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

ABSTRACT: We applied whole-genome sequencing (WGS) to children diagnosed with neoplasms and found to carry apparently balanced constitutional translocations to discover novel genic disruptions.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.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.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.

SUBMITTER: Ritter DI

PROVIDER: S-EPMC4496310 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

Ritter Deborah I DI Haines Katherine K Cheung Hannah H Davis Caleb F CF Lau Ching C CC Berg Jonathan S JS Brown Chester W CW Thompson Patrick A PA Gibbs Richard R Wheeler David A DA Plon Sharon E SE

Genetics in medicine : official journal of the American College of Medical Genetics 20150108 10

<h4>Purpose</h4>We applied whole-genome sequencing (WGS) to children diagnosed with neoplasms and found to carry apparently balanced constitutional translocations to discover novel genic disruptions.<h4>Methods</h4>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.<h4>Results</h4>We identified the breakpoints for t(6;12)(p21.1;q24.31), disrup ...[more]

PMID: 25569436

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Project description:Background: Balanced chromosomal aberrations, especially balanced translocations, can cause infertility, recurrent miscarriage or having chromosomally defective offspring. Preimplantation genetic testing for structural rearrangement (PGT-SR) has been widely implemented to improve the clinical outcomes by selecting euploid embryos for transfer, whereas embryos with balanced translocation karyotype were difficult to be distinguished by routine genetic techniques from those with a normal karyotype. Method: In this present study, we developed a clinically applicable method for reciprocal translocation carriers to reduce the risk of pregnancy loss. In the preclinical phase, we identified reciprocal translocation breakpoints in blood of translocation carriers by long-read Oxford Nanopore sequencing, followed by junction-spanning polymerase chain reaction (PCR) and Sanger sequencing. In the clinical phase of embryo diagnosis, aneuploidies and unbalanced translocations were screened by comprehensive chromosomal screening (CCS) with single nucleotide polymorphism (SNP) microarray, carrier embryos were diagnosed by junction-spanning PCR and family haplotype linkage analysis of the breakpoints region. Amniocentesis and cytogenetic analysis of fetuses in the second trimester were performed after embryo transfer to conform the results diagnosed by the presented method. Results: All the accurate reciprocal translocation breakpoints were effectively identified by Nanopore sequencing and confirmed by Sanger sequencing. Twelve embryos were biopsied and detected, the results of junction-spanning PCR and haplotype linkage analysis were consistent. In total, 12 biopsied blastocysts diagnosed to be euploid, in which 6 were aneuploid or unbalanced, three blastocysts were identified to be balanced translocation carriers and three to be normal karyotypes. Two euploid embryos were subsequently transferred back to patients and late prenatal karyotype analysis of amniotic fluid cells was performed. The outcomes diagnosed by the current approach were totally consistent with the fetal karyotypes. Conclusions: In summary, these investigations in our study illustrated that chromosomal reciprocal translocations in embryos can be accurately diagnosed. Long-read Nanopore sequencing and breakpoint analysis contributes to precisely evaluate the genetic risk of disrupted genes, and provides a way of selecting embryos with normal karyotype, especially for couples those without a reference.

Dataset Information

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

Publications

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

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