一例非特异性精神发育迟滞家系OPHN1基因突变分析并文献复习
Genotype Analysis of OPHN1 Gene Mutation in Non-Specific Mental Retardation Family with Literature Review

目的：对一个中国河南省精神发育迟滞家系进行致病基因突变筛查。方法：收集1个精神发育迟滞家系，应用高通量测序技术对先证者进行智力障碍相关基因检测，发现可疑致病基因后，采用Sanger测序技术对先证者亲属进行突变筛查，确定该家系的可疑致病位点。结果：高通量测序结果提示先证者携带两个可疑致病位点：OPHN1基因c.1973T>G(p.L658W)半合子变异和GRIN2B基因c.190G>T(p.V64L)杂合变异，并进行了一代测序验证。Sanger测序结果显示先证者母亲携带GRIN2B基因c.190G>T(p.V64L)杂合变异，由于母亲未发病，不符合常染色体显性遗传疾病发病机制，排除此位点致病的可能性。先证者母亲和外祖母均携带OPHN1基因c.1973T>G(p.L658W)杂合变异，先证者妹妹和姨妈未携带OPHN1基因c.1973T>G(p.L658W)变异，符合X-连锁隐性遗传方式。结论：OPHN1基因c.1973T>G(p.L658W)变异为新的变异，可能是该非特异性精神发育迟滞家系的致病原因，高通量测序结合Sanger测序方法可以高效准确地对该病进行基因诊断。
Objective: To detect genetic causes of mental retardation in a Chinese mental retardation family in Henan Province. Method: A mental retardation pedigree was recruited and the proband was performed high-throughput sequencing to detect the intellectual impairment-related genes, and then the mutations in the candidate genes were verified by Sanger sequencing. Result: High-throughput sequencing results suggested that the proband carried two suspected pathogenic sites. They were OPHN1gene c.1973T>G(p.L658W) and GRIN2B gene c.190G>T(p.V64L), and Sanger sequencing was used to verify the two mutation sites in the proband. Sanger sequencing result also showed that the mother of the proband carried the heterozygous c.190G>T(p.V64L) in GRIN2B gene but had no symptoms. This did not meet the pathogenesis of the autosomal dominant disease, so the causing possibility of GRIN2B gene c.190G>T(p.V64L) site was ruled out. The mother and grandmother of the proband both carried the heterozygous variation c.1973T>G(p.L658W) in OPHN1 gene, and the sister and maternal aunt did not carry OPHN1 gene c.1973T>G(p.L658W) mutation. This was conformed to X-linked recessive inheritance. Conclusion: The mutation c.1973T>G(p.L658W) in OPHN1 gene was a novel mutation, which may be the cause of mental retardation in this non-specific mental retardation family. High-throughput sequencing combined with Sanger sequencing technology can diagnose mental retardation disease efficiently and accurately.