Author information

• ¹Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
• ²Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
• ³National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
• ⁴Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
• ⁵Department of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas School of Public Health, Houston, Texas, USA.
• ⁶Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.
• ⁷Brotman Baty Institute for Precision Medicine, Seattle, Washington, USA.
• ⁸Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
• ⁹Genetics and Environment Interaction Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
• ¹⁰Birth Defects Registry, New York State Department of Health, Albany, New York, USA.
• ¹¹Department of Epidemiology and Biostatistics, School of Public Health, University at Albany, Rensselaer, New York, USA.
• ¹²Birth Defects Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, Texas, USA.
• ¹³Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
• ¹⁴Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, USA.
• ¹⁵Department of Medicine, Center for Precision Environmental Health, Baylor College of Medicine, Houston, Texas, USA.
• ¹⁶Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, USA.
• ¹⁷Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA.
• ¹⁸Department of Epidemiology, University of Iowa College of Public Health, Iowa City, Iowa, USA.
• ¹⁹Department of Epidemiology, Boston University, Boston, Massachusetts, USA.
• ²⁰Gastroenterology, Hepatology and Nutrition, Texas Children's Hospital, Houston, Texas, USA.

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.