脑眼面骨骼综合征一家系临床与遗传学研究

Clinical and genetic study of a family with cerebro - oculo - facio - skeletal syndrome

目的 分析1个脑眼面骨骼（COFS）综合征家系的临床特点和致病基因突变，总结本病表型与基因型的关系。方法 收集1个COFS综合征家系先证者及其父母的临床资料，提取先证者及其父母外周血基因组DNA，采用目标区序列捕获及第二代高通量测序技术对临床诊断的1例COFS综合征患儿进行检测，同时采用Sanger测序技术对患者突变进行验证。结果 先证者，1岁3个月余，小头畸形，眼球震颤，大耳廓，鼻尖突出，高腭弓，上嘴唇突出，小下颌，宽乳距，四肢关节屈曲，喂养困难，发育迟缓，其父母均表型正常。该家系先证者的ERCC2基因上同时存在c.1843G〉T （P.G615W）与c.1996C〉T（P.R666W） 2个杂合突变，先证者之父、母分别携带c.1843G〉T （P.G615W）与c.1996C〉T（P.R666W） 2个杂合突变，其中c.1996C〉T（P.R666W）为明确的致病性突变。结论 COFS综合征主要临床特征包括小头畸形、鼻尖突出、四肢关节屈曲、发育迟滞。本例患儿为国内报道的第1例COFS综合征，通过遗传学研究明确了该家系中的致病基因突变及相关个体基因状况，为准确的遗传咨询和进一步的产前诊断打下了基础。

Objective To analyze the clinical features and pathogenic gene mutation in a Chinese family with cerebro-oculo-facio-skeletal（COFS） syndrome, in order to summarize the relationship between phenotype and genotype.Methods The clinical data of the proband and his family members were collected.Genomic DNA from the proband and his parents were extracted by using standard procedures from the peripheral blood leukocytes.Next-generation sequencing was used to detect gene mutation in the patient with COFS syndrome.Sanger sequencing was applied to confirm the results.Results The proband, male, 1 year and 3 months old, presented with microcephaly nystagmus, large ears, prominent nose, high arched palate, overhanging upper lip, micrognathia, widely set nipples, flexion contractures （especially involving the elbows and knees）, failure to thrive, developmental retardation and feeding difficulty.His parents were normal phenotype.Two different heterozygous mutations c. 1843G〉T （P.G615W） and c. 1996 C〉 T（P.R666W） were identified in the ERCC2 gene.The proband′s father had the heterozygous mutation c. 1843G〉T （P.G615W） and his mother had the heterozygous mutation c. 1996 C〉 T（P.R666W）. Meanwhile, this heterozygous mutation c. 1996 C〉 T（P.R666W） had been reported as a pathogenic gene mutation.Conclusions COFS syndrome is characterized by microcephaly, prominent nose, arthrogryposis and severe developmental delay.This is the first report on COFS syndrome patient in the mainland of China.The pathogenic gene mutations and gene status were identified through genetic studies.The result has laid the foundation for accurate genetic counseling and further prenatal diagnosis.