一种新的SLC25A13基因大片段缺失变异的识别:1例希特林缺陷病患者临床和遗传学分析

Identification of a novel large deletion in the SLC25A13 gene:clinical and genetic analysis of a patient with Citrin Deficiency

目的:探讨1例希特林缺陷导致的新生儿肝内胆汁淤积症(NICCD)患儿的临床和分子遗传学特征。方法:整理分析患儿临床资料,提取患儿及其父母外周血DNA标本,采用高通量测序检测致病突变,通过Sanger测序验证阳性发现,并根据ACMG指南和标准,分析新变异的致病性。结果:患儿为1.5月龄女婴,因发现皮肤黄染1月余入院。体检发现皮肤巩膜黄染,肝右肋下1 cm,质软。生化检查示血清总胆汁酸、直接胆红素、γ-谷氨酰转肽酶、甲胎蛋白等水平升高,伴低蛋白血症、凝血功能障碍和贫血。诊断为胆汁淤积症。遗传学分析发现患儿为SLC25A13基因c.852_855del与c.1314-4144_c.1452+3373del7658bp的复合杂合子;前者为母源性致病性变异,后者导致整个外显子14缺失,为父源性新变异,根据ACMG标准判定为致病性变异,病因诊断NICCD。经更换无乳糖并强化中链甘油胆汁的配方奶粉喂养,患儿病情迅速好转。结论:通过分析1例NICCD患儿的临床和分子遗传学特征,识别一个长达7658bp的SLC25A13基因缺失变异,扩展了SLC25A13突变谱,为NICCD确诊和遗传咨询提供了新的分子标记物。

Objective:To explore the clinical and genetic features of an infant with Neonatal Intrahepatic Cholestasis by Citrin Deficiency(NICCD).Methods:Clinical data of the patient was collected and analyzed.Genomic DNA was extracted from peripheral blood of the patient and her parents.The underlining genetic cause was explored by next generation sequencing,the positive findings were verified by Sanger sequencing,and the pathogenicity of the novel variant was analyzed according to the ACMG standards and guidelines.Results:The patient,a girl aged 1.5 months,was referred to the hospital with the complaint of jaundiced skin over 1 month.On physical examination,jaundice of the skin and sclera was discovered.The liver was 1cm below the right subcostal margin with soft texture.The laboratory tests revealed elevation of the total bile acids,direct bilirubin,γ-glutamyl transpepetidase,and alpha-fetoprotein along with hypoproteinemia,coagulopathy and anemia.The diagnosis was cholestasis.On genetic analysis,the patient was a compound heterozygote of the SLC25A13 variants c.852_855del and c.1312-4144_c.1452+3373del7658bp.According to the ACMG guidelines and standards,the former variant was judged as a pathogenic variant with maternal origin,while the latter one led to deletion of the entire exon 14.The etiology diagnosis of NICCD was thus made,and the baby s condition got improved rapidly in response to feeding on lactose-free with medium-chain triglycerides-enriched formula.Conclusion:This study reported the clinical and molecular genetic characteristics of a NICCD patient.Genetic analysis revealed a novel pathogenic SLC25A13 deletion of 7658bp,which expanded the gene mutation spectrum and provided a new biomarker for the definite diagnosis and genetic counseling of NICCD.