title: Constitutional mismatch repair-deficiency and whole-exome sequencing as the means of the rapid detection of the causative MSH6 defect.
abstract: BACKGROUND
  Cases of children with more than one type of cancer either diagnosed simultaneously or successively, rarely occur in pediatric oncology. A second malignant neoplasm may be caused by mutagenic effects of the treatment of the primary malignancy and/or may point towards an underlying genetic cancer susceptibility syndrome. One example of such a syndrome is constitutional mismatch repair-deficiency, (CMMR-D) which carries an increased risk of various tumors including childhood hematologic malignancies and Lynch syndrome associated tumors. Timely diagnosis of CMMR-D is crucial, since this diagnosis has implications for the entire family.
  
  
  METHODS
  We report the case of a 15-year-old girl who was born to consanguineous parents. At the age of 20 months she was diagnosed with a T-cell non-Hodgkin lymphoma. Treatment was given according to NHL-BFM 95. 12 years later, an invasive adenocarcinoma of the colon was surgically removed which relapsed shortly afterwards.
  
  
  METHODS
  Whole-exome sequencing of germline DNA was employed to rapidly detect the underlying mutation in this suspected CMMR-D patient.
  
  
  RESULTS
  After a short turnaround time of less than 3 weeks, the diagnosis of CMMR-D could be confirmed by the identification of a homozygous 29-bp deletion in MSH6 (exon 6), which was confirmed by independent methods.
  
  
  CONCLUSIONS
  We demonstrate that "bed-side" whole-exome sequencing is both feasible and cost-effective and may be the method of choice to rapidly uncover the genetical basis of (inherited) diseases.
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany.
authors.forename: J I
authors.initials: JI
authors.lastname: Hoell
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Gombert
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Ginzel
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Loth
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Landgraf
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Käfer
authors.affiliation: Department of Pediatrics, Division of Pediatric Oncology and Hematology, Municipal Clinics of Cologne, Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Streiter
authors.affiliation: Department of Pediatrics, Division of Pediatric Oncology and Hematology, Municipal Clinics of Cologne, Cologne, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Prokop
authors.affiliation: Department of Pediatrics, Division of Pediatric Oncology and Hematology, Municipal Clinics of Cologne, Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Weiss
authors.affiliation: Department of Computer Science, Bonn-Rhine-Sieg University of Applied Sciences, Sankt-Augustin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Thiele
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Borkhardt
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000235:genetics; D000293:Adolescent; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D002872:Chromosome Deletion; D003110:Colonic Neoplasms / Q000175:diagnosis / Q000235:genetics; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D003241:Consanguinity; D004268:DNA-Binding Proteins / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006689:Hodgkin Disease / Q000175:diagnosis / Q000235:genetics; D006720:Homozygote; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000235:genetics; D009378:Neoplasms, Multiple Primary / Q000175:diagnosis / Q000235:genetics; D009386:Neoplastic Syndromes, Hereditary / Q000175:diagnosis* / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein