title: Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity.
abstract: OBJECTIVE
  Our aim was to determine the molecular cause of autosomal dominant familial retinal arteriolar tortuosity (FRAT) in a family with three affected subjects.
  
  
  METHODS
  Ophthalmologic evaluation included determination of best-corrected visual acuity (BCVA), slit-lamp and dilated fundus inspection, applanation tonometry, fundus photography, and fluorescein retinal angiography (FA). Molecular methods included whole exome sequencing analysis and Sanger sequencing validation of putative causal mutation in DNA from affected individuals.
  
  
  RESULTS
  Typical signs of familial retinal arteriolar tortuosity were observed in all three patients. Exome sequencing identified a heterozygous c.1528G > A (p. Gly510Arg) mutation in COL4A1. Sanger sequencing confirmed that all three patients harbored the same pathogenetic mutation in COL4A1. The p. Gly510Arg variant in COL4A1 was absent in DNA from an available unaffected daughter, from a set of control alleles, and from publicly available databases.
  
  
  CONCLUSIONS
  The molecular basis of familial retinal arteriolar tortuosity was identified for the first time, thus expanding the human phenotypes linked to COL4A1 mutations. Interestingly, the COL4A1 p.Gly510Arg mutation has been previously identified in a family with HANAC (Hereditary Angiopathy with Nephropathy, Aneurysm and Cramps), a multisystemic disease featuring retinal arteriolar tortuosity. No cerebral, neurologic, renal, cardiac or vascular anomalies were recognized in the pedigree described here. These data indicate that identical mutations in COL4A1 can originate both eye-restricted and systemic phenotypes.
authors.affiliation: Genetics Department and Research Unit, Institute of Ophthalmology "Conde de Valenciana" and Biochemistry Department, Faculty of Medicine, National Autonomous University of Mexico (UNAM), Chimalpopoca 14, Col. Obrera, Mexico City, CP, 06800, Mexico, jczenteno@institutodeoftalmologia.org.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Zenteno
authors.forename: Jaume
authors.initials: J
authors.lastname: Crespí
authors.forename: Beatriz
authors.initials: B
authors.lastname: Buentello-Volante
authors.forename: Jose A
authors.initials: JA
authors.lastname: Buil
authors.forename: Francisca
authors.initials: F
authors.lastname: Bassaganyas
authors.forename: Jose I
authors.initials: JI
authors.lastname: Vela-Segarra
authors.forename: Jesus
authors.initials: J
authors.lastname: Diaz-Cascajosa
authors.forename: Maria T
authors.initials: MT
authors.lastname: Marieges
mesh_terms: D000293:Adolescent; D001160:Arterioles / Q000002:abnormalities / Q000473:pathology; D024141:Collagen Type IV / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D005451:Fluorescein Angiography; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D018810:Magnetic Resonance Angiography; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012161:Retinal Artery / Q000002:abnormalities* / Q000473:pathology; D012166:Retinal Hemorrhage / Q000235:genetics*; D058456:Retinal Telangiectasis / Q000235:genetics*; D014792:Visual Acuity; D055815:Young Adult
chemical_list: C547475:COL4A1 protein, human; D024141:Collagen Type IV