首例非白人婴儿肝衰竭综合征1型患儿临床特点和分子诊断研究

Clinical feature and molecular diagnostic analysis of the first non-caucasian child with infantile liver failure syndrome type 1

摘要:

婴儿肝衰竭综合征1型（ILFS1）是一种由胞质亮氨酰-tRNA合成酶基因（LARS）突变所导致的常染色体隐性遗传病。本研究报道首例非白人ILFS1患者的临床特点和分子诊断经过，为ILFS1的诊治提供参考。患者为2岁9个月男孩，因发现肝脾肿大1年余就诊。1岁5个月时发现肝脾大，实验室检查发现丙氨酸氨基转移酶和门冬氨酸氨基转移酶偏高、低蛋白血症、凝血功能异常和贫血，肝脏病理提示肝硬化和脂肪肝；SLC25A13基因高频突变筛查和一代测序分析仅检测到一个父源性突变c.1658G > A，cDNA克隆分析也未发现母源性SLC25A13等位基因异常转录子；代谢性肝病相关基因外显子组捕获二代测序在患儿LARS基因检出父源性突变c.2133_2135del （p.L712del）和母源性突变c.1183G > A （p.D395N），经一代测序验证，最终确诊为ILFS1。目前随访至4岁，肝功能正常，无贫血，仍有低蛋白血症。

Abstract:

Infantile liver failure syndrome type 1 (ILFS1) is a Mendelian disease due to biallelic mutations in the cytoplasmic leucyl-tRNA synthetase gene (LARS). This study aimed to report the clinical and molecular features of the first non-caucasian ILFS1 patient, providing reliable evidences for the definite diagnosis of ILFS1. The 2 years and 9 months old male patient was referred to the hospital with hepatosplenomegaly over 1 year. At age 17 months, he was found to have hepatosplenomegaly and anemia. Since then, he had been managed in different hospitals. The laboratory tests showed liver dysfunction, hypoproteinemia, coagulopathy and anemia, along with histologically-confirmed cirrhosis and fatty liver; however, the etiology remained undetermined. The subsequent SLC25A13 mutation analysis by means of prevalent mutation screening and Sanger sequencing only revealed a paternally-inherited mutation c.1658G > A, and no aberrant SLC25A13 transcripts could be detected from the maternal allele on cDNA cloning analysis, ruling out the possibility of citrin deficiency. Further target exome high-throughout sequencing of genes relevant to genetic liver diseases detected a paternal c.2133_2135del (p.L712del) and a maternal c.1183G > A (p.D395N) mutation in LARS gene. This finding was then confirmed by Sanger sequencing, and ILFS1 was thus definitely diagnosed. The child has been followed up till age 4 years, and his condition became stabilized.