五个睑裂狭小综合征家系FOXL2基因突变的研究

Analysis of FOXL2 gene mutations in 5 families affected with blepharophimosis, ptosis and epicanthus inversus syndrome

目的对5个先天性睑裂狭小-倒转型内眦赘皮-上睑下垂综合征（blepharophimosis, ptosis,and epicanthus inversus syndrome,BPES）家庭进行FOXL2基因突变检测，分析FOXL2基因型和临床表型的关系，为这些家庭的生育指导提供依据。方法抽取其中2个家族性BPES中的3例患者及3例散发BPES患者的外周静脉血，提取DNA，应用聚合酶链反应扩增6例患者FOXL2基因编码区及侧翼序列，随后进行Sanger测序，并对发现的突变进行文献回顾和生物信息学分析。结果家系1先证者和患者（Ⅳ14）及家系2先证者FOXL2基因均存在c．672_701dup30（p．Ala225-Ala234dup）杂合突变，3例散发患者FOXL2基因分别存在c．462_468del（p．Prol56Argfs＊113）杂合突变、c．251T〉A（p．Ile84Asn）杂合突变和c．988_989insG（p．Ala330Glyfs＊204）杂合突变。通过生物信息学分析及文献回顾，本研究发现的4种突变均为致病突变。结论明确了3例家族性及3例散发BPES患者的致病原因，为其遗传咨询和生育指导提供了理论依据。同时FOXL2基因c.462_468del突变和c．988_989insG突变为未曾报道的新突变，丰富了FOXL2基因突变谱。

Objective To screen for FOXL2 gene mutations in 6 patients with blepharophimosis, ptosis, and epicanthus inversus syndrome （BPES）, and explore their genotype - phenotype correlation. Methods Peripheral venous blood samples were collected from the patients for the extraction of genomic DNA. PCR and Sanger sequencing were employed to analyze the coding region and flanking sequences of the FOXL2 gene. Pathogenicity of the identified mutations was verified through literature review and bioinformatic analysis. Results A heterozygous c. 672_701dup30 mutation was found in the probands from the two familial cases, while three heterozygous mutations （two were novel）, namely c. 462_468del （p. Pro156Argfs＊113）, c. 251T〉A （p. Ile84Asn） and c. 988_989insG （p. Ala330Glyfs ＊ 204） were detected in the three sporadic cases. Literature review and bioinformatic analysis indicated that all these mutations are pathogenic. Conclusion Identification of causative mutations in the BPES patients has provided a basis for genetic counseling and reproductive guidance. The novel mutations have enriched the mutation spectrum of the FOXL2 gene.