Novel findings from family-based exome sequencing for children with biliary atresia

Abstract

Biliary atresia (BA) is a progressive inflammation and fibrosis of the biliary tree characterized by the obstruction of bile flow, which results in liver failure, scarring and cirrhosis. This study aimed to explore the elusive aetiology of BA by conducting whole exome sequencing for 41 children with BA and their parents (35 trios, including 1 family with 2 BA-diagnosed children and 5 child-mother cases). We exclusively identified and validated a total of 28 variants (17 X-linked, 6 de novo and 5 homozygous) in 25 candidate genes from our BA cohort. These variants were among the 10% most deleterious and had a low minor allele frequency against the employed databases: Kinh Vietnamese (KHV), GnomAD and 1000 Genome Project. Interestingly, AMER1, INVS and OCRL variants were found in unrelated probands and were first reported in a BA cohort. Liver specimens and blood samples showed identical variants, suggesting that somatic variants were unlikely to occur during morphogenesis. Consistent with earlier attempts, this study implicated genetic heterogeneity and non-Mendelian inheritance of BA.

Rare sequence variants associated with the risk of non‐syndromic biliary atresia

“…We examined the frequencies of 60 known BA‐related SNPs in the patient and control groups. These SNPs were selected based on the previous reports 5–28 . We confirmed that the identified SNPs were in Hardy–Weinberg equilibrium.…”

“…Similarly, the significance of the p.Ala421Thr variant of THOC2 is questionable. Previous WES for 41 Vietnamese BA patients identified this variant in two 9 . However, considering that the allele frequency of this variant in the ToMMo database is as high as 0.013, the p.Ala421Thr variant is unlikely to exert strong deleterious effects.…”

“…To date, candidate gene approaches, genome‐wide association studies, and whole exome sequencing (WES) detected 60 single‐nucleotide polymorphisms (SNPs) and 75 genes associated with the risk for non‐syndromic BA 5–28 . For example, WES by Gürünlüoğlu et al.…”

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

“…This absence in replication of previously reported de novo variants could be attributed to the genetic ancestry of the study populations or the genetic heterogeneity of BA. For example, two recent family‐based sequencing assessments of BA among Asian children identified variants in novel genes including AMER1 , INVS , OCRL , PCNT , KIF3B , and TTC17 suggesting a genetic heterogeneity of BA (Lam et al, 2021; Tran et al, 2021). The lack of replication and identification of de novo variants across multiple studies highlight the complexity of the etiology of BA and support the hypothesis that isolated BA is multifactorial.…”

Biliary atresia and congenital disorders of the extrahepatic bile ducts

“…PKD1L1 encodes Polycystin 1 Like 1 and regulates cilier functions, and both gene defects are associated with visceral heterotaxy. Heterozygous CFC1 and PKD1L1 mutations have been determined in some patients with BASM[ 31 , 32 ]. XPNPEP1 (mediates the metabolism of inflammatory mediators in epithelial cells) and ADD3 (plays a role in the spectrin-actin network in the biliary tract) mutations have been observed in some patients with BA[ 33 ].…”