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Cecile Delettre, Maxime Hebrard, Francois Halloy, agathe roubertie, Christian Hamel, Guy Lenaers; New candidate genes for inherited optic atrophy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1356.
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Primary hereditary optic neuropathies comprise a group of disorders that are characterized by visual loss due to retinal ganglion cell death. The most common forms of optic neuropathy are Leber hereditary optic neuropathy (LHON) with mitochondrial transmission (OMIM 535000) and autosomal dominant optic atrophy (OMIM 165500). Autosomal recessive optic neuropathies are uncommon and are mostly observed in association with multisystem diseases. To identify novel candidate genes for inherited optic neuropathies we have undertaken whole exome sequencing (WES) in patients with syndromic or non syndromic optic atrophy without mutation in OPA1, OPA3, and mitochondrial DNA.
Families with recessive inheritance are selected and passed on 250k SNP chips. Homozygosity mapping was done using a homemade software name TASE. We the performed Whole Exome Sequencing on families.
To prioritise putative causative variants, we filtred using the 1000 Genomes (http://www.1000genomes.org/) and NHLBI Exome Sequencing Project (ESP: http//evsgs.washington.edu/EVS/) to exclude known variants and focused on those predicted to alter protein sequence. Potential candidates genes were confirmed by sequencing and co-segregation with available family members examined. Using this approach disease causing mutations were found in 3 families within 3 different genes not previously implicated in optic atrophy but within pathways relevant to mitochondrial function.
Combination of WES with traditional approaches, consistent with linkage analysis, has a greatest impact to discover new genes.
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