七个鸟氨酸氨甲酰基转移酶缺陷症家系基因变异分析及产前诊断

目的对7个鸟氨酸氨甲酰基转移酶缺陷症(ornithine transcarbamylase deficiency,OTCD)家系进行OTC基因变异检测,明确其致病原因并为家系的遗传咨询和产前诊断提供依据。方法应用靶向高通量测序(next-generation sequencing,NGS)技术对7例经串联质谱筛查或临床诊断可疑OTCD的患儿或其母亲进行遗传代谢病相关基因panel检测,发现可疑致病变异位点后,应用PCR扩增和Sanger测序进行变异验证分析。在患儿母亲再次妊娠时抽取绒毛或羊水细胞进行相应基因变异检测,用于产前诊断。结果7个家系中共检测到7种OTC基因变异,分别为c.583G>A(p.Glyl95Arg).c.6260 T(p.Ala209Val)、c.6740 T(p.Pro225Leu)、c.482A>G(p.Asnl61Ser)、IVS1-2A>G、c.116G>T(p.Gly39Val).c.898delT(p.300Phefs*22),其中IVSl-2A>G、c・116G>T(p.Gly39Val)和c.898delT(p.300Phefs*22)为未报道过的新变异。产前诊断家系中3例胎儿基因测序均发现携带OTC基因变异半合子,性别为男性,孕妇选择终止妊娠,胎儿流产组织基因变异分析结果与产前诊断一致;另1例胎儿为OTC基因杂合变异,性别为女性,出生后新生儿筛查结果阴性,随访12个月,生长发育未见异常。结论OTC基因变异为7个OTCD家系的致病原因,致病变异的检出为家系的遗传咨询和产前诊断提供了依据。

Genetic testing and prenatal diagnosis in seven pedigrees affected with ornithine transcarbamylase deficiency

Objective To detect genetic variants among 7 pedigrees affected with ornithine transcarbamylase deficiency(OTCD)and provide prenatal diagnosis for them.Methods The pedigrees were subjected to targeted next-generation sequencing(NGS)with a gene panel for inherited metabolic diseases.Suspected pathological variants were confirmed by Sanger sequencing of the probands and their family members.Prenatal diagnosis was provided for 4 of the pedigrees.Results Seven variants of the OTC gene,including c.583G>A(p.Glyl95Arg),c.626C>T(p.Ala209Val),c.674C>T(p.Pro225Leu),c.482A>G(p.Asnl61Ser),IVS1-2A>G,c.1160 T(p.Gly39Val),c.898delT(p.300Phefs*22),were detected,among which IVS1-2A>G,c.116G>A(p.Gly39Val)and c.898delT(p.300Phefs*22)were unreported previously.Three male fetuses were found to carry hemizygotic variants upon prenatal diagnosis.One female fetus were found to be heterozygous for a variant,and appeared to be normal at birth as well as by newborn screening.Conclusion OTC gene variant is the etiology of OTCD in the 7 pedigrees.Genetic testing of OTC could assist physicians in OTCD diagnosis and provide genetic counseling and prenatal diagnosis for the pedigrees.