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John Suk, Akhila Alapati, Kerry Goetz, Santa Tumminia, Radha Ayyagari, ; Molecular diagnostic testing by eyeGENE®: Analysis of patients with hereditary maculopathy and/or Cone Rod Dystrophy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1359.
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© ARVO (1962-2015); The Authors (2016-present)
Analyze 214 probands with a diagnosis of hereditary maculopathy and/or cone-Rod dystrophy (CRD) referred to eyeGENE® for molecular diagnostic testing.
Thirty nine patients with a clinical diagnosis of Best’s macular degeneration (BMD), 26 with Doyne’s Honey Comb dystrophy (DHRD), 9 with Sorsby’s fundus dystrophy (SFD), and 6 with late-onset retinal degeneration (LORD) were screened for mutations in BEST1, EFEMP1, TIMP3, and CTRP5 genes respectively. In addition, 74 patients with a diagnosis of pattern dystrophy alone and 6 with both pattern dystrophy and BMD were screened for mutation(s) in one or more of the following genes: RDS, BEST1, ELOVL4 and ABCA4. Furthermore, 54 patients with a diagnosis of CRD were screened for mutations in one or more of the following: CRX, ABCA4, RDS, ELOVL4 genes and GUCY2D codon 838. Mutation analysis was carried out by PCR and dideoxy sequencing. Impact of novel variants was evaluated using PolyPhen.
Of the 39 patients with BMD, 24 carry a known mutation and 1 carries a variant of unknown significance (VUS) in BEST1. Of the 26 patients with DHRD, 2 have a known mutation and one has a novel VUS in EFEMP1. Among the 9 patients with SFD, 3 have a known mutation in TIMP3. None with LORD carry causative mutations in CTRP5. All 80 patients with pattern dystrophy were screened for mutations in RDS, 10 were additionally screened for ABCA4, 5 for ELOVL4, 1 for CTRP5, and 6 for BEST1. Twelve of these patients carry a known heterozygous mutation, 1 has a heterozygous VUS, and another has 2 known heterozygous mutations in the RDS gene while one patient has a VUS in BEST1. Three patients have known causative mutations in ABCA4. Of the 54 CRD patients, 42 have recessive mutations and 12 have dominant CRD. Of the 42 recessive CRD patients, 1 has a known GUCY2D codon 838 mutation in the homozygous state, and 17 have known mutations or VUS in the homozygous or compound heterozygous state in ABCA4. Of the 12 patients with dominant CRD, 5 have a known GUCY2D codon 838 mutation. One of these five patients also has a VUS in CRX.
Molecular diagnostic testing provided by eyeGENE® for inherited maculopathies identified the underlying cause of disease in ~33% of referred cases. These data indicate that the candidate gene approach only has a limited ability for identifying the genetic basis for maculopathies and/or CRD.
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