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

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.

Genetic Contributions to Biliary Atresia: A Developmental Cholangiopathy

“…Complementing this finding is the result from another group who performed whole exome sequencing in a cohort of isolated BA patients and found two patients with rare compound heterozygous mutations in the PKD1L1 gene. 76 A larger transmembrane protein with limited functional annotations, PKD1L1, a PKD1 family member, works in conjugation with polycystin family members PKD2 or PKD2L1 to modulate intracellular and intraciliary calcium signaling. [77][78][79] How this gene functions in developing and mature cholangiocytes is unknown, but it is expressed in human intra-and extrahepatic cholangiocytes.…”