目的：探讨外斜视多代家系中HOXA1和FOXF2基因变异与遗传易感性的关联性，揭示外斜视的分子遗传病因学机制。方法：本遗传学研究自2023年9月至2025年2月招募10个具有明确外斜视家族史的多代家系，共计165名成员(其中87例外斜视患者和78名正常成员作为对照)。进行详细的眼科检查，构建家系图谱，采集外周血样本，提取基因组DNA，采用PCR扩增和Sanger测序技术对HOXA1和FOXF2基因的外显子及侧翼序列进行检测，并对发现的基因变异进行分类分析和关联研究。结果：纳入10个家系中，共发现HOXA1基因5个变异位点(c.218G>A，c.385C>T，c.496A>G，c.652T>C，c.874C>T)和FOXF2基因4个变异位点(c.102C>T，c.344G>A，c.576T>C，c.892A>G)。HOXA1基因c.496A>G变异携带组患者外斜视角度、外斜视类型、立体视、视差与不携带组比较均有差异(均P<0.05)。FOXF2基因c.344G>A变异携带组患者发病年龄小于非携带组(t=3.55，P=0.004)。结论：HOXA1和FOXF2基因变异与外斜视的遗传易感性存在显著关联，尤其与发病年龄和外斜视角度相关，为外斜视的分子诊断和精准治疗提供了新的靶点。

AIM: To investigate the association between HOXA1 and FOXF2 gene variants and genetic susceptibility in multigenerational families with exotropia, and to elucidate the molecular genetic etiological mechanisms of exotropia.METHODS:A total of 10 multigenerational families with a definitive history of exotropia were recruited from September 2023 to February 2025, comprising 165 members(87 exotropia patients and 78 normal controls). Detailed ophthalmological examinations were performed, family pedigrees were constructed, peripheral blood samples were collected, genomic DNA was extracted, and PCR amplification followed by Sanger sequencing were used to detect exons and flanking sequences of the HOXA1 and FOXF2 genes. Identified variants were subjected to pathogenicity classification and association analyses.RESULTS:Among the 10 families, 5 variant sites in HOXA1(c.218G>A, c.385C>T, c.496A>G, c.652T>C, c.874C>T)and 4 in FOXF2(c.102C>T, c.344G>A, c.576T>C, c.892A>G)were identified. The HOXA1 c.496A>G variant showed statistically significant differences between carrier and noncarrier in exotropia angle, exotropia type, stereoscopic vision, and parallax(all P<0.05). The age of onset of FOXF2 gene c.344G>A mutation carrier group was younger than that of the non-carrier group(t=3.55, P=0.004).CONCLUSION:HOXA1 and FOXF2 gene variants are significantly associated with genetic susceptibility to exotropia, particularly influencing age of onset and deviation angle, offering novel targets for molecular diagnosis and precision treatment of exotropia.