title: High-frequency detection of deletions and variable rearrangements at the ornithine transcarbamylase (OTC) locus by oligonucleotide array CGH.
abstract: Ornithine transcarbamylase (OTC) deficiency is an X-linked inborn error of metabolism characterized by impaired synthesis of citrulline from carbamylphosphate and ornithine. Previously reported data suggest that only approximately 80% of OTC deficiency (OTCD) patients have a mutation identified by OTC gene sequencing. To elucidate the molecular etiology in patients with clinical signs of OTCD and negative OTC sequencing, we subjected their DNA to array comparative genomic hybridization (aCGH) using a custom-designed targeted 44k oligonucleotide array. Whenever possible, parental DNA was analyzed to determine the inheritance or to rule out copy number variants in the OTC locus. DNA samples from a total of 70 OTCD patients were analyzed. Forty-three patients (43/70 or 61.5%) were found to have disease-causing point mutations in the OTC gene. The remaining 27 patients (27/70 or 38.5%) showed normal sequencing results or failure to amplify all or part of the OTC gene. Among those patients, eleven (11/70 or 15.7%) were found to have deletions ranging from 4.5kb to 10.6Mb, all involving the OTC gene. Sixteen OTCD patients (16/70 or 22.8%) had normal sequencing and oligoarray results. Analysis of the deletions did not reveal shared breakpoints, suggesting that non-homologous end joining or a replication-based mechanism might be responsible for the formation of the observed rearrangements. In summary, we demonstrate that approximately half of the patients with negative OTC sequencing may have OTC gene deletions readily identifiable by the targeted oligonucleotide-based aCGH. Thus, the test should be considered in OTC sequencing-negative patients with classic symptoms of the disease.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Shchelochkov
authors.forename: Fang-Yuan
authors.initials: FY
authors.lastname: Li
authors.forename: Michael T
authors.initials: MT
authors.lastname: Geraghty
authors.forename: Renata C
authors.initials: RC
authors.lastname: Gallagher
authors.forename: Johan L
authors.initials: JL
authors.lastname: Van Hove
authors.forename: Uta
authors.initials: U
authors.lastname: Lichter-Konecki
authors.forename: Paul M
authors.initials: PM
authors.lastname: Fernhoff
authors.forename: Sara
authors.initials: S
authors.lastname: Copeland
authors.forename: Tyler
authors.initials: T
authors.lastname: Reimschisel
authors.forename: Stephen
authors.initials: S
authors.lastname: Cederbaum
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
authors.forename: A Craig
authors.initials: AC
authors.lastname: Chinault
authors.forename: Lee-Jun
authors.initials: LJ
authors.lastname: Wong
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D005260:Female; D017353:Gene Deletion; D015321:Gene Rearrangement; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D009954:Ornithine Carbamoyltransferase / Q000235:genetics* / Q000378:metabolism; D020163:Ornithine Carbamoyltransferase Deficiency Disease / Q000235:genetics*; D017354:Point Mutation; D016415:Sequence Alignment; D055815:Young Adult
chemical_list: D009954:Ornithine Carbamoyltransferase