PDF(Pubmed)
Abstract：
Anophthalmia and microphthalmia (A/M) are among the most severe congenital developmental eye disorders. Despite the advancements in genome screening technologies, more than half of A/M patients do not receive a molecular diagnosis. We included seven consanguineous families affected with A/M from Pakistani cohort and an unknown molecular basis. Single gene testing of FOXE3 was performed, followed by genome sequencing for unsolved probands in order to establish a genetic diagnosis for these families. All seven families were provided with a genetic diagnosis. The identified variants were all homozygous, classified as (likely) pathogenic and present in an A/M-associated gene. Targeted FOXE3 sequencing revealed two previously reported pathogenic FOXE3 variants in four families. In the remaining families, genome sequencing revealed a known pathogenic PXDN variant, a novel 13bp deletion in VSX2, and one novel deep intronic splice variant in PXDN. An in vitro splice assay was performed for the PXDN splice variant which revealed a severe splicing defect. Our study confirmed the utility of genome sequencing as a diagnostic tool for A/M-affected individuals. Furthermore, the identification of a novel deep intronic pathogenic variant in PXDN highlights the role of non-coding variants in A/M-disorders and the value of genome sequencing for the identification of this type of variants.
摘要：
无眼症和小眼症（A/M）是最严重的先天性发育性眼部疾病。尽管基因组筛选技术取得了进步，超过一半的A/M患者没有接受分子诊断。我们包括来自巴基斯坦队列和未知分子基础的七个受A/M影响的近亲家庭。进行了FOXE3的单基因检测，然后对未解决的先证者进行基因组测序，以便为这些家庭建立遗传诊断。所有七个家庭都接受了基因诊断。鉴定的变体都是纯合的，分类为（可能）致病性，并存在于A/M相关基因中。靶向FOXE3测序揭示了四个家族中的两个先前报道的致病性FOXE3变体。在剩下的家庭里,基因组测序揭示了一种已知的致病性PXDN变体，VSX2中的一个新的13bp缺失，以及PXDN中的一个新的深内含子剪接变体。对显示严重剪接缺陷的PXDN剪接变体进行体外剪接测定。我们的研究证实了基因组测序作为A/M感染个体的诊断工具的实用性。此外，在PXDN中鉴定一种新的深层内含子致病变异体,突出了非编码变异体在A/M-疾病中的作用以及基因组测序对鉴定这类变异体的价值.
