Ocular coloboma is caused by failure of optic fissure closure during development and recognized as part of the microphthalmia, anophthalmia, and coloboma (MAC) spectrum. While many genes are known to cause colobomatous microphthalmia, relatively few have been reported in coloboma with normal eye size. Genetic analysis including trio exome sequencing and Sanger sequencing was undertaken in a family with two siblings affected with bilateral coloboma of the iris, retina, and choroid. Pathogenic variants in MAC genes were excluded. Trio analysis identified compound heterozygous donor splice site variants in CDON, a cell‐surface receptor known to function in the Sonic Hedgehog pathway, c.928 + 1G > A and c.2650 + 1G > T, in both affected individuals. Heterozygous missense and truncating CDON variants are associated with dominant holoprosencephaly (HPE) with incomplete penetrance and Cdon−/− mice display variable HPE and coloboma. A homozygous nonsense allele of uncertain significance was recently identified in a consanguineous patient with coloboma and a second molecular diagnosis. We report the first compound heterozygous variants in CDON as a cause of isolated coloboma. CDON is the first HPE gene identified to cause recessive coloboma. Given the phenotypic overlap, further examination of HPE genes in coloboma is indicated.

中文翻译：

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复合杂合剪接 CDON 变体导致孤立的眼部缺损。

眼缺损是由发育过程中视裂闭合失败引起的，被认为是小眼、无眼和缺损 (MAC) 谱的一部分。虽然已知许多基因会导致缺损性小眼症，但在眼睛大小正常的缺损症中报道的基因却相对较少。包括三重外显子组测序和 Sanger 测序在内的遗传分析是在一个有两个兄弟姐妹患有虹膜、视网膜和脉络膜双侧缺损的家庭中进行的。MAC 基因中的致病变异被排除在外。Trio 分析在CDON 中鉴定了复合杂合供体剪接位点变异，CDON 是一种已知在 Sonic Hedgehog 通路中起作用的细胞表面受体，c.928 + 1G > A 和 c.2650 + 1G > T，在两个受影响的个体中。杂合错义和截断CDON变异与显性全前脑畸形 (HPE) 相关，外显率不完全，Cdon-/-小鼠显示可变的 HPE 和缺损。最近在一名患有缺损和第二次分子诊断的近亲患者中发现了一个意义不确定的纯合无义等位基因。我们报告了CDON 中第一个复合杂合变体作为孤立缺损的原因。CDON是第一个被鉴定为导致隐性缺损的 HPE 基因。鉴于表型重叠，需要进一步检查缺损中的 HPE 基因。