Abstract
BackgroundThe commonest genetic form of juvenile or early adult onset macular degeneration is Stargardt Disease (STGD) caused by recessive mutations in the gene ABCA4. However, high phenotypic and allelic heterogeneity and a small but non-trivial amount of locus heterogeneity currently impede conclusive molecular diagnosis in a significant proportion of cases.MethodsWe performed whole exome sequencing (WES) of nine putative Stargardt Disease probands and searched for potentially disease-causing genetic variants in previously identified retinal or macular dystrophy genes. Follow-up dideoxy sequencing was performed for confirmation and to screen for mutations in an additional set of affected individuals lacking a definitive molecular diagnosis.ResultsWhole exome sequencing revealed seven likely disease-causing variants across four genes, providing a confident genetic diagnosis in six previously uncharacterized participants. We identified four previously missed mutations in ABCA4 across three individuals. Likely disease-causing mutations in RDS/PRPH2, ELOVL, and CRB1 were also identified.ConclusionsOur findings highlight the enormous potential of whole exome sequencing in Stargardt Disease molecular diagnosis and research. WES adequately assayed all coding sequences and canonical splice sites of ABCA4 in this study. Additionally, WES enables the identification of disease-related alleles in other genes. This work highlights the importance of collecting parental genetic material for WES testing as the current knowledge of human genome variation limits the determination of causality between identified variants and disease. While larger sample sizes are required to establish the precision and accuracy of this type of testing, this study supports WES for inherited early onset macular degeneration disorders as an alternative to standard mutation screening techniques.
Highlights
The commonest genetic form of juvenile or early adult onset macular degeneration is Stargardt Disease (STGD) caused by recessive mutations in the gene ABCA4
While we do not limit the term “retinitis pigmentosa” to a phenotype caused by mutations in a single gene, there are those who believe STGD should be restricted to only those cases caused by ABCA4 mutations and “Stargardtlike” or juvenile macular dystrophy should be used for other genetic etiologies
The two individuals of African American descent had an increased proportion of novel variants, consistent with the higher levels of genetic heterogeneity in that sub-population. Both the total number of variants and proportion of which overlap a known polymorphism were tightly correlated with read depth and are within the expected limits based on other studies [23]
Summary
The commonest genetic form of juvenile or early adult onset macular degeneration is Stargardt Disease (STGD) caused by recessive mutations in the gene ABCA4. While each population appears to carry some founder mutations accounting for a significant proportion of disease alleles, hundreds of extremely rare or private variants have been identified [19]. This allelic heterogeneity hampers the viability of standard panel-based mutation screening techniques and has lead to the creation of an ABCA4 array designed to genotype over 600 individual DNA variants [19]. While this array is an effective screening tool, the high rate of private mutations in STGD prevents it from being a comprehensive solution
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