title: Rare genetic variants in Tunisian Jewish patients suffering from age-related macular degeneration.
abstract: OBJECTIVE
  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.
authors.affiliation: The Matlow's Ophthalmo-Genetics Laboratory, Department of Ophthalmology, Assaf-Harofeh Medical Center, Zerifin, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Pras
authors.affiliation: Department of Ophthalmology, Edith-Wolfson Medical Center, Holon, Israel.
authors.forename: Dana
authors.initials: D
authors.lastname: Kristal
authors.affiliation: The Matlow's Ophthalmo-Genetics Laboratory, Department of Ophthalmology, Assaf-Harofeh Medical Center, Zerifin, Israel.
authors.forename: Nadav
authors.initials: N
authors.lastname: Shoshany
authors.affiliation: Dyn Labs, Assaf-Harofeh Medical Center, Zerifin, Israel.
authors.forename: Dina
authors.initials: D
authors.lastname: Volodarsky
authors.affiliation: Dyn Labs, Assaf-Harofeh Medical Center, Zerifin, Israel.
authors.forename: Inna
authors.initials: I
authors.lastname: Vulih
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Functional Genomics Laboratory, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Gershon
authors.initials: G
authors.lastname: Celniker
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Functional Genomics Laboratory, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Isakov
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Functional Genomics Laboratory, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Noam
authors.initials: N
authors.lastname: Shomron
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Danek Gartener Institute of Human Genetics, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Elon
authors.initials: E
authors.lastname: Pras
mesh_terms: D017668:Age of Onset; D001483:Base Sequence; D017244:Complement Factor I / Q000235:genetics*; D019295:Computational Biology; D059472:Exome / Q000235:genetics; D005820:Genetic Testing; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D007585:Jews / Q000235:genetics*; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology*; D008969:Molecular Sequence Data; D010641:Phenotype; D017422:Sequence Analysis, DNA; D014416:Tunisia
chemical_list: C488168:HMCN1 protein, human; D007136:Immunoglobulins; C493611:CFI protein, human; D017244:Complement Factor I
keywords: AMD; CFI; Fibulin 6; HMCN1; Whole Exome Sequencing