TY - JOUR
T1 - Late-Onset Autosomal Dominant Macular Degeneration Caused by Deletion of the CRX Gene
AU - Yahya, Samar
AU - Smith, Claire E. L.
AU - Poulter, James A.
AU - McKibbin, Martin
AU - Arno, Gavin
AU - Ellingford, Jamie
AU - Kämpjärvi, Kati
AU - Khan, Muhammad I.
AU - Cremers, Frans P. M.
AU - Hardcastle, Alison J.
AU - Castle, Bruce
AU - Steel, David H. W.
AU - Webster, Andrew R.
AU - Black, Graeme C.
AU - El-Asrag, Mohammed E.
AU - Ali, Manir
AU - Toomes, Carmel
AU - Inglehearn, Chris F.
PY - 2023/1
Y1 - 2023/1
N2 - PURPOSE: To characterize the phenotype observed in a case series with macular disease and determine the cause.DESIGN: Multicenter case series.PARTICIPANTS: Six families (7 patients) with sporadic or multiplex macular disease with onset at 20 to 78 years, and 1 patient with age-related macular degeneration.METHODS: Patients underwent ophthalmic examination; exome, genome, or targeted sequencing; and/or polymerase chain reaction (PCR) amplification of the breakpoint, followed by cloning and Sanger sequencing or direct Sanger sequencing.MAIN OUTCOME MEASURES: Clinical phenotypes, genomic findings, and a hypothesis explaining the mechanism underlying disease in these patients.RESULTS: All 8 cases carried the same deletion encompassing the genes TPRX1, CRX, and SULT2A1, which was absent from 382 control individuals screened by breakpoint PCR and 13 096 Clinical Genetics patients with a range of other inherited conditions screened by array comparative genomic hybridization. Microsatellite genotypes showed that these 7 families are not closely related, but genotypes immediately adjacent to the deletion breakpoints suggest they may share a distant common ancestor.CONCLUSIONS: Previous studies had found that carriers for a single defective CRX allele that was predicted to produce no functional CRX protein had a normal ocular phenotype. Here, we show that CRX whole-gene deletion in fact does cause a dominant late-onset macular disease.
AB - PURPOSE: To characterize the phenotype observed in a case series with macular disease and determine the cause.DESIGN: Multicenter case series.PARTICIPANTS: Six families (7 patients) with sporadic or multiplex macular disease with onset at 20 to 78 years, and 1 patient with age-related macular degeneration.METHODS: Patients underwent ophthalmic examination; exome, genome, or targeted sequencing; and/or polymerase chain reaction (PCR) amplification of the breakpoint, followed by cloning and Sanger sequencing or direct Sanger sequencing.MAIN OUTCOME MEASURES: Clinical phenotypes, genomic findings, and a hypothesis explaining the mechanism underlying disease in these patients.RESULTS: All 8 cases carried the same deletion encompassing the genes TPRX1, CRX, and SULT2A1, which was absent from 382 control individuals screened by breakpoint PCR and 13 096 Clinical Genetics patients with a range of other inherited conditions screened by array comparative genomic hybridization. Microsatellite genotypes showed that these 7 families are not closely related, but genotypes immediately adjacent to the deletion breakpoints suggest they may share a distant common ancestor.CONCLUSIONS: Previous studies had found that carriers for a single defective CRX allele that was predicted to produce no functional CRX protein had a normal ocular phenotype. Here, we show that CRX whole-gene deletion in fact does cause a dominant late-onset macular disease.
KW - Humans
KW - Comparative Genomic Hybridization
KW - Macular Degeneration/diagnosis
KW - Pedigree
KW - Phenotype
KW - Trans-Activators/genetics
KW - Homeodomain Proteins/genetics
UR - https://www.aaojournal.org/article/S0161-6420(22)00565-6/fulltext
U2 - 10.1016/j.ophtha.2022.07.023
DO - 10.1016/j.ophtha.2022.07.023
M3 - Article
C2 - 35934205
SN - 0161-6420
VL - 130
SP - 68
EP - 76
JO - Ophthalmology
JF - Ophthalmology
IS - 1
ER -