摘要目的:探讨IFT122基因变异引起的婴儿胆汁淤积症患儿的临床特征及其对初级纤毛影响的分子机制。方法:病例报告。收集复旦大学附属儿科医院2022年9月1例婴儿胆汁淤积症患儿临床资料，采用全外显子组测序筛选出候选变异，并在家系中进行Sanger测序验证，通过慢病毒感染获得永生化细胞系后进行免疫荧光实验分析变异对初级纤毛的影响，采用独立样本 t检验，Mann-Whitney U检验进行组间比较。 结果:患儿，男，4月龄，临床表现为黄疸、特殊面容、矢状缝早闭，血生化检测提示直接胆红素、总胆汁酸和转氨酶升高，γ-谷氨酰转肽酶（GGT）明显升高。肝组织活检提示巨细胞肝炎伴胆汁淤积，胆管发育不良。基因分析结果显示患儿为IFT122基因（NM_052989.3）复合杂合变异，c.88G>C（p.Ala30Pro）和 c.240G>C（p.Trp80Cys）。细胞免疫荧光提示，IFT122基因复合杂合错义变异显著降低纤毛阳性细胞比例，且导致ADP核糖基化因子样GTPase13B（ARL13B）在纤毛上的定位异常，同时降低了肌醇 1，4，5-三磷酸5-磷酸酶 E（INPP5E）在纤毛上的积累，差异均有统计学意义（均 P<0.05）。 结论:IFT122基因复合杂合错义变异不仅损伤了纤毛发生，还导致纤毛膜蛋白ARL13B和INPP5E定位异常，最终引发高GGT型婴儿胆汁淤积症。

abstractsObjective:To investigate the clinical characteristics of infantile cholestasis caused by IFT122 gene variants and the molecular mechanism underlying its impact on primary cilia.Methods:The clinical data of an infant with cholestasis from the Children′s Hospital of Fudan University in September 2022 were retrospectively analyzed. The whole-exome sequencing was performed to identify candidate variants, which were validated by Sanger sequencing in the family. Immortalized cell lines were generated using lentiviral infection, followed by immunofluorescence staining to assess the impact of the variants on primary cilia. Intergroup comparisons were performed using the independent sample t-test and Mann-Whitney U test. Results:The proband was a 4-month-old male infant presenting with jaundice, distinctive facial features, and sagittal craniosynostosis. Blood biochemistry indicated elevated direct bilirubin, total bile acids, and transaminases, with markedly increased γ-glutamyltransferase (GGT). Liver pathology demonstrated giant cell hepatitis with cholestasis and bile duct dysplasia. Genetic analysis identified compound heterozygous variants in IFT122 (NM_052989.3) gene c.88G>C (p.Ala30Pro) and c.240G>C (p.Trp80Cys), which co-segregated with the disease in the family. Immunofluorescence analysis demonstrated that the IFT122 gene compound heterozygous missense variants not only significantly reduced the proportion of cilia-positive cells but also led to aberrant ciliary localization of ADP-ribosylation factor-like protein 13B (ARL13B).In addition, ciliary deposition with phosphatidylinositol polyphosphate 5-phosphatase type Ⅳ (INPP5E) was reduced. All differences were statistically significant (all P<0.05). Conclusion:The compound heterozygous missense variants in IFT122 gene not only impair ciliogenesis but also disrupt the ciliary localization of ARL13B and INPP5E, ultimately resulting in high-GGT infantile cholestasis.