SLC40A1基因c.430A>G杂合突变的Ⅳ型遗传性血色病一家系的临床研究

Pedigree analysis of typeⅣhereditary hemochromatosis caused by c.430A>G heterozygous mutation of SLC40A1 gene

目的研究SLC40A1基因c.430A>G杂合突变的Ⅳ型遗传性血色病的临床表型,以及基因型与表型的相关性,探索筛查该基因型血色病的铁蛋白截断值。方法2020年7月在南京医科大学第一附属医院就诊的1例SLC40A1基因c.430A>G杂合突变的Ⅳ型遗传性血色病患者及其家系5代成员共47人,对其进行系统的临床调查,检测现存39人铁蛋白、肝功能、空腹血糖和性激素,Sanger测序验证突变位点,绘制家系图。铁蛋白与其他指标间的相关分析采用Spearman相关分析,用受试者工作特征曲线计算铁蛋白,筛查该基因型血色病的截断值。结果39名家系成员中,SLC40A1基因c.430A>G杂合突变患者10例,其中5例确诊为血色病,外显率不全。以是否发生SLC40A1基因c.430A>G杂合突变分层,2组间铁蛋白和天冬氨酸转氨酶(AST;均P<0.01)、空腹血糖以及低促性腺激素性性腺功能减退发生率和关节炎发生率(均P<0.05)差异有统计学意义,丙氨酸转氨酶(ALT)差异无统计学意义。Spearman相关分析显示,在SLC40A1基因c.430A>G杂合突变者中,铁蛋白水平与ALT(r=0.903)、AST(r=0.879)、空腹血糖(r=0.782)、低促性腺激素性性腺功能减退发生率(r=0.798)及关节炎发生率(r=0.798)显著相关(均P<0.01)。铁蛋白筛查SLC40A1基因c.430A>G杂合突变遗传性血色病的截断值为1036.7μg/L,灵敏度和特异度分别为100%和94.3%。结论SLC40A1基因c.430A>G杂合突变与AST和空腹血糖水平升高、低促性腺激素性性腺功能减退和关节炎发生率升高密切相关,铁蛋白截断值有助于筛查该基因型血色病。

Objective To investigate clinical phenotypes of typeⅣhereditary hemochromatosis caused by c.430A>G heterozygous mutation of SLC40A1 gene and the correlation between genotype and phenotype,exploring ferritin cutoff value for screening.Methods One case of typeⅣhereditary hemochromatosis with c.430A>G heterozygous mutation in the SLC40A1 gene and 5 generations of their family lineage with a total of 47 members who were seen at the First Affiliated Hospital of Nanjing Medical University in July 2020 were studied for systematic clinical investigation.Thirty-nine surviving individuals were tested for ferritin,liver function,fasting plasma glucose(FPG),and sex hormones,and Sanger sequencing was performed to verify the mutation loci and to map the family tree.Spearman correlation analysis was used to explore the relationship between ferritin and other indicators,and receiver operating characteristic curves were used to calculate the ferritin cutoff value for screening for this genotype of hemochromatosis.Results Ten patients with c.430A>G heterozygous mutation in the SLC40A1 gene were identified among 39 family members,and five of them were diagnosed with hemochromatosis,presenting incomplete penetrance.The differences in levels of ferritin,aspartate aminotransferase(AST;both P<0.01)and FPG,as well as incidences of hypogonadotropic hypogonadism and arthritis(all P<0.05)between group of mutation positive and group negative were statistically significant,while the difference in alanine aminotransferase(ALT)was not.Spearman correlation analysis showed that,ferritin levels were significantly associated with ALT(r=0.903),AST(r=0.879),FPG(r=0.782),and the incidences of hypogonadotropic hypogonadism(r=0.798)and arthritis(r=0.798;all P<0.01)in those with the c.430A>G heterozygous mutation in the SLC40A1 gene.The ferritin cutoff value for screening of hereditary hemochromatosis with c.430A>G heterozygous mutation in the SLC40A1 gene was 1036.7μg/L,with a sensitivity and specificity of 100%and 94.3%,respectively.Conclusion The SLC40A1 gene c.430A>G heterozygous mutation is closely associated with elevated levels of AST and FPG,increased incidences of hypogonadotropic hypogonadism and arthritis,and the ferritin cutoff value is a useful screening parameter.