Defects in optic fissure closure can lead to congenital ocular coloboma. This ocular malformation, often associated with microphthalmia, is described in various clinical forms with different inheritance patterns and genetic heterogeneity. In recent times, the identification of an increased number of genes involved in numerous cellular functions has led to a better understanding in optic fissure closure mechanisms. Nevertheless, most of these genes are also involved in wider eye growth defects such as micro-anophthalmia, questioning the mechanisms controlling both extension and severity of optic fissure closure defects. However, some genes, such as FZD5, have only been so far identified in isolated coloboma. Thus, to estimate the frequency of implication of different ocular genes, we screened a cohort of 50 patients affected by ocular coloboma by using targeted sequencing of 119 genes involved in ocular development. This analysis revealed seven heterozygous (likely) pathogenic variants in RARB, MAB21L2, RBP4, TFAP2A, and FZD5. Surprisingly, three out of the seven variants detected herein were novel disease-causing variants in FZD5 identified in three unrelated families with dominant inheritance. Although molecular diagnosis rate remains relatively low in patients with ocular coloboma (14% (7/50) in this work), these results, however, highlight the importance of genetic screening, especially of FZD5, in such patients. Indeed, in our series, FZD5 variants represent half of the genetic causes, constituting 6% (3/50) of the patients who benefited from a molecular diagnosis. Our findings support the involvement of FZD5 in ocular coloboma and provide clues for screening this gene during current diagnostic procedures.

视裂闭合缺陷可导致先天性眼缺损。这种通常与小眼症相关的眼部畸形在具有不同遗传模式和遗传异质性的各种临床形式中都有描述。近年来，对涉及多种细胞功能的基因数量增加的鉴定使人们对视裂闭合机制有了更好的了解。尽管如此，这些基因中的大多数还涉及更广泛的眼睛生长缺陷，例如微眼缺失，质疑控制视裂闭合缺陷的扩展和严重程度的机制。然而，一些基因，如FZD5，到目前为止仅在孤立的缺损中被发现。因此，为了估计不同眼部基因的影响频率，我们通过对 119 个参与眼部发育的基因进行靶向测序，筛选了 50 名受眼部缺损影响的患者。该分析揭示了RARB、MAB21L2、RBP4、TFAP2A和FZD5 中的七个杂合（可能）致病变异。令人惊讶的是，本文检测到的七个变异中有三个是FZD5中的新型致病变异在具有显性遗传的三个不相关的家族中确定。尽管眼缺损患者的分子诊断率仍然相对较低（在这项工作中为 14%（7/50）），但是，这些结果强调了基因筛查的重要性，尤其是FZD5，在此类患者中。事实上，在我们的系列中，FZD5变异代表了一半的遗传原因，占从分子诊断中受益的患者的 6% (3/50)。我们的研究结果支持FZD5参与眼缺损，并为在当前诊断程序中筛选该基因提供线索。