%0 Journal Article %J Genet Med %D 2015 %T Identifying gene disruptions in novel balanced de novo constitutional translocations in childhood cancer patients by whole-genome sequencing. %A Ritter, Deborah I %A Haines, Katherine %A Cheung, Hannah %A Davis, Caleb F %A Lau, Ching C %A Berg, Jonathan S %A Brown, Chester W %A Thompson, Patrick A %A Gibbs, Richard %A Wheeler, David A %A Plon, Sharon E %K Adenoma %K Adult %K Age Factors %K Base Sequence %K Child %K Child, Preschool %K Chromosome Breakpoints %K Chromosomes, Human, Pair 12 %K Chromosomes, Human, Pair 18 %K Chromosomes, Human, Pair 5 %K Chromosomes, Human, Pair 6 %K DCC Receptor %K Diabetes Mellitus, Type 2 %K DNA Copy Number Variations %K Female %K Genetic Association Studies %K Genome, Human %K Genomics %K High-Throughput Nucleotide Sequencing %K Humans %K INDEL Mutation %K Liver Neoplasms %K Male %K Membrane Proteins %K Molecular Sequence Data %K Neoplasms %K Polymorphism, Single Nucleotide %K Receptors, Cell Surface %K Translocation, Genetic %K Tumor Suppressor Proteins %X

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.

%B Genet Med %V 17 %P 831-5 %8 2015 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/25569436?dopt=Abstract %R 10.1038/gim.2014.189