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Original article
Rare genetic variants in Tunisian Jewish patients suffering from age-related macular degeneration
  1. Eran Pras1,2,
  2. Dana Kristal3,
  3. Nadav Shoshany1,
  4. Dina Volodarsky4,
  5. Inna Vulih4,
  6. Gershon Celniker2,5,
  7. Ofer Isakov2,5,
  8. Noam Shomron2,5,
  9. Elon Pras2,6
  1. 1The Matlow's Ophthalmo-Genetics Laboratory, Department of Ophthalmology, Assaf-Harofeh Medical Center, Zerifin, Israel
  2. 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
  3. 3Department of Ophthalmology, Edith-Wolfson Medical Center, Holon, Israel
  4. 4Dyn Labs, Assaf-Harofeh Medical Center, Zerifin, Israel
  5. 5Functional Genomics Laboratory, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
  6. 6Danek Gartener Institute of Human Genetics, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel
  1. Correspondence to Dr Eran Pras, Department of Ophthalmology, “Assaf Harofeh” Medical Center, Zerifin, 70300, Israel; eranpras{at}gmail.com

Abstract

Purpose To explore the molecular basis of familial, early onset, age-related macular degeneration (AMD) with diverse phenotypes, using whole exome sequencing (WES).

Methods We performed WES on four patients (two sibs from two families) manifesting early-onset AMD and searched for disease-causing genetic variants in previously identified macular degeneration related genes. Validation studies of the variants included bioinformatics tools, segregation analysis of mutations within the families and mutation screening in an AMD cohort of patients.

Results The index patients were in their 50s when diagnosed and displayed a wide variety of clinical AMD presentations: from limited drusen in the posterior pole to multiple basal-laminar drusen extending peripherally. Severe visual impairment due to extensive geographic atrophy and/or choroidal-neovascularisation was common by the age of 75 years. Approximately, 400 000 genomic variants for each DNA sample were included in the downstream bioinformatics analysis, which ended in the discovery of two novel variants; in one family a single bp deletion was identified in the Hemicentin (HMCN1) gene (c.4162delC), whereas in the other, a missense variant (p.V412M) in the Complement Factor-I (CFI) gene was found. Screening for these variants in a cohort of patients with AMD identified another family with the CFI variant.

Conclusions This report uses WES to uncover rare genetic variants in AMD. A null-variant in HMCN1 has been identified in one AMD family, and a missense variant in CFI was discovered in two other families. These variants confirm the genetic complexity and significance of rare genetic variants in the pathogenesis of AMD.

  • AMD
  • HMCN1
  • Fibulin 6
  • CFI
  • Whole Exome Sequencing

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