title: Analysis of mRNA transcripts improves the success rate of molecular genetic testing in OTC deficiency.
abstract: BACKGROUND
  Ornithine transcarbamylase (OTC) deficiency is the most common inborn error of urea metabolism that can lead to hyperammonemic crises and orotic aciduria. To date, a total of 341 causative mutations within the OTC gene have been described. However, in about 20% of the patients with enzymatically confirmed OTC deficiency no mutation can be detected when sequencing of genomic DNA analyzing exons and adjacent intronic segments of the OTC gene is performed.
  
  
  METHODS
  Standard genomic DNA analysis of the OTC gene in five consecutive patients from five families revealed no mutation. Hence, liver tissue was obtained by needle sampling or open biopsy and RNA extracted from liver was analyzed.
  
  
  RESULTS
  Complex rearrangements of the OTC transcript (three insertions and two deletions) were found in all five patients.
  
  
  CONCLUSIONS
  In patients with a strong suspicion of OTC deficiency despite normal results of sequencing exonic regions of the OTC gene, characterization of liver OTC mRNA is highly effective in resolving the genotype. Liver tissue sampling by needle aspiration allows for both enzymatic analysis and RNA based diagnostics of OTC deficiency.
authors.affiliation: Universitätsklinikum Münster, Klinik und Poliklinik für Kinder- und Jugendmedizin, Albert-Schweitzer-Strasse 33, 48149 Münster, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Engel
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Nuoffer
authors.forename: Chris
authors.initials: C
authors.lastname: Mühlhausen
authors.forename: Vera
authors.initials: V
authors.lastname: Klaus
authors.forename: Carlo R
authors.initials: CR
authors.lastname: Largiadèr
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Tsiakas
authors.forename: René
authors.initials: R
authors.lastname: Santer
authors.forename: Bendicht
authors.initials: B
authors.lastname: Wermuth
authors.forename: Johannes
authors.initials: J
authors.lastname: Häberle
mesh_terms: D001483:Base Sequence; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D015997:Neonatal Screening / Q000379:methods; D009954:Ornithine Carbamoyltransferase / Q000032:analysis* / Q000235:genetics; D020163:Ornithine Carbamoyltransferase Deficiency Disease / Q000175:diagnosis* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis*; D012680:Sensitivity and Specificity
chemical_list: D012333:RNA, Messenger; D009954:Ornithine Carbamoyltransferase