Department of Ophthalmology, The Central Hospital of Enshi Tujia And Miao Autonomous Prefecture, Enshi Clinical College of Wuhan University, Enshi, China.
Department of Eye Center, Renmin Hospital of Wuhan University, Wuhan, China.
Ophthalmic Physiol Opt. 2020 May;40(3):271-280. doi: 10.1111/opo.12683. Epub 2020 Mar 25.
To detect variants in 17 known potentially causative genes for non-syndromic myopia in 67 Tujia Chinese patients with early-onset high myopia (eo-HM).
DNA from 67 unrelated patients with early onset (<7 years old) high myopia (refraction error ≤ -6.00D or axial length > 26 mm) were subjected to whole-exome sequencing (WES). Variants in 17 candidate genes were analysed by multistep bioinformatics analysis. Subsequently, Sanger sequencing was used to verify identified candidate mutations and to assess available family members for co-segregation with myopia.
A multistep systematic analysis of variants in 17 potentially causative genes for eo-HM revealed four novel pathogenic mutations and three potential pathogenic mutations in 4 of 17 genes in 7 of 67 (10.4%) probands. The pathogenic group included one missense mutation (c.100G > C, p.Asp34His) and one splice donor mutation (c.989 + 1G >A) in ARR3, one missense mutation (c.995C > A, p.Thr332Lys) in NDUFAF7 and one novel frameshift mutation (c.726dupA, p.Arg243fs*140) in SLC39A5. The potential pathogenic group included two missense mutations (c.3266A > G, p.Tyr1089Cys; c.913G > A, p.Glu305Lys) in ZNF644 and one missense mutation (c.960T > A, p.His320Gln) in NDUFAF7. Sequence changes were confirmed by Sanger sequencing; all had an allele frequency <0.01 in the 1000G, EVS, ExAC and gnomAD databases. Additionally, both the pathogenic and potentially pathogenic mutations were predicted to be damaging by SIFT, Polyphen-2, PROVEAN, MutationTaster2, CADD and REVEL except the p.Tyr1089Cys and p.Glu305Lys changes were predicted to be neutral by PROVEAN.
Our research provides more evidence to support the hypothesis that mutations in ARR3, SLC39A5 and NDUFAF7 are disease-causing genes for eo-HM and broadens the eo-HM mutation spectrum among different ethnic groups. It also deepens understanding of the contributions of ARR3, SLC39A5, and NDUFAF7 to eo-HM.
在 67 名患有早发性高度近视（eo-HM）的土家族患者中，检测 17 个已知与非综合征性近视相关的潜在致病基因中的变异。
对 67 名无亲缘关系的早发性（<7 岁）高度近视患者（屈光度≤-6.00D 或眼轴长度>26mm）的 DNA 进行全外显子组测序（WES）。通过多步生物信息学分析分析 17 个候选基因中的变异。随后，使用 Sanger 测序验证鉴定的候选突变，并评估可获得的家族成员是否与近视共分离。
对 17 个可能导致 eo-HM 的潜在致病基因中的变异进行多步系统分析，在 67 名先证者中的 7 名（10.4%）的 4 个基因中发现了 4 个新的致病性突变和 3 个潜在致病性突变。致病组包括 ARR3 中的一个错义突变（c.100G>C，p.Asp34His）和一个剪接供体位点突变（c.989+1G>A）、NDUFAF7 中的一个错义突变（c.995C>A，p.Thr332Lys）和 SLC39A5 中的一个新的移码突变（c.726dupA，p.Arg243fs*140）。潜在致病组包括 ZNF644 中的两个错义突变（c.3266A>G，p.Tyr1089Cys；c.913G>A，p.Glu305Lys）和 NDUFAF7 中的一个错义突变（c.960T>A，p.His320Gln）。通过 Sanger 测序证实了序列变化；所有突变在 1000G、EVS、ExAC 和 gnomAD 数据库中的等位基因频率均<0.01。此外，除 p.Tyr1089Cys 和 p.Glu305Lys 变化被 PROVEAN 预测为中性外，SIFT、Polyphen-2、PROVEAN、MutationTaster2、CADD 和 REVEL 预测所有致病性和潜在致病性突变均为有害。
我们的研究为 ARR3、SLC39A5 和 NDUFAF7 中的突变是 eo-HM 的致病基因提供了更多证据，并拓宽了不同种族群体中 eo-HM 突变谱。它还加深了对 ARR3、SLC39A5 和 NDUFAF7 对 eo-HM 贡献的理解。
