Identifying gene disruptions in novel balanced de novo constitutional translocations in childhood cancer patients by whole-genome sequencing.

TitleIdentifying gene disruptions in novel balanced de novo constitutional translocations in childhood cancer patients by whole-genome sequencing.
Publication TypeJournal Article
Year of Publication2015
AuthorsRitter, DI, Haines, K, Cheung, H, Davis, CF, Lau, CC, Berg, JS, Brown, CW, Thompson, PA, Gibbs, RA, Wheeler, DA, Plon, SE
JournalGenet Med
Volume17
Issue10
Pagination831-5
Date Published2015 Oct
ISSN1530-0366
KeywordsAdenoma, Adult, Age Factors, Base Sequence, Child, Child, Preschool, Chromosome Breakpoints, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 18, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 6, Diabetes Mellitus, Type 2, DNA Copy Number Variations, Female, Genetic Association Studies, Genome, Human, Genomics, High-Throughput Nucleotide Sequencing, Humans, INDEL Mutation, Liver Neoplasms, Male, Membrane Proteins, Molecular Sequence Data, Neoplasms, Polymorphism, Single Nucleotide, Receptors, Cell Surface, Translocation, Genetic, Tumor Suppressor Proteins
Abstract

PURPOSE: 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.

CONCLUSION: 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.

DOI10.1038/gim.2014.189
Alternate JournalGenet. Med.
PubMed ID25569436
PubMed Central IDPMC4496310
Grant ListK12 GM084897 / GM / NIGMS NIH HHS / United States
R01-CA138836 / CA / NCI NIH HHS / United States
R01 CA138836 / CA / NCI NIH HHS / United States
K12 GM084897-06 / GM / NIGMS NIH HHS / United States
T32 GM08307-22 / GM / NIGMS NIH HHS / United States
T15 LM007093 / LM / NLM NIH HHS / United States