| Summary: | <p>Abstract</p> <p>Background</p> <p>Krabbe disease is an autosomal recessive lysosomal storage disorder caused by mutations in the <it>GALC</it> gene. The most common mutation in the Caucasian population is a 30-kb deletion of exons 11 through 17. There are few other reports of intragenic <it>GALC</it> deletions or duplications, due in part to difficulties detecting them.</p> <p>Methods and results</p> <p>We used gene-targeted array comparative genomic hybridization (CGH) to analyze the <it>GALC</it> gene in individuals with Krabbe disease in whom sequence analysis with 30-kb deletion analysis identified only one mutation. In our sample of 33 cases, traditional approaches failed to identify two pathogenic mutations in five (15.2%) individuals with confirmed Krabbe disease. The addition of array CGH deletion/duplication analysis to the genetic testing strategy led to the identification of a second pathogenic mutation in three (9.1%) of these five individuals. In all three cases, the deletion or duplication identified through array CGH was a novel <it>GALC</it> mutation, including the only reported duplication in the <it>GALC</it> gene, which would have been missed by traditional testing methodologies. We report these three cases in detail. The second mutation remains unknown in the remaining two individuals (6.1%), despite our full battery of testing.</p> <p>Conclusions</p> <p>Analysis of the <it>GALC</it> gene using array CGH deletion/duplication testing increased the two-mutation detection rate from 84.8% to 93.9% in affected individuals. Better mutation detection rates are important for improving molecular diagnosis of Krabbe disease, as well as for providing prenatal and carrier testing in family members.</p>
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