Eye Research Institute, Rochester, MI 48309, USA.
Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA.
Genes (Basel). 2022 Mar 11;13(3):495. doi: 10.3390/genes13030495.
While Inherited Retinal Diseases (IRDs) are typically considered rare diseases, Familial Exudative Vitreo-Retinopathy (FEVR) and Norrie Disease (ND) are more rare than retinitis pigmentosa. We wanted to determine if multigenic protein-altering variants are common in FEVR subjects within a set of FEVR-related genes. The potential occurrence of protein-altering variants in two different genes has been documented in a very small percentage of patients, but potential multigenic contributions to FEVR remain unclear. Genes involved in these orphan pediatric retinal diseases are not universally included in available IRD targeted-sequencing panels, and cost is also a factor limiting multigenic-sequence-based testing for these rare conditions. To provide an accurate solution at lower cost, we developed a targeted-sequencing protocol that includes seven genes involved in Familial Exudative Vitreo-Retinopathy (FEVR) and Norrie disease. Seventy-six DNA samples from persons refered to clinic with possible FEVR and some close relatives were sequenced using a novel Oakland-ERI orphan pediatric retinal disease panel (version 2) providing 900 times average read coverage. The seven genes involved in FEVR/ND were: (ChrX), (Chr3); (Chr7); (Chr10), (Chr11), (Chr11), (Chr11). A total of 33 variants were found that alter protein sequence, with the following relative distribution: 13/33 (40%), 9/33 (27%), 6/33 (18%), ( 3/33 (9%), 1/33 (3%), 1/33 (3%). Most protein-altering variants, 85%, were found in three genes: , , and . Four previously known pathogenic variants were detected in five families and two unrelated individuals. Two novel, likely pathogenic variants were detected in one family (FZD4: Cys450ter), and a likely pathogenic frame shift termination variant was detected in one unrelated individual (LRP5: Ala919CysfsTer67). The average number of genes with protein-altering variants was greater in subjects with confirmed FEVR (1.46, = 30) compared to subjects confirmed unaffected by FEVR (0.95, = 20), ( = 0.009). Thirty-four percent of persons sequenced had digenic and trigenic protein-altering variants within this set of FEVR genes, which was much greater than expected in the general population (3.6%), as derived from GnomAD data. While the potential contributions to FEVR are not known for most of the variants in a multigenic context, the high multigenic frequency suggests that potential multigenic contributions to FEVR severity warrant future investigation. The targeted-sequencing format developed will support such exploration by reducing the testing cost to $250 (US) for seven genes and facilitating greater access to genetic testing for families with this very rare inherited retinal disease.
虽然遗传性视网膜疾病（IRDs）通常被认为是罕见疾病，但家族性渗出性玻璃体视网膜病变（FEVR）和 Norrie 病（ND）比色素性视网膜炎更为罕见。我们想确定在一组与 FEVR 相关的基因中，FEVR 患者是否常见多基因蛋白改变变体。在极少数患者中已经记录到两种不同基因中存在蛋白改变变体的潜在情况，但 FEVR 潜在的多基因贡献仍不清楚。这些孤儿儿科视网膜疾病相关的基因并非普遍包含在现有的 IRD 靶向测序面板中，并且成本也是限制这些罕见疾病进行多基因序列检测的一个因素。为了以更低的成本提供准确的解决方案，我们开发了一种靶向测序方案，其中包括七个与家族性渗出性玻璃体视网膜病变（FEVR）和 Norrie 病相关的基因。使用新型 Oakland-ERI 孤儿儿科视网膜疾病面板（版本 2）对 76 个来自可能患有 FEVR 并伴有一些近亲的人的 DNA 样本进行了测序，该面板提供了 900 倍的平均读长覆盖度。与 FEVR/ND 相关的七个基因是： （chrX）、 （chr3）； （chr7）； （chr10）、 （chr11）、 （chr11）、 （chr11）。总共发现了 33 种改变蛋白序列的变体，其相对分布如下： 13/33（40%）、9/33（27%）、6/33（18%）、（3/33（9%）、1/33（3%）、1/33（3%）。大多数蛋白改变变体（85%）存在于三个基因中： 、 和 。在五个家庭和两个无关个体中检测到四个先前已知的致病性变体。在一个家庭中检测到两个新的、可能的致病性变异（FZD4：Cys450ter），在一个无关个体中检测到一个可能的致病性移码终止变异（LRP5：Ala919CysfsTer67）。与未受 FEVR 影响的个体（0.95， = 20）相比，经证实患有 FEVR 的个体（1.46， = 30）的基因中具有蛋白改变变体的数量更多（ = 0.009）。在这个 FEVR 基因集中，34%的测序个体具有双基因和三基因蛋白改变变体，这比从 GnomAD 数据中得出的一般人群中的预期（3.6%）高得多。虽然在多基因背景下大多数变体的潜在贡献尚不清楚，但高频多基因表明，FEVR 严重程度的潜在多基因贡献值得进一步研究。开发的靶向测序格式将通过将七个基因的测试成本降低到 250 美元（美国），并为有这种非常罕见遗传性视网膜疾病的家庭提供更多的基因测试机会，从而支持这种探索。
