Abstract
CILIARY AND CELL STRUCTURE GENE VARIANTS CONTRIBUTE TO THE ETIOPATHOGENESIS OF BILIARY ATRESIA (BA): EXOME AND SNP ARRAY ANALYSIS OF >1700 NORTH AMERICAN CHILDREN WITH BA
Background:
Biliary atresia (BA) is the principal indication for liver transplantation in children, yet there is little information regarding its underlying etiology. Recent data strongly places BA as a developmental cholangiopathy suggesting that there are gene variant contributions that can be discovered using modern gene sequencing and analytical technologies. Exome analysis of a subset of BA patients with laterality features (BASM) identified causative variants in a ciliary gene, PKD1L1, supporting this approach; however, a larger dataset with multiple analytical approaches is needed to explore the likely multiple genetic contributors to BA.
Methods:
DNA was obtained from participants with BA enrolled in the NIH-supported NIDDK ChiLDReN consortium, a prospective study of cholestatic infants from 14 sites in North America. Exome sequencing and SNP microarray (Illumina 654k) were performed on participant DNA. Analyses were performed using heuristic filtering and artificial intelligence approaches that rely on evolutionary conservation, allele frequency, inheritance patterns, predicted protein impact and ClinVar annotation. Rare, protein-altering variants in genes identified by Gene Ontology (GO) pathway analyses were investigated.
Results:
1751 BA participants (1564 BA and 187 BASM) underwent both exome and SNP array analysis. In both BA and BASM cases, rare protein-coding variants in several genes including DNAH11, DNAH5, CCDC40, KMT2D as well as PKD1L1 were identified in expected inheritance patterns as previously reported to cause Mendelian human disease. Employing GO analytics for both BA and BASM subsets yielded several significant pathways (multiple test corrected p-values < 0.05) with variants in genes participating in crucial functions including: cell adhesion processes, microtubule processes and transport, ciliary assembly and structure.
Conclusion:
A combination of a large multi-center dataset and multiple methodologies has identified rare, presumably functionally relevant mutations in a number of genes known to cause human disease. Pathway approaches have identified a greater-than-expected number of variants in genes implicated in in ciliary, microtubule, and cell structural pathways. Taken together, these results provide a number of attractive BA candidate genes and pathways that can be explored and validated in suitable cell, organoid and animal-based models to better understand the genetic and mechanistic landscape of BA.