Abstract：
Many inherited conditions cause hepatocellular cholestasis in infancy, including progressive familial intrahepatic cholestasis (PFIC), a heterogeneous group of diseases with highly overlapping symptoms. In our study, six unrelated Tunisian infants with PFIC suspicion were the subject of a panel-target sequencing followed by an exhaustive bioinformatic and modeling investigations. Results revealed five disease-causative variants including known ones: (the p.Asp482Gly and p.Tyr354 * in the ABCB11 gene and the p.Arg446 * in the ABCC2 gene), a novel p.Ala98Cys variant in the ATP-binding cassette subfamily G member 5 (ABCG5) gene and a first homozygous description of the p.Gln312His in the ABCB11 gene. The p.Gln312His disrupts the interaction pattern of the bile salt export pump as well as the flexibility of the second intracellular loop domain harboring this residue. As for the p.Ala98Cys, it modulates both the interactions within the first nucleotide-binding domain of the bile transporter and its accessibility. Two additional potentially modifier variants in cholestasis-associated genes were retained based on their pathogenicity (p.Gly758Val in the ABCC2 gene) and functionality (p.Asp19His in the ABCG8 gene). Molecular findings allowed a PFIC2 diagnosis in five patients and an unexpected diagnosis of sisterolemia in one case. The absence of genotype/phenotype correlation suggests the implication of environmental and epigenetic factors as well as modifier variants involved directly or indirectly in the bile composition, which could explain the cholestasis phenotypic variability.
摘要：
许多遗传性疾病会在婴儿期引起肝细胞胆汁淤积，包括进行性家族性肝内胆汁淤积（PFIC），一组具有高度重叠症状的异质性疾病。在我们的研究中,6名有PFIC嫌疑的无关突尼斯婴儿接受了小组目标测序,随后进行了详尽的生物信息学和建模调查.结果显示了五种致病变异，包括已知变异：（ABCB11基因中的p.Asp482Gly和p.Tyr354*和ABCC2基因中的p.Arg446*），ATP结合盒亚家族G成员5（ABCG5）基因中的新型p.Ala98Cys变体，以及ABCB11基因中p.Gln312His的第一个纯合描述。p.Gln312His破坏了胆盐输出泵的相互作用模式以及带有该残基的第二胞内环结构域的灵活性。至于p.Ala98Cys，它调节胆汁转运蛋白的第一个核苷酸结合域内的相互作用及其可及性。根据其致病性，保留了胆汁淤积相关基因中的另外两个潜在修饰变体（p。ABCC2基因中的Gly758Val）和功能（p。ABCG8基因中的Asp19His)。分子研究结果允许在5例患者中诊断出PFIC2，在1例患者中意外诊断出了白血病。基因型/表型相关性的缺乏表明环境和表观遗传因素以及直接或间接参与胆汁成分的修饰变体的含义。这可以解释胆汁淤积的表型变异。
