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Fernanda Belga Ottoni Porto, Evan Jones, Renata Toscano Simões, Rui Chen, Justine Branch; c.2991+1655A>G CEP290 intronic mutation is a recurrent founder allele in Brazilian Individuals with Leber Congenital Amaurosis. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2761.
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The purpose of this study was to describe: the segregation of the c.2991+1655A>G CEP290 intronic mutation in a large non-consanguineous family with 7 affected individuals and 4 generations, from Pinheiro – Maranhão; identify blocks of homozygosity between individuals; describe the molecular diagnosis of additional 12 patients with Leber Congenital Amaurosis identified in the surrounding cities.
The proband was sequenced using a targeted capture panel including 224 known retinal disease genes. Next-generation sequencing (NGS) data was then aligned, processed and filtered against control datasets using an in-house custom pipeline. The mutation was validated through Sanger sequencing. DNA samples of the proband parents and two additional individuals affected in the pedigree were Sanger sequenced for the presence of the c.2991+1655A>G mutation. After confirming this mutation in these samples, they were genotyped using the whole-exome Illumina InfiniumCoreExome. The SNP report was filtered, sorted by chromosome, and used to infer homozygous blocks across each of these individuals. DNA samples of the 12 additional unrelated individuals in the surrounding cities and parents were collected and screened for the c.2991+1655A>G mutation.
The c.2991+1655A>G has been identified as homozygous in the proband and further segregated with the disease. Whole exome genotyping of the un-affected parents and affected grandmother’s first cousin identified roughly 86MB block of homozygousity surrounding this variant in the homozygous affected individuals. Without confirmation of consanguinity but the presumed hidden-consanguinity of this family and on the basis of the conserved 86MB linked to this pathogenic variant, we propose that the c.2991+1655A>G spread through the family and this region by a recent founder effect.
The c.2991+1655A>G allele represents a founder mutation in our population causing a severe form of LCA. The identification of this founder effect and subsequent mutation may improve genetic counseling and greatly simplify the molecular diagnosis of this relevant disease.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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