国内首报Legius综合征一家系及基因突变分析

【摘要】 目的 检测1例以多发咖啡斑为主要临床表现的Legius综合征家系的基因突变情况，并明确其诊断。方法 收集1例以多发咖啡斑为主要临床表现的先证者及其父母和外祖父母临床资料，采集上述受试者外周血提取基因组DNA，对先证者进行全外显子组测序，确定突变位点，再在家系中对突变位点进行PCR扩增及Sanger测序进行验证，并明确其诊断。结果 先证者男，12岁，躯干可见10余处长径 > 5 mm的咖啡斑，腋窝、腹股沟多发雀斑。先证者外周血基因组DNA中编码Sprouty相关EVH1功能域蛋白1的SPRED1基因第7号外显子中存在小片段杂合缺失（c.1220_1238del），引起氨基酸序列发生移码突变（p.L407fs*），先证者患病母亲检出该突变，外祖父母及父亲未检出该突变。该突变为新发突变，先证者突变遗传自母亲，突变与疾病符合共分离，确诊为Legius综合征。 结论 Legius综合征与神经纤维瘤病Ⅰ型早期临床症状相近，基因检测有助于早期诊断、判断预后和制定随访计划。

Gene mutation analysis in a family with Legius syndrome firstly reported in China

Objective To identify the underlying gene mutation in a family with Legius syndrome mainly manifesting as multiple café-au-lait spots,and to confirm the diagnosis.Methods Clinical data were collected from a proband with multiple café-au-lait spots as the main clinical manifestation,his parents and grandparents.Genomic DNA was extracted from peripheral blood samples of the above subjects.Whole-exome sequencing was performed to identify mutation sites in the proband,PCR and Sanger sequencing were performed to verify the candidate mutation among the family members,and to confirm the diagnosis.Results The proband,a 12-year-old male patient,presented with more than 10 café-au-lait spots with a major diameter of>5 mm on the trunk,and multiple freckles on the axilla and groin.Mutation analysis of the proband revealed a small heterozygous deletion mutation(c.1220_1238del)in exon 7 of the SPRED1 gene encoding Sprouty-related EVH1 domain-containing protein 1,causing a frameshift mutation in the amino acid sequence(p.L407fs*).This mutation was detected in the affected mother of the proband,but not in his father or grandparents.The mutation in the proband was a novel mutation,and was inherited from his mother.The mutation was co-segregated with the disease in the family,and a diagnosis of Legius syndrome was made.Conclusion Clinical symptoms of Legius syndrome are similar to those of early-stage neurofibromatosis typeⅠ,and genetic testing is helpful for early diagnosis,prognosis prediction and follow-up scheduling.