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Lorah T Perlee, Robert Vitti; A novel structural variant in VIEW1 neovascular age-related macular degeneration (AMD) patients. Invest. Ophthalmol. Vis. Sci. 2017;58(8):894.
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© ARVO (1962-2015); The Authors (2016-present)
Variants in Complement Factor H (CFH), including Y402H and the rare mutation R1210C are known risk alleles for advanced AMD. Incomplete penetrance suggests other genetic risk factors and/or additional environmental contributors to disease risk and severity. In this retrospective ad-hoc analysis, whole genome sequencing was performed on a select subgroup of AMD patients enrolled in the VIEW1 study to determine if additional genetic structural variation at the Regulators of Complement Activation (RCA) locus on chromosome 1 involving the CFH-related (CFHR) genes might explain why patients lacking the major risk alleles developed advanced AMD.
The samples surveyed lacked the major disease susceptibility alleles at CFH, ARMS2 and C3 and included 1 patient sample heterozygous for the R1210C mutation. Sequencing libraries were prepared using Illumina TruSeq Nano DNA library prep and sequenced on an Illumina HiSeq X Sequencer. Fragments were aligned using Isaaac Aligner and variant caller software. Copy number analysis was conducted using Control-FREEC and structural variants were identified using Manta structural variant caller. Average sequencing read length was 150bp and > 95% of sequenced bases achieved a 30X coverage.
In addition to the known CFHR3/CFHR1 deletions in this region, paired end analysis identified a structural variation detected a 9.2kb inversion containing exon 1 of the CFHR3 gene in having8 of the 11 patients devoid of the major AMD risk alleles and in the one patient harboring the CHF R1210C mutation. Samples homozygous for the CFH Y402H risk variant (H1/H1 haplotype) did not contain the CFHR3 exon 1 inversion..
The presence of a novel shared structural variant in CFHR3, a key regulatory protein associated with maintaining homeostasis of the alternative complement pathway (AP), was identified in neovascular AMD patients. These finding are intriguing and could suggest that the increased susceptibility associated with disease in patients lacking the known major risk CHF alleles might be influenced by AP dysregulation conferred by genetic variations in CFHR proteins that modulate CFH activity.
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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