Copy-number variation is an important contributor to the genetic causality of inherited retinal degenerations.
Copy-number variation is an important contributor to the genetic causality of inherited retinal degenerations.
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DOI：
10.1038/gim.2016.158
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发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
Pierce EA
中科院分区：
文献类型：
--
作者：
Bujakowska KM;Fernandez-Godino R;Place E;Consugar M;Navarro-Gomez D;White J;Bedoukian EC;Zhu X;Xie HM;Gai X;Leroy BP;Pierce EA
尽管测序方面取得了重大进展，但目前的策略只能从基因角度解决约 55-60% 的遗传性视网膜变性 (IRD) 病例。这部分归因于已知 IRD 基因中难以捉摸的突变，这些突变不易被靶向下一代测序 (NGS) 或桑格测序方法识别。我们假设拷贝数变异 (CNV) 是 IRD 难以捉摸的遗传因果关系的主要原因。之前通过靶向 NGS 无法解决的 28 名患者接受了全基因组 SNP 和 CGH 阵列的研究。在 28 个家族中的 5 个中检测到 IRD 基因缺失，其中包括从头缺失。我们认为从头删除是通过非等位基因同源重组（NAHR）发生的，并且我们构建了具有重叠 IRD 基因的 NAHR 易发区域的基因组图谱。在这项研究中，我们还报告了一个由 SNRNP200 复合杂合突变引起的隐性视网膜色素变性的罕见病例，该基因通常与该疾病的显性形式相关。 CNV 作图极大地提高了 IRD 的遗传诊断率，在之前未解决的病例中检测到了 18% 的遗传因果关系。将搜索扩展到其他结构变异（SV）可能会证明对 IRD 遗传因果关系的贡献更大。
Despite substantial progress in sequencing, current strategies can genetically solve only about 55–60% of inherited retinal degeneration (IRD) cases. This can partially be attributed to elusive mutations in the known IRD genes, which are not easily identified by the targeted next-generation sequencing (NGS) or Sanger sequencing approaches. We hypothesized that copy number variations (CNVs) are a major contributor to the elusive genetic causality of IRDs. Twenty-eight patients, previously unsolved with a targeted NGS, were investigated with whole-genome SNP and CGH arrays. Deletions in the IRD genes were detected in five of twenty-eight families, including a de novo deletion. We suggest that the de novo deletion occurred through non-allelic homologous recombination (NAHR) and we constructed a genomic map of NAHR-prone regions with overlapping IRD genes. In this study we also report an unusual case of recessive retinitis pigmentosa due to compound heterozygous mutations in SNRNP200, a gene that is typically associated with the dominant form of this disease. CNV mapping substantially increased the genetic diagnostic rate of IRDs, detecting genetic causality in 18% of previously unsolved cases. Extending the search to other structural variations (SVs) will likely demonstrate an even higher contribution to genetic causality of IRDs.
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影响因子：
1.8
作者：
Carroll, Joseph;Rossi, Ethan A.;Porter, Jason;Neitz, Jay;Roorda, Austin;Williams, David R.;Neitz, Maureen
通讯作者：
Neitz, Maureen
影响因子：
3.5
作者：
McKie, AB;McHale, JC;Inglehearn, CF
通讯作者：
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8.8
作者：
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影响因子：
3.5
作者：
Chakarova, CF;Hims, MM;Bhattacharya, SS
通讯作者：
Bhattacharya, SS
影响因子：
9.8
作者：
Fromer, Menachem;Moran, Jennifer L.;Purcell, Shaun M.
通讯作者：
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