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Logo of bmcmdBioMed Centralsearchsubmit a manuscriptregisterthis articleBMC Medical Genetics
 
BMC Med Genet. 2012; 13: 67.
Published online Aug 3, 2012. doi:  10.1186/1471-2350-13-67
PMCID: PMC3459799
Molecular diagnosis of putative Stargardt disease probands by exome sequencing
Samuel P Strom,corresponding author1 Yong-Qing Gao,1 Ariadna Martinez,1 Carolina Ortube,1 Zugen Chen,2 Stanley F Nelson,2 Steven Nusinowitz,1 Deborah B Farber,1 and Michael B Gorin1
1Jules Stein Eye Institute, University of California Los Angeles, 200 Stein Plaza, Los Angeles, CA, 90095, USA
2Department of Human Genetics, University of California Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA, 90095, USA
corresponding authorCorresponding author.
Samuel P Strom: strom/at/jsei.ucla.edu; Yong-Qing Gao: yonggao8963/at/gmail.com; Ariadna Martinez: amartinez/at/jsei.ucla.edu; Carolina Ortube: ortube/at/jsei.ucla.edu; Zugen Chen: zugenchen/at/mednet.ucla.edu; Stanley F Nelson: snelson/at/ucla.edu; Steven Nusinowitz: nusinowitz/at/jsei.ucla.edu; Deborah B Farber: farber/at/jsei.ucla.edu; Michael B Gorin: gorin/at/jsei.ucla.edu
Received April 11, 2012; Accepted July 25, 2012.
Abstract
Background
The 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.
Methods
We 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.
Results
Whole 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.
Conclusions
Our 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.
Keywords: Stargardt Disease, Macular Degeneration, Exome, Mutation Screening, Molecular Diagnostics, ABCA4, PRPH2
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