title: Identifying gene disruptions in novel balanced de novo constitutional translocations in childhood cancer patients by whole-genome sequencing.
abstract: OBJECTIVE
  We applied whole-genome sequencing (WGS) to children diagnosed with neoplasms and found to carry apparently balanced constitutional translocations to discover novel genic disruptions.
  
  
  METHODS
  We applied the structural variation (SV) calling programs CREST, BreakDancer, SV-STAT, and CGAP-CNV, and we developed an annotative filtering strategy to achieve nucleotide resolution at the translocations.
  
  
  RESULTS
  We identified the breakpoints for t(6;12)(p21.1;q24.31), disrupting HNF1A in a patient diagnosed with hepatic adenomas and maturity-onset diabetes of the young (MODY). Translocation as the disruptive event of HNF1A, a gene known to be involved in MODY3, has not been previously reported. In a subject with Hodgkin lymphoma and subsequent low-grade glioma, we identified t(5;18)(q35.1;q21.2), disrupting both SLIT3 and DCC, genes previously implicated in both glioma and lymphoma.
  
  
  CONCLUSIONS
  These examples suggest that implementing clinical WGS in the diagnostic workup of patients with novel but apparently balanced translocations may reveal unanticipated disruption of disease-associated genes and aid in prediction of the clinical phenotype.
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Deborah I
authors.initials: DI
authors.lastname: Ritter
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Haines
authors.affiliation: Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Cheung
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Caleb F
authors.initials: CF
authors.lastname: Davis
authors.affiliation: Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Ching C
authors.initials: CC
authors.lastname: Lau
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Berg
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Chester W
authors.identifier: http://orcid.org/0000-0003-2828-7616
authors.initials: CW
authors.lastname: Brown
authors.affiliation: Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Thompson
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Gibbs
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Plon
mesh_terms: D000236:Adenoma / Q000175:diagnosis / Q000235:genetics; D000328:Adult; D000367:Age Factors; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D056905:Chromosome Breakpoints; D002881:Chromosomes, Human, Pair 12; D002887:Chromosomes, Human, Pair 18; D002895:Chromosomes, Human, Pair 5; D002896:Chromosomes, Human, Pair 6; D000075389:DCC Receptor; D056915:DNA Copy Number Variations; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D015894:Genome, Human; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D054643:INDEL Mutation; D008113:Liver Neoplasms / Q000175:diagnosis / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000175:diagnosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D000075389:DCC Receptor; C501909:DCC protein, human; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; C498990:SLIT3 protein, human; D025521:Tumor Suppressor Proteins