一例N-乙酰谷氨酸合成酶缺乏症家系的基因分析与产前诊断

Genetic analysis and prenatal diagnosis for a Chinese pedigree affected with N-acetylglutamate synthase deficiency

目的探讨1例N-乙酰谷氨酸合成酶缺乏症家系的遗传学病因,并为该家系再次生育提供遗传咨询和产前诊断。方法应用Trio全外显子组测序寻找N-乙酰谷氨酸合成酶缺乏症家系的致病原因。根据美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMGG)推荐的基因变异临床意义分类标准对检出的变异进行分类,评估其致病风险。该家系再次生育时,应用Sanger测序针对检出的变异进行产前诊断。结果Trio全外显子组测序结果显示:患儿NAGS基因存在c.68delG和c.796G>C复合杂合变异,其父母分别携带c.796G>C和c.68delG杂合变异。上述变异均未见文献报道,根据ACMGG变异判读指南,c.68delG为"疑似致病"变异(PVS1+PM2),c.796G>C为"临床意义不明确"变异(PM2+BP4)。Sanger测序验证了Trio全外显子组测序的检测结果,并在羊水细胞中仅检测出c.796G>C杂合变异。该胎儿出生后6个月随访,未发现明显异常。结论NAGS基因c.68delG和c.796G>C复合杂合变异可能为该家系中患儿的致病原因,基因检测结果为家系的遗传咨询和产前诊断提供了依据。

Objective To explore the genetic basis for a Chinese pedigree affected with N-acetylglutamate synthase deficiency.Methods Trio whole exome sequencing(WES)was carried out for the pedigree.Pathogenicity of the identified variant was predicted based on the latest recommendation of the American College of Medical Genetics and Genomics(ACMG).Prenatal diagnosis was provided for subsequent pregnancy through Sanger sequencing.Results Trio WES showed that the proband has carried compound heterozygous c.68delG and c.796G>C variants of NAGS gene,for which the mother and father were respectively heterozygous carriers.Neither variant was reported previously.Based on the ACMG guidelines,the c.68delG variant was classified as"likely pathogenic"(PVS1+PM2),while the c.796G>C variant was classified as with"uncertain significance"(PM2+BP4).Sanger sequencing validated the above findings,and only detected the heterozygous c.796G>C variant in the amniotic fluid sample.The fetus was followed up till 6 month after birth with no obvious abnormality.Conclusion The compound heterozygous c.68delG and c.796G>Cvariants of the NAGS gene probably underlay the disorder in this pedigree,and the resulth asenabled genetic counseling and prenatal diagnosis for this pedigree.