Whole-exome sequencing identifies ALMS1, IQCB1, CNGA3 , and MYO7A mutations in patients with leber congenital amaurosis

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Human Mutation (Impact Factor: 5.05). 12/2011; 32(12):1450-9. DOI: 10.1002/humu.21587
Source: PubMed

ABSTRACT It has been well documented that mutations in the same retinal disease gene can result in different clinical phenotypes due to difference in the mutant allele and/or genetic background. To evaluate this, a set of consanguineous patient families with Leber congenital amaurosis (LCA) that do not carry mutations in known LCA disease genes was characterized through homozygosity mapping followed by targeted exon/whole-exome sequencing to identify genetic variations. Among these families, a total of five putative disease-causing mutations, including four novel alleles, were found for six families. These five mutations are located in four genes, ALMS1, IQCB1, CNGA3, and MYO7A. Therefore, in our LCA collection from Saudi Arabia, three of the 37 unassigned families carry mutations in retinal disease genes ALMS1, CNGA3, and MYO7A, which have not been previously associated with LCA, and 3 of the 37 carry novel mutations in IQCB1, which has been recently associated with LCA. Together with other reports, our results emphasize that the molecular heterogeneity underlying LCA, and likely other retinal diseases, may be highly complex. Thus, to obtain accurate diagnosis and gain a complete picture of the disease, it is essential to sequence a larger set of retinal disease genes and combine the clinical phenotype with molecular diagnosis.

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    • "This new phenomenon extends our understanding of genotype-phenotype correlations. How a mutated gene can cause a complex, extensive syndrome in one patient and isolated RP in another is currently not understood, but it is postulated to result from the complex interaction between genetic modifiers and environmental differences (Wang et al. 2011). One of the utilities of molecular information is to improve diagnostic accuracy when coupled with clinic information. "
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