Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland.
Department of Ophthalmology, Poznan University of Medical Sciences, Poznan, Poland.
Am J Med Genet A. 2021 Jan;185(1):250-255. doi: 10.1002/ajmg.a.61938. Epub 2020 Oct 27.
Anophthalmia and microphthalmia (A/M) represent severe developmental ocular malformations, corresponding, respectively, to absent eyeball or reduced size of the eye. Both anophthalmia and microphthalmia may occur in isolation or as part of a syndrome. Genetic heterogeneity has been demonstrated, and many genes have been reported to be associated with A/M. The advances in high-throughput sequencing have proven highly effective in defining the molecular basis of A/M. Nevertheless, there are still many patients with unsolved genetic background of the disease, who pose a significant challenge in the molecular diagnostics of A/M. Here we describe a family, with three males affected with the non-syndromic A/M. Whole exome-sequencing performed in Patient 1, revealed the presence of a novel probably pathogenic variant c.734A>G, (p.[Tyr245Cys]) in the PORCN gene. Pedigree analysis and segregation of the identified variant in the family confirmed the X-linked recessive pattern of inheritance. This is the first report of X-linked recessive non-syndromic A/M. Until now, pathogenic variants in the PORCN gene have been identified in the patients with Goltz syndrome, but they were inherited in X-linked dominant mode. The ocular phenotype is the only finding observed in the patients, which allows to exclude the diagnosis of Goltz syndrome.
先天性无眼和小眼球（A/M）是严重的眼部发育畸形，分别对应于眼球缺失或眼睛尺寸缩小。先天性无眼和小眼球既可以单独发生，也可以作为综合征的一部分。已经证明存在遗传异质性，许多基因已被报道与 A/M 相关。高通量测序的进步已被证明在定义 A/M 的分子基础方面非常有效。然而，仍然有许多患者的疾病遗传背景尚未解决，这对 A/M 的分子诊断构成了重大挑战。在这里，我们描述了一个家族，其中有 3 名男性患有非综合征性 A/M。对患者 1 进行全外显子组测序，发现 PORCN 基因中存在一个新的可能致病变异 c.734A>G（p.[Tyr245Cys]）。家系分析和家族中鉴定出的变异的分离证实了 X 连锁隐性遗传模式。这是首例 X 连锁隐性非综合征性 A/M 的报道。到目前为止，PORCN 基因中的致病变异已在 Goltz 综合征患者中被发现，但它们以 X 连锁显性模式遗传。眼部表型是仅在患者中观察到的发现，这排除了 Goltz 综合征的诊断。
