四个遗传性耳聋家系的TMC1基因变异分析及产前诊断

目的对4个耳聋家系进行遗传性耳聋基因变异的筛查,为家系遗传咨询与产前诊断提供依据。方法应用二代测序技术对家系先证者进行耳聋基因检测,并对可疑基因变异采用Sanger双向测序对先证者及家系成员进行验证,确定可疑致病变异后,对3个家系高危胎儿进行产前诊断。结果家系1先证者检测到TMC1基因c.100C>T(p.R34X)和c.642+4A>C复合杂合变异,家系2先证者检测到TMC1基因c.582G>A(p.W194X)和c.589G>A(p.G197R)复合杂合变异,家系3先证者检测到TMC1基因c.1396_1398delAAC和c.1571T>C(p.F524S)复合杂合变异,家系4先证者检测到TMC1基因c.2050G>C(p.D684H)纯合变异,4个家系先证者父母均为携带者,其中c.642+4A>C、c.1571T>C(p.F524S)变异位点既往未见报道;产前诊断结果显示3个家系胎儿均不是患者,出生后随访至2019年9月,听力未见异常。结论TMC1基因变异是4个耳聋家系的可能致病原因,分子生物学的发现增加了对TMC1基因功能的认识并丰富了人类基因变异数据库,为家系遗传咨询和产前诊断提供了依据。

Analysis of TMC1 gene variants and prenatal diagnosis in four Chinese families affected with deafness

Objective To explore the genetic basis of four Chinese families affected with deafness.Methods All probands were subjected to next generation sequencing(NGS).Suspected variant were verified by Sanger sequencing among the family members.Prenatal diagnosis was provided for three couples through Sanger sequencing.Results All probands were found to carry pathogenic variants of the TMC1 gene,which included c.100C>T(p.R34X)and c.642+4A>C in family 1,c.582G>A(p.W194X)and c.589G>A(p.G197R)in family 2,c.1396_1398delAAC and c.1571T>C(p.F524S)in family 3,and homozygosity of c.2050G>C(p.D684H)in family 4.All parents were heterozygous carriers of the variants.The c.642+4A>C and c.1571T>C(p.F524S)were unreported previously.Prenatal diagnosis revealed that none of the fetuses were affected.Follow-up confirmed that all newborns had normal hearing.Conclusion Variant of the TMC1 gene probably underlay the deafness in the four families.Above findings have enhanced our understanding of the function of the TMC1 gene and enriched its variant spectrum.The results also facilitated genetic counseling and prenatal diagnosis for the families.