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Muhammad Arif Nadeem Saqib, Ehsan Ullah, Falak Sher Khan, Giulia Venturini, Konstantinos Nikopoulos, Muhammad Ansar, Carlo Rivolta; Homozygosity Mapping and Disease Genes Screening in Pakistani Families with Inherited Retinal Dystrophies. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3292.
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Inherited retinal disorders result from the degeneration of cones, rods, or both, and are caused by mutations in more than 150 distinct genes. Depending on symptoms and their onset, disease progression, and/or the pattern of photoreceptor loss, these diseases are classified as retinitis pigmentosa, congenital stationary night blindness, Leber congenital amaurosis, cone or cone-rod dystrophies, etc. In this study, we analyzed 11 consanguineous Pakistani families with retinal dystrophies to identify the molecular causes of such diseases.
Homozygosity mapping was performed following DNA hybridization on single nucleotide polymorphism (SNP) arrays containing ~300,000 markers and the HomozygosityMapper software. Known genes in autozygous regions were screened for DNA variants by standard exon-PCR and Sanger sequencing.
Nine of the 11 analyzed families showed clear-cut homozygous regions encompassing genes known to cause inherited retinal dystrophies. Sequence analysis showed novel homozygous mutations in two families (c.2656C>T, p.L886F in RPGRIP1 and the IVS-1G>A splice variant in CNGB1) and previously-reported mutations in four families, including: c.448G>A (p.Glu150Lys) in RHO, c.G646A (p.R216X) in CNGB3, c.A3956C (p.H1019P) in GUCY2D, and IVS10-2A>G in PDE6A. No mutations were found in three families showing intervals of autozygosity comprising the genes RPE65, GNAT1, and KCNV2.
Homozygosity mapping is an appropriate approach to identify causative mutations in population where consanguineous marriages are common. Analysis of known genes and mutations provides an opportunity to directly correlate phenotype and genotype in individuals with hereditary retinal dystrophies.
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