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samar Yahya, Claire Smith, James Poulter, Martin McKibbin, Gavin Arno, Jamie Ellingford, Andrew Webster, Graeme Black, Manir Ali, Carmel Toomes, Chris Inglehearn; A founder allele deleting CRX causes late-onset macular disease by haploinsufficiency. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1536.
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To characterise the phenotype in eight cases with macular disease and determine the cause and molecular mechanism underpinning their condition.
Patients underwent ophthalmic examination and probands from each family were subject to exome or genome sequencing, and PCR amplification of the breakpoint followed by cloning and Sanger sequencing or direct Sanger sequencing. Microsatellites in or near the CRX locus were genotyped for haplotype analysis.
All eight cases carry the same heterozygous 126 kb deletion encompassing TPRX1, CRX and SULT2A1. 294 base pairs of sequence at each end of the deletion is 78% identical, corresponding to Alu repeats, suggesting these have driven non-allelic homologous recombination (NAHR) to create this deletion. The deletion was absent from 382 controls screened by breakpoint PCR and 13,096 Clinical Genetics patients with a range of inherited conditions screened by array CGH. The Database of Genomic Variants highlights two potentially similar deletions in a study of 29,084 patients with developmental disorders, though precise breakpoints are unclear. Microsatellite genotypes suggest that the seven families studied herein are not closely related, but SNP genotypes immediately adjacent to the breakpoints point to a distant ancestral founder.
Previous reports found that heterozygous putative CRX null alleles were associated with a normal ocular phenotype, implying loss of function of one copy of CRX is tolerated. However, we now show that CRX whole-gene deletion causes a dominant macular disease with late onset, proving that CRX haploinsufficiency causes retinal dystrophy. Previous reports of haploinsufficiency in asymptomatic carriers could be the result of variable expressivity, non-penetrance in younger carriers, or a relatively mild phenotype that was overlooked. Since heterozygous deletions of this size may be difficult to detect, and given the previous published suggestion that heterozygous CRX null alleles do not cause retinal disease, this variant may have been overlooked in previous genetic screens.
This is a 2021 ARVO Annual Meeting abstract.
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