title: Molecular diagnostic testing by eyeGENE: analysis of patients with hereditary retinal dystrophy phenotypes involving central vision loss.
abstract: OBJECTIVE
  To analyze the genetic test results of probands referred to eyeGENE with a diagnosis of hereditary maculopathy.
  
  
  METHODS
  Patients with Best macular dystrophy (BMD), Doyne honeycomb retinal dystrophy (DHRD), Sorsby fundus dystrophy (SFD), or late-onset retinal degeneration (LORD) were screened for mutations in BEST1, EFEMP1, TIMP3, and CTRP5, respectively. Patients with pattern dystrophy (PD) were screened for mutations in PRPH2, BEST1, ELOVL4, CTRP5, and ABCA4; patients with cone-rod dystrophy (CRD) were screened for mutations in CRX, ABCA4, PRPH2, ELOVL4, and the c.2513G>A p.Arg838His variant in GUCY2D. Mutation analysis was performed by dideoxy sequencing. Impact of novel variants was evaluated using the computational tool PolyPhen.
  
  
  RESULTS
  Among the 213 unrelated patients, 38 had BMD, 26 DHRD, 74 PD, 8 SFD, 6 LORD, and 54 CRD; six had both PD and BMD, and one had no specific clinical diagnosis. BEST1 variants were identified in 25 BMD patients, five with novel variants of unknown significance (VUS). Among the five patients with VUS, one was diagnosed with both BMD and PD. A novel EFEMP1 variant was identified in one DHRD patient. TIMP3 novel variants were found in two SFD patients, PRPH2 variants in 14 PD patients, ABCA4 variants in four PD patients, and p.Arg838His GUCY2D mutation in six patients diagnosed with dominant CRD; one patient additionally had a CRX VUS. ABCA4 mutations were identified in 15 patients with recessive CRD.
  
  
  CONCLUSIONS
  Of the 213 samples, 55 patients (26%) had known causative mutations, and 13 (6%) patients had a VUS that was possibly pathogenic. Overall, selective screening for mutations in BEST1, PRPH2, and ABCA4 would likely yield the highest success rate in identifying the genetic basis for macular dystrophy phenotypes. Because of the overlap in phenotypes between BMD and PD, it would be beneficial to screen genes associated with both diseases.
authors.affiliation: Shiley Eye Center, University of California-San Diego, La Jolla, California, United States.
authors.forename: Akhila
authors.initials: A
authors.lastname: Alapati
authors.affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States.
authors.forename: Kerry
authors.initials: K
authors.lastname: Goetz
authors.affiliation: Shiley Eye Center, University of California-San Diego, La Jolla, California, United States.
authors.forename: John
authors.initials: J
authors.lastname: Suk
authors.affiliation: Shiley Eye Center, University of California-San Diego, La Jolla, California, United States.
authors.forename: Mili
authors.initials: M
authors.lastname: Navani
authors.affiliation: W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, United States.
authors.forename: Amani
authors.initials: A
authors.lastname: Al-Tarouti
authors.affiliation: W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, United States.
authors.forename: Thiran
authors.initials: T
authors.lastname: Jayasundera
authors.affiliation: Office of the Director, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States.
authors.forename: Santa J
authors.initials: SJ
authors.lastname: Tumminia
authors.affiliation: Shiley Eye Center, University of California-San Diego, La Jolla, California, United States.
authors.forename: Pauline
authors.initials: P
authors.lastname: Lee
authors.affiliation: Shiley Eye Center, University of California-San Diego, La Jolla, California, United States.
authors.forename: Radha
authors.initials: R
authors.lastname: Ayyagari
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015785:Eye Diseases, Hereditary / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D036281:Genetic Research; D005820:Genetic Testing / Q000379:methods*; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D009154:Mutation; D010641:Phenotype; D058499:Retinal Dystrophies / Q000235:genetics*; D014786:Vision Disorders / Q000209:etiology*; D014794:Visual Fields
keywords: eyeGENE; genetic testing; macular dystrophy
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