目的：对3个小睑裂综合征家系进行全外显子组测序(WES)分析，确定其致病基因位点，寻找新的致病突变，进一步丰富该疾病有关致病基因的突变谱。

方法：回顾性研究。收集2021年1月至2021年8月就诊于云南省第二人民医院眼科的小睑裂综合征患者共3个家系30名参与者(小睑裂综合征诊断标准：出生时即有双侧睑裂狭小、上睑下垂、逆向型内眦赘皮以及内眦间距过宽的典型眼睑四联征)，其中包括8例患者和22名未受影响的正常成员。采集患者及相关家系成员外周血样本并提取基因组DNA进行全外显子组测序，对测序结果筛选并锁定候选基因致病位点，采用Sanger测序技术进行验证。

结果：WES在3个小睑裂综合征家系中鉴定出致病基因突变：家系1(共6名成员，3例患者，连续三代发病)患者携带PIEZO2基因一个新发杂合突变(位于11号外显子上游36 bp处，G>C)，经Sanger测序验证，该突变存在于所有患者而未见于家系内正常成员，且为首次报道； 家系2(共14名成员，2例患者)和家系3(共10名成员，3例患者)患者则携带已知的FOXL2基因杂合突变，分别为错义突变c.313A>C(p.N105H)和整码突变c.672_701dupAGCGGCTGCAGCAGCTGCGGCTGCAGCCGC(p.A225_A234dupAAAAAAAAAA)。

结论：WES成功鉴定了两个家族性小睑裂综合征家系的致病原因(分别为已知的FOXL2基因突变和新发现的PIEZO2基因突变)，为其遗传咨询与生育指导提供了理论依据； 其中，家系1中检出的PIEZO2基因突变(位于11号外显子上游36 bp，G>C)为首次报道，是该家系发病的重要因素。对此新突变的深入研究，不仅可拓宽小睑裂综合征的基因突变谱，更有助于深化对其发病机制的认识。

METHODS:Retrospective study. A total of 3 pedigrees and 30 patients with BPES(with criteria of bilateral blepharophimosis, ptosis, epicanthus inversus and wider inner canthal distance at birth)treated in the Ophthalmology Department of the Second People's Hospital of Yunnan Province were collected from January 2021 to August 2021, including 8 patients and 22 unaffected family members. Peripheral blood samples were collected from patients and related family members, and genomic DNA was extracted for whole exome sequencing. The sequencing results were screened to identify potential pathogenic gene loci, and candidate mutations were validated using Sanger sequencing.

RESULTS:WES analysis identified pathogenic gene mutations in 3 BPES pedigrees: pedigree 1(6 members, 3 affected individuals, with a history of disease across three generations)harbored a novel heterozygous mutation in the PIEZO2 gene(located 36 bp upstream of exon 11, G>C). Sanger sequencing confirmed that this mutation was present in all affected individuals and absent in normal family members, and it represents the first report of this mutation. Pedigree 2(14 members, 2 affected individuals)and pedigree 3(10 members, 3 affected individuals)carried known heterozygous mutations in the FOXL2 gene, namely the missense mutation c.313A>C(p.N105H)and the in-frame mutation c.672_701dupAGCGGCTGCAGCAGCTGCGGCTGCAGCCGC(p.A225_A234dupAAAAAAAAAA), respectively.

CONCLUSION:WES successfully identified the pathogenesis of familial congenital BPES in two families, including a known FOXL2 gene mutation and a newly discovered PIEZO2 gene mutation. These findings provide a theoretical basis for genetic counseling and reproductive guidance. Notably, the PIEZO2 gene mutation(located 36 bp upstream of exon 11, G>C)discovered in the pedigree 1 is reported for the first time and plays a critical role in the onset of the disease in this family. Further investigation of this new mutation could not only expand the mutation spectrum of BPES, but also enhance our understanding of its pathogenic mechanisms.