Purchase this article with an account.
Alice E. Davidson, Panagiotis I. Sergouniotis, Donna S. Mackay, Zheng Li, Anthony T. Moore, Vincent Plagnol, Andrew R. Webster; Linkage Analysis, Homozygosity Mapping, And Exome Sequencing Of A Cohort Of Families With Autosomal Recessive Retinal Disease. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4522.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
To identify novel genetic causes of autosomal recessive retinal disease.
Over 120 families presenting to the inherited eye disease clinics at Moorfields Eye Hospital with presumed autosomal recessive forms of retinal disease were recruited as part of an ongoing study. Linkage analysis, with additional homozygosity mapping in those with consanguinity, was performed using Affymetrix single nucleotide polymorphism (SNP) arrays to prioritise specific genomic regions. Of these, twenty families were thought likely to be segregating novel causative genes and probands from each were selected for exome sequencing using an Agilent 38 Mb targeted exome capture array, and Illumina HighSeq2000 parallel sequencing.
To date, proven bi-allelic disease-causing variants have been detected in 7/20 patients investigated including; mutations in KCNJ13 proven to be a novel genetic causes of Leber Congenital Amaurosis (LCA) and mutations in PLA2G5 proven to cause benign fleck retina. Unexpectedly, 2/20 patients of known consanguineous ancestry were identified to harbor compound heterozygous mutations in genes previously known to be associated with their respective conditions: LCA (CRB1) and Familial Exudative Vitreoretinopathy (LRP5). Ongoing analysis in 2/20 patients is currently being performed to verify the genetic cause of their condition. Determining the causative variants among the background of nonpathogenic variation has not been possible, to date, in 10/20 families.
Exome sequencing is an efficient strategy for genetically dissecting autosomal recessive disease, particularly in combination with linkage analysis and homozygosity mapping; however present technology still does not allow the identification a molecular diagnosis in many instances.
This PDF is available to Subscribers Only