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Michael B. Gorin, Samuel P. Strom, Yong-Qing Gao, Ariadna Martinez, Pei-Wen Chiang, Steven Nusinowitz, Debora B. Farber; Mutation Screening of 121 Individuals with Stargardt Disease. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4558.
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© ARVO (1962-2015); The Authors (2016-present)
The spectrum of mutations in Stargardt Disease (STGD) is exceptionally broad. Hundreds of rare or private variants disrupting the ATP-binding cassette transporter gene ABCA4 have been reported. We screened for mutations in ABCA4 and in three other genes associated with the STGD phenotype in 121 affected individuals.
Participants were comprehensively phenotyped as part of a natural history genotype-phenotype study. Mutation screening of ABCA4 was done by either Sanger sequencing or microarray genotyping (ASPER600). Whole exome sequencing was carried out for 10 cases negative by Sanger sequencing. Mutation screening by sequencing of PRPH2, ELOVL4 and VMD2, was also performed.
Two likely causal ABCA4 mutations were found in 60% of participants, while 25% had one. While most observed variants are previously described, 33 appear novel. The remaining 15% of participants have no observable variants in ABCA4. One such individual has a disease-causing mutation in ELOVL4. A total of 10 individuals in 8 families have PRPH2 mutations, including one compound heterozygote. In one family the proband has two mutant ABCA4 alleles, but also shares a disease-causing PRPH2 mutation with two affected, ABCA4-negative sibs. Two unrelated probands with PRPH2 mutations have either one or two ABCA4 mutations.
STGD may be more genetically heterogeneous than previously appreciated. PRPH2 mutations were identified in 6 pedigrees with uninformative family histories, while 2 probands reported the presence of retinal disease in a family member consistent with dominant inheritance. PRPH2 mutations must be considered in STGD cases with one or no ABCA4 mutations and, despite reported phenotypic overlap, ELOVL4 and VMD2 mutations do not appear to be a major contributors to the STGD phenotype. The excess of STGD individuals with a single ABCA4 mutation demands further explanation, for which we are evaluating 4 genetic models: 1) non-coding variation effecting ABCA4 splicing or expression; 2) digenic inheritance; 3) locus heterogeneity (as seen with PRPH2); 4) dominant ABCA4 mutations either de novo or partially penetrant. Exploring these models is the focus of ongoing efforts and will shed light on the genetic basis of STGD.
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