Biliary atresia (BA) is the most common obstructive cholangiopathy in neonates, often progressing to end-stage cirrhosis. BA pathogenesis is believed to be multifactorial, but the genetic contribution remains poorly defined. We conducted exome sequencing on 89 nonsyndromic BA trios. In 31.5% of the patients, rare and deleterious de novo, homozygous recessive and/or compound heterozygous variants were detected in liver-expressed ciliary genes of diverse ciliary functions. Enrichment of deleterious mutations in liver-expressed ciliary geneset was significant compared to 148 control trios (OR 2.58, 95% CI 1.15-6.07). KIF3B , PCNT and TTC17 are essential for ciliogenesis. Reduced ciliary proteins expression were detected in the BA livers with KIF3B and TTC17 mutations. CRISPR/Cas9-engineered zebrafish knockouts of KIF3B, PCNT and TTC17 displayed reduced biliary flow. Our findings support a larger genetic contribution to nonsyndromic BA risk than expected. Ciliary gene mutations leading to cholangiocyte cilia malformation and dysfunction could be a key biological mechanism in BA pathogenesis.

中文翻译：

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整个外显子组测序揭示了非综合征性胆道闭锁的多种睫状体基因突变

胆道闭锁（BA）是新生儿中最常见的阻塞性胆管病，通常会发展为晚期肝硬化。人们认为BA的发病机理是多因素的，但是遗传贡献仍然不清楚。我们对89个非综合征BA三重奏进行了外显子组测序。在31.5％的患者中，在肝脏表达的各种纤毛功能的纤毛基因中检测到罕见和有害的从头，纯合的隐性和/或复合杂合变体。与148个对照三重奏组相比，肝表达的睫状基因组中有害突变的富集显着（OR 2.58，95％CI 1.15-6.07）。KIF3B ，PCNT和TTC17对纤毛形成至关重要。使用KIF3B在BA肝脏中检测到睫状蛋白表达降低和TTC17突变。KIF3B，PCNT和TTC17的CRISPR / Cas9工程斑马鱼基因敲除显示出胆汁流量减少。我们的发现支持非综合征BA风险的遗传贡献超出预期。导致胆管细胞纤毛畸形和功能异常的睫状体基因突变可能是BA发病的关键生物学机制。