Confirming and expanding the phenotypes of FZD5 variants: Coloboma, inferior chorioretinal hypoplasia, and high myopia
Confirming and expanding the phenotypes of FZD5 variants: Coloboma, inferior chorioretinal hypoplasia, and high myopia
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确认和扩展 FZD5 变异的表型：缺损、下脉络膜视网膜发育不全和高度近视
作者：
Yi Jiang;Jiamin Ouyang;Shiqiang Li;Xueshan Xiao;Wenmin Sun;Qingjiong Zhang
目的在以往的研究中，FZD5的两个移码和两个内切变体分别在两个不完全外显的家系和两个孤立的病例中被报道导致缺损。本研究旨在通过对FZD5变异体的基因-表型分析，证实这种关联，并扩展相关的特定表型。方法从5845名具有不同眼部状况的先证者的内部外显子测序数据中收集FZD5基因的变异。采用多步骤生物信息学分析对变异进行分类。在家系分离和基因-表型分析的基础上，进一步评估潜在的致病变异和表型变异。结果FZD5基因共检测到63个罕见变异。多步生物信息学和基因-表型分析表明，9个家系中的8个罕见杂合变异可能是潜在的致病变异：3个新的移码变异(c.350_356delCGCCGCT/p.Ser117*，c.1403_1406dupACCT/p.Tyr470Pros*130，c.1428delG/p.Ser477Alafs*130)和5个新的错义变异(c.388C>；A/p.Arg130Ser，c.794G>；T/p.Arg265Leu，c.1162G>；A/p.Gly388Ser，c.1232A>；G/p.Tyr411Cys，和c.1510A>；T/p.Met504Leu)。在9个家系中，这些变异的携带者表现出重叠的表型，包括典型的葡萄膜缺损(来自4个家系的7名患者的12只眼)、下脉络膜视网膜发育不良(ICH)或视盘发育不良(ODH；来自6个家系的8名患者的12只眼)、高度近视(来自5个家系的5名患者的10只眼)。结论本研究证实FZD5基因的变异不仅是移码变异，也是错义变异，是葡萄膜缺损的常见原因。此外，ICH、ODH和高度近视可能是经常与FZD5变异相关的变异表型。
Purpose Two frameshift and two indel variants in FZD5 have been reported to cause coloboma in two families with incomplete penetrance and in two isolated cases in previous studies, respectively. This study aims to confirm this association and expand related specific phenotypes based on the genotype-phenotype analysis of FZD5 variants. Methods Variants in FZD5 were collected from our in-house exome sequencing data of 5,845 probands with different eye conditions. Multistep bioinformatics analysis was used to classify the variants. Potential pathogenic variants and phenotypic variations were further evaluated based on family segregation and genotype-phenotype analysis. Results In total, 63 rare variants were detected in FZD5. Multistep bioinformatics and genotype-phenotype analyses suggested that eight rare heterozygous variants in nine families should be considered potential pathogenic variants: three novel frameshift variants (c.350_356delCGCCGCT/p.Ser117*, c.1403_1406dupACCT/p.Tyr470Profs*130, and c.1428delG/p.Ser477Alafs*130) and five novel missense variants (c.388C>A/p.Arg130Ser, c.794G>T/p.Arg265Leu, c.1162G>A/p.Gly388Ser, c.1232A>G/p.Tyr411Cys, and c.1510A>T/p.Met504Leu). Among the nine families, carriers of these variants showed overlapping phenotypes, including typical uveal coloboma (12 eyes of seven patients from four families), inferior chorioretinal hypoplasia (ICH) or optic disc hypoplasia (ODH; 12 eyes of eight patients from six families), and high myopia (10 eyes of five patients from five families) within individual families or among different families. Conclusions The data presented in this study confirmed that variants in FZD5, not only frameshift variants but also missense variants, are a common cause of uveal coloboma. In addition, ICH, ODH, and high myopia may be variant phenotypes that are frequently associated with FZD5 variants.
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