzan L. ; Chong, Jessica X. ; Dugan-Perez, Shannon ; Feldkamp, Marcia L. ; Finnell, Richard H. ; Gibbs, Richard A. ; Kay, Denise M. ; Lei, Yunping ; Meng, Qingchang ; Moore, Cynthia A. ; Mullikin, James C. ; Muzny, Donna ; Olshan, Andrew F. ; Pangilinan, Faith ; Reefhuis, Jennita ; Romitti, Paul A. ; Schraw, Jeremy M. ; Shaw, Gary M. ; Werler, Martha M. ; Harpavat, Sanjiv ; Lupo, Philip J.
• Corporate Authors:
  University of Washington Center for Mendelian Genomics, NISC Comparative Sequencing Program, the National Birth Defects Prevention Study
• Description:
  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.
• Subjects:
  Biliary Atresia Case-Control Studies Exome Homozygote Humans Membrane Proteins Parents
• Keywords:
  Biliary Atresia Birth Defect NBDPS Rare Variants Whole Exome Sequencing
• Source:
  Am J Med Genet A. 191(6):1546-1556
• Pubmed ID:
  36942736
• Pubmed Central ID:
  PMC10947986
• Document Type:
  Journal Article
• Funding:
  U01 DD001285/DD/NCBDD CDC HHSUnited States/ ; U01DD001285/ACL/ACL HHSUnited States/ ; P30 ES030285/ES/NIEHS NIH HHSUnited States/ ; CC999999/ImCDC/Intramural CDC HHSUnited States/ ; EP-D-18-001/EPA/EPAUnited States/ ; UM1 HG006493/HG/NHGRI NIH HHSUnited States/ ; U24 HG008956/HG/NHGRI NIH HHSUnited States/ ; R01 HD093660/HD/NICHD NIH HHSUnited States/ ; U01 DD001229/DD/NCBDD CDC HHSUnited States/ ; CDP 13-003/HX/HSRD VAUnited States/
• Volume:
  191
• Issue:
  6
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:f017b27e22b40a3e5e894164c2835d2a381e7633236acd0eb84f79c77299873b
• Download URL:
  https://stacks.cdc.gov/view/cdc/151757/cdc_151757_DS1.pdf
• File Type:
  [PDF - 514.20 KB ]