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Radha Ayyagari, Bhubanananda Sahu, Igor Kozak, Sangeetha Vishweswaraiah, Henry A. Ferreyra, Venkata Harini Gudiseva, Sandra Soares, Pauline Lee, S Amer Riazuddin, Terry Gaasterland; Genetic Analysis Of Simplex Retinal Dystrophy Patients Using Exome Sequencing. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4526.
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To determine the utility of exome analysis in identifying the genetic basis of retinal dystrophy (RD) in simplex cases.
Clinical evaluation of all affected individuals was carried out by complete ophthalmic examination including measurement of visual acuities, visual fields, fundus photography, fluorescein angiography, optical coherence tomography and collection of family history. Blood samples were collected from affected individuals, parents and unaffected siblings and/or offsprings. Exome capture was carried out using Nimblegen SeqCap EZ V2.0 probes and sequenced on Illumina HiSeq. Reads were mapped to reference hg19 using a tiered strategy we developed. SNP calling and annotation were carried out using published protocols. Potential causative variants in genes involved in RD were identified using specific filtering criteria. Presence of potential pathogenic variants detected was confirmed by dideoxy sequencing and their segregation was determined by analyzing additional family members including parents. Selected novel variants were analyzed in 100 ethnicity-matched controls.
Six unrelated individuals (5 males and one female) with no family history of retinal disease were diagnosed with RD. Their visual acuities ranged from 20/50 to light perception by age 50, visual fields were constricted, and retina showed severe degeneration. Exome analysis identified a known homozygous mutation in the DHDDS gene in one affected male. Three other male patients had novel and potentially pathogenic homozygous or compound heterozygous variants in either the DHDDS or ARL6 or USH2A genes. All these changes segregated with RD in their respective families. These patients had no additional homozygous or compound heterozygous causative changes in known retinal disease genes. Two remaining affected individuals had neither known causative mutations nor novel pathogenic changes in the homozygous or compound heterozygous state in genes associated with RD.
Screening known retinal disease genes using whole exome sequencing revealed either novel potentially pathogenic variants or known pathogenic mutations along with novel variants in four out of six patients with simplex RD. These findings suggest that private mutations in known retinal disease genes may underlie a significant proportion of simplex RD cases.
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