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Article

A Survey of Multigenic Protein-Altering Variant Frequency in Familial Exudative Vitreo-Retinopathy (FEVR) Patients by Targeted Sequencing of Seven FEVR-Linked Genes

1
Eye Research Institute, Rochester, MI 48309, USA
2
Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA
3
Associated Retinal Consultants LLC, Royal Oak, MI 48073, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Se Joon Woo and Dror Sharon
Genes 2022, 13(3), 495; https://doi.org/10.3390/genes13030495
Received: 16 June 2021 / Revised: 4 March 2022 / Accepted: 9 March 2022 / Published: 11 March 2022
(This article belongs to the Special Issue Study of Inherited Retinal Diseases)
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. View Full-Text
Keywords: FEVR; retinal disease; pediatric; inherited retinal disease; DNA sequencing; targeted sequencing; NGS; multigenic; protein variants FEVR; retinal disease; pediatric; inherited retinal disease; DNA sequencing; targeted sequencing; NGS; multigenic; protein variants
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MDPI and ACS Style

Cicerone, A.P.; Dailey, W.; Sun, M.; Santos, A.; Jeong, D.; Jones, L.; Koustas, K.; Drekh, M.; Schmitz, K.; Haque, N.; Felisky, J.A.; Guzman, A.E.; Mellert, K.; Trese, M.T.; Capone, A.; Drenser, K.A.; Mitton, K.P. A Survey of Multigenic Protein-Altering Variant Frequency in Familial Exudative Vitreo-Retinopathy (FEVR) Patients by Targeted Sequencing of Seven FEVR-Linked Genes. Genes 2022, 13, 495. https://doi.org/10.3390/genes13030495

AMA Style

Cicerone AP, Dailey W, Sun M, Santos A, Jeong D, Jones L, Koustas K, Drekh M, Schmitz K, Haque N, Felisky JA, Guzman AE, Mellert K, Trese MT, Capone A, Drenser KA, Mitton KP. A Survey of Multigenic Protein-Altering Variant Frequency in Familial Exudative Vitreo-Retinopathy (FEVR) Patients by Targeted Sequencing of Seven FEVR-Linked Genes. Genes. 2022; 13(3):495. https://doi.org/10.3390/genes13030495

Chicago/Turabian Style

Cicerone, Amanda P., Wendy Dailey, Michael Sun, Andrew Santos, Daeun Jeong, Lance Jones, Konstaninos Koustas, Mary Drekh, Keaton Schmitz, Naomi Haque, Jennifer A. Felisky, Alvaro E. Guzman, Kendra Mellert, Michael T. Trese, Antonio Capone, Kimberly A. Drenser, and Kenneth P. Mitton. 2022. "A Survey of Multigenic Protein-Altering Variant Frequency in Familial Exudative Vitreo-Retinopathy (FEVR) Patients by Targeted Sequencing of Seven FEVR-Linked Genes" Genes 13, no. 3: 495. https://doi.org/10.3390/genes13030495

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