title: Targeted array CGH as a valuable molecular diagnostic approach: experience in the diagnosis of mitochondrial and metabolic disorders.
abstract: Oligonucleotide array-based comparative genomic hybridization (aCGH) targeted to coding exons of genes of interest has been proven to be a valuable diagnostic tool to complement with Sanger sequencing for the detection of large deletions/duplications. We have developed a custom designed oligonucleotide aCGH platform for this purpose. This array platform provides tiled coverage of the entire mitochondrial genome and high-density coverage of a set of nuclear genes involving mitochondrial and metabolic disorders and can be used to evaluate large deletions in targeted genes. A total of 1280 DNA samples from patients suspected of having mitochondrial or metabolic disorders were evaluated using this targeted aCGH. We detected 40 (3%) pathogenic large deletions in unrelated individuals, including 6 in genes responsible for mitochondrial DNA (mtDNA) depletion syndromes, 23 in urea cycle genes, 11 in metabolic and related genes. Deletion breakpoints have been confirmed in 31 cases by PCR and sequencing. The possible deletion mechanism has been discussed. These results illustrate the successful utilization of targeted aCGH to detect large deletions in nuclear and mitochondrial genomes. This technology is particularly useful as a complementary diagnostic test in the context of a recessive disease when only one mutant allele is found by sequencing. For female carriers of X-linked disorders, if sequencing analysis does not detect point mutations, targeted aCGH should be considered for the detection of large heterozygous deletions.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Hongli
authors.initials: H
authors.lastname: Zhan
authors.forename: Fang-Yuan
authors.initials: FY
authors.lastname: Li
authors.forename: Amber N
authors.initials: AN
authors.lastname: Pursley
authors.forename: Eric S
authors.initials: ES
authors.lastname: Schmitt
authors.forename: Lee-Jun
authors.initials: LJ
authors.lastname: Wong
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D019457:Chromosome Breakage; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D004272:DNA, Mitochondrial; D005260:Female; D017353:Gene Deletion; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008659:Metabolic Diseases / Q000175:diagnosis* / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000175:diagnosis* / Q000235:genetics*; D008969:Molecular Sequence Data; D009954:Ornithine Carbamoyltransferase / Q000235:genetics; D056806:Urea Cycle Disorders, Inborn / Q000235:genetics; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; D009954:Ornithine Carbamoyltransferase