[Study on spectrum of UGT1A1 mutations in connection with inherited non-hemolytic unconjugated hyperbilirubinemia].

Objective: To compare and analyze patient's general condition, changes in laboratory parameters, and the spectrum of UGT1A1 mutations in patients with inherited non-hemolytic unconjugated hyperbilirubinemia. Methods: A retrospective study was conducted at Nanjing Second Hospital from January 2015 to July 2018 and patients' demographic characteristics, liver function test, and UGT1A1 gene were analyzed. The categorical variable data were compared by χ (2) test. The normal distribution continuous variable data were compared by t-test and the non-normal distribution continuous variable data were compared using Mann-Whitney U test. Results: Of the 51 patients with inherited non-hemolytic unconjugated hyperbilirubinemia, 44 (86.3%) were Gilbert's syndrome (GS) and seven (13.7%) were Crigler-Najjar syndrome type II (CNS- II). The male to female ratio was 2.9:1 and the average age was 36.11 ± 13.17 years. Six variant types were detected: C. -40_-39insTA, C. -3279T > G, c.211G > A (p.G71R), c.686C > A (p.P229Q), c.1091C > T (p.P364L), c.1456T > G (P.Y486D). Among them, c.211G > A accounted for 58.82% (30/51), c.-40_-39insTA accounted for 27.5% (14/51), and c.1456T > G accounted for 25.5% (13/51). The total bilirubin(TB) and unconjugated bilirubin (UCB) in CNS-II patients were significantly higher than GS patients[155.91 (130 ~ 207) vs. 38.25(29 ~ 52.15) μmol/L, U = 0, P < 0.01; 144.13 (120.8 ~ 197) vs. 30.00 (21.7 ~ 46.75) μmol/L, U = 0.00, P < 0.01, respectively]. Exon mutations of c.1091C > T and c.1456T > G were statistically significant(P < 0.01).There were no differences in age, TB, UCB, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) between the c.211G > A homozygous variants and heterozygous variants (P > 0.05). Conclusion: The common pathogenic mutations of UGT1A1 gene were c.211G > A, c.-40_-39insTA, c.1456T > G. c.211G > A. The mutation has little effect on the level of total bilirubin, but c.1091C > T, c.1456T > G mutations has great influence on the level of total bilirubin.目的： 分析不同类型的遗传性非溶血性非结合型胆红素血症患者的UGT1A1突变谱及一般情况、实验室指标的变化。方法： 回顾性分析2015年1月至2018年7月就诊的遗传性非溶血性非结合型胆红素血症患者的UGT1A1基因、人口学特点、肝脏生物化学指标。分类变量资料比较采用χ(2)检验；正态分布连续变量资料比较采用t检验、非正态分布的连续变量资料比较采用Mann-Whitney U检验。结果： 51例遗传性非溶血性非结合型胆红素血症的患者中，44例（86.3%）为Gilbert综合征，7例（13.7%）为Crigler-Najjar综合征II型。男女比例2.9∶1，平均年龄为（36.11±13.17）岁。共检测到6个变异类型：c.-40_-39insTA、c.-3279T > G、c.211G > A（p.G71R）、c.686C > A（p.P229Q）、c.1091C > T（p.P364L）、c.1456T > G（P.Y486D）。其中c.211G > A占58.82% (30/51），c.-40_-39insTA占27.5%（14/51），c.1456T > G占25.5%（13/51）；Crigler-NajjarⅡ组总胆红素[155.91（130～207）μmol/L]和非结合型胆红素[144.13（120.8～197）μmol/L]均较Gilbert综合征组[分别为38.25（29～52.15）μmol/L，U = 0, P < 0.01；30.00（21.7～46.75）μmol/L，U = 0，P < 0.01]高, 两组外显子4 c.1091C > T、外显子5 c.1456T > G突变差异有统计学意义（P < 0.01）；c.211G > A杂合型和纯合型的年龄、总胆红素、非结合胆红素、丙氨酸氨基转移酶和天冬氨酸氨基转移酶差异均无统计学意义（P > 0.05）。结论： UGT1A1基因常见致病变异依次为c.211G > A、c.-40_-39insTA、c.1456T > G。c.211G > A突变对胆红素影响差异性较小，c.1091C > T、c.1456T > G变异对胆红素影响差异性较大。.