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H. V. Gudiseva, A. J. Karoukis, R. Aatre-Kesavamurthy, R. C. Caruso, S. Periasamy, I. M. MacDonald, P. Sieving, A. Villanueva, J. R. Heckenlively, R. Ayyagari; Molecular Basis of Disease in Patients With Retinal Dystrophies. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2166. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To determine the molecular genetic basis of retinal degeneration in 456 probands from clinically well characterized pedigrees.
Mutational analysis was carried out on 48 patients with autosomal recessive retinal degeneration (arRP), 266 with Stargardt macular dystrophy, 9 with LCA, 15 with dominant RP, 49 with dominant Stargardt-like macular dystrophy, 22 with pattern dystrophy and 19 with late-onset dominant macular degeneration. Patients with LCA, STGD1 and arRP were analyzed initially for known sequence changes by using an appropriate set of arrayed primer extension chips (ASPER). Mutations identified by this method were confirmed by di-deoxy sequencing. The complete coding sequence of ABCA4, ELOVL4, Bestrophin, EFEMP1, RDS, TIMP3 and CTRP5 were screened in patients with relevant phenotypes. Segregation analysis of identified mutations was studied in 55 parents/siblings.
Among the patients tested, two causative changes were found in 10 out of 48 probands with arRP, 4 of 9 with LCA and 112 of 266 with Stargardt macular dystrophy (STGD1). Among patients with dominant dystrophies, single causative changes were found in the RDS gene in 6 out of 22 patients, Bestrophin in 9 out of 21, the EFEMP1 gene in 1 out of 5, and ELOVL4 in 4 of 49 patients with dominant Stargardt-like macular dystrophy. Out of 19 patients with late-onset macular degeneration, 5 were found to have mutations in one of the genes tested. In addition, single causative mutations were detected in 3 out of 15 patients diagnosed with dominant retinitis pigmentosa (adRP).
Among the 456 probands screened, the molecular genetic basis of the disease was identified in 238. Sequence analysis of the coding region of the ABCA4 gene led to identification of novel changes in 15.4 % of patients tested. Screening ABCA4 gene by sequencing the coding region identified 2 or more disease-causative changes in 57% of patients compared to 46% found by screening only for known mutations in ABCA4. In the cohort of patients we tested, the molecular genetic basis of disease was identified in 37.8% of patients screened for mutations in recessive retinal disease genes and 24.4% of patients screened for mutations in dominant disease genes. Yet to be identified genes may be associated with the pathology in the patients with no causative mutations detected.
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