{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T17:38:43Z","timestamp":1778953123487,"version":"3.51.4"},"reference-count":23,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T00:00:00Z","timestamp":1646956800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Pediatric Retinal Research Foundation, Michigan, USA.","award":["1-2019"],"award-info":[{"award-number":["1-2019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>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: NDP (ChrX), CTNNB1 (Chr3); TSPAN12 (Chr7); KIF11 (Chr10), FZD4 (Chr11), LRP5 (Chr11), ZNF408 (Chr11). A total of 33 variants were found that alter protein sequence, with the following relative distribution: LRP5 13\/33 (40%), FZD4 9\/33 (27%), ZNF408 6\/33 (18%), (KIF11 3\/33 (9%), NDP 1\/33 (3%), CTNNB1 1\/33 (3%). Most protein-altering variants, 85%, were found in three genes: FZD4, LRP5, and ZNF408. 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, n = 30) compared to subjects confirmed unaffected by FEVR (0.95, n = 20), (p = 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.<\/jats:p>","DOI":"10.3390\/genes13030495","type":"journal-article","created":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T12:58:36Z","timestamp":1647003516000},"page":"495","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["A Survey of Multigenic Protein-Altering Variant Frequency in Familial Exudative Vitreo-Retinopathy (FEVR) Patients by Targeted Sequencing of Seven FEVR-Linked Genes"],"prefix":"10.3390","volume":"13","author":[{"given":"Amanda Petrelli","family":"Cicerone","sequence":"first","affiliation":[{"name":"Eye Research Institute, Rochester, MI 48309, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wendy","family":"Dailey","sequence":"additional","affiliation":[{"name":"Eye Research Institute, Rochester, MI 48309, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Sun","sequence":"additional","affiliation":[{"name":"Eye Research Institute, Rochester, MI 48309, USA"},{"name":"Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Santos","sequence":"additional","affiliation":[{"name":"Eye Research Institute, Rochester, MI 48309, USA"},{"name":"Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1493-8596","authenticated-orcid":false,"given":"Daeun","family":"Jeong","sequence":"additional","affiliation":[{"name":"Eye Research Institute, Rochester, MI 48309, USA"},{"name":"Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lance","family":"Jones","sequence":"additional","affiliation":[{"name":"Eye Research Institute, Rochester, MI 48309, USA"},{"name":"Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstaninos","family":"Koustas","sequence":"additional","affiliation":[{"name":"Eye Research Institute, Rochester, MI 48309, USA"},{"name":"Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary","family":"Drekh","sequence":"additional","affiliation":[{"name":"Eye Research Institute, Rochester, MI 48309, USA"},{"name":"Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keaton","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Eye Research Institute, Rochester, MI 48309, USA"},{"name":"Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naomi","family":"Haque","sequence":"additional","affiliation":[{"name":"Eye Research Institute, Rochester, MI 48309, USA"},{"name":"Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer A.","family":"Felisky","sequence":"additional","affiliation":[{"name":"Eye Research Institute, Rochester, MI 48309, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alvaro E.","family":"Guzman","sequence":"additional","affiliation":[{"name":"Eye Research Institute, Rochester, MI 48309, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kendra","family":"Mellert","sequence":"additional","affiliation":[{"name":"Associated Retinal Consultants LLC, Royal Oak, MI 48073, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael T.","family":"Trese","sequence":"additional","affiliation":[{"name":"Associated Retinal Consultants LLC, Royal Oak, MI 48073, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Capone","sequence":"additional","affiliation":[{"name":"Associated Retinal Consultants LLC, Royal Oak, MI 48073, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberly A.","family":"Drenser","sequence":"additional","affiliation":[{"name":"Associated Retinal Consultants LLC, Royal Oak, MI 48073, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4751-7440","authenticated-orcid":false,"given":"Kenneth P.","family":"Mitton","sequence":"additional","affiliation":[{"name":"Eye Research Institute, Rochester, MI 48309, USA"},{"name":"Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1001\/archophthalmol.2009.322","article-title":"Clinical Presentation and Genetic Correlation of Patients With Mutations Affecting the FZD4 Gene","volume":"127","author":"Drenser","year":"2009","journal-title":"Arch. 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