Breakpoint mapping by next generation sequencing reveals causative gene disruption in patients carrying apparently balanced chromosome rearrangements with intellectual deficiency and/or congenital malformations

Schluth-Bolard, Caroline; Labalme, Audrey; Cordier, Marie‐Pierre; Till, Marianne; Nadeau, Gwenaël; Tevissen, Hélène; Lesca, Gaëtan; Boutry‐Kryza, Nadia; Rossignol, Sylvie; Rocas, Delphine; Dubruc, Estelle; Edery, Patrick; Sanlaville, Damien

doi:10.1136/jmedgenet-2012-101351

Cited by 97 publications

(90 citation statements)

References 40 publications

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“…S7). In humans, numerous abnormal phenotypes, including intellectual disability and congenital anomalies, are caused by gene disruptions resulting from balanced rearrangements (Fruhmesser et al 2013;Schluth-Bolard et al 2013;Moyses-Oliveira et al 2015;Schneider et al 2015). This would occur in 6% of de novo reciprocal translocations and 9% of de novo inversions, but these events are detrimental and therefore remain rare in the population.…”

Section: Discussionmentioning

confidence: 99%

Reconstruction of ancestral chromosome architecture and gene repertoire reveals principles of genome evolution in a model yeast genus

et al. 2016

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Reconstructing genome history is complex but necessary to reveal quantitative principles governing genome evolution. Such reconstruction requires recapitulating into a single evolutionary framework the evolution of genome architecture and gene repertoire. Here, we reconstructed the genome history of the genus Lachancea that appeared to cover a continuous evolutionary range from closely related to more diverged yeast species. Our approach integrated the generation of a high-quality genome data set; the development of AnChro, a new algorithm for reconstructing ancestral genome architecture; and a comprehensive analysis of gene repertoire evolution. We found that the ancestral genome of the genus Lachancea contained eight chromosomes and about 5173 protein-coding genes. Moreover, we characterized 24 horizontal gene transfers and 159 putative gene creation events that punctuated species diversification. We retraced all chromosomal rearrangements, including gene losses, gene duplications, chromosomal inversions and translocations at single gene resolution. Gene duplications outnumbered losses and balanced rearrangements with 1503, 929, and 423 events, respectively. Gene content variations between extant species are mainly driven by differential gene losses, while gene duplications remained globally constant in all lineages. Remarkably, we discovered that balanced chromosomal rearrangements could be responsible for up to 14% of all gene losses by disrupting genes at their breakpoints. Finally, we found that nonsynonymous substitutions reached fixation at a coordinated pace with chromosomal inversions, translocations, and duplications, but not deletions. Overall, we provide a granular view of genome evolution within an entire eukaryotic genus, linking gene content, chromosome rearrangements, and protein divergence into a single evolutionary framework.

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Section: Discussionmentioning

confidence: 99%

Reconstruction of ancestral chromosome architecture and gene repertoire reveals principles of genome evolution in a model yeast genus

et al. 2016

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“…Translocations can exert phenotypic effects either because of copy number changes in dosage-sensitive genes within the chromosome regions involved in the translocation or because of the disruption of genes at one or more of the breakpoints [Schluth-Bolard et al, 2013]. In the present cases, we hypothesized that it was less likely that gene disruption at the breakpoint had a significant contribution compared to the relative dosage effects caused by inheritance of a derivative chromosome.…”

Section: Discussionmentioning

confidence: 73%

Unbalanced Translocations Involving Chromosome Region 10q25.3q26.3 in Patients with Intellectual Disability and Complex Phenotypes

Hryshchenko

Bychkova²,

Tavokina³

et al. 2014

Cytogenet Genome Res

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We describe 2 Ukrainian families with unbalanced reciprocal translocations (RTs) involving the distal part of chromosome 10q. In both families, the fathers were healthy carriers of the RT. Two affected patients from the first family had an ∼2.3-Mb loss at 10q26.3 and an ∼25-Mb gain at 2q35qter, and the patient from the other family had an ∼12.5-Mb loss at 5p15.2pter and an ∼18-Mb gain at 10q25.3q26.3. We assume that intellectual disability (ID) in association with congenital anomalies observed in our patients was the result of the cumulative effect of both gains and losses of the chromosomal regions involved in each translocation. Comparison of the sizes of the deleted and duplicated segments in our families as well as in other published families with translocations affecting the distal part of 10q showed that generally deletions seem to be ∼2 times more harmful than duplications of the same size. The data obtained here may contribute to improve the diagnosis and genetic counseling of families with similar chromosomal imbalances.

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“…Previous work has shown that paired-end mapping or mate pair sequencing has unprecedented resolution for the detection of SV breakpoints of balanced genomic rearrangements in patients with ID/MCA and may thus be a valuable tool for diagnostic implementation. [16][17][18][19][20][21][22][23] Here we made a systematic comparison between mate pair sequencing versus array CGH and karyotyping. As a first important conclusion from this work, we demonstrate that all types of pathogenic SVs previously found with array CGH or karyotyping could also be found using a combined strength of the cluster and DOC signatures of mate pair sequencing.…”

Section: Discussionmentioning

confidence: 99%

“…Korbel et al 15 were the first to use NGS to map structural variations in the human genome, and several other groups have used this technique to finemap the breakpoints of specific structural aberrations (mostly apparently balanced chromosomal aberrations) in patients with ID/MCA. [16][17][18][19][20][21][22][23] Therefore, the technique has proven its usability in characterizing individual SVs. Here we describe the first systematic comparison between mate pair sequencing, genomic microarrays and karyotyping in a large cohort of ID/MCA patients referred to our diagnostic departments.…”

Section: Introductionmentioning

confidence: 99%

Mate pair sequencing for the detection of chromosomal aberrations in patients with intellectual disability and congenital malformations

et al. 2013

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Recently, microarrays have replaced karyotyping as a first tier test in patients with idiopathic intellectual disability and/or multiple congenital abnormalities (ID/MCA) in many laboratories. Although in about 14-18% of such patients, DNA copy-number variants (CNVs) with clinical significance can be detected, microarrays have the disadvantage of missing balanced rearrangements, as well as providing no information about the genomic architecture of structural variants (SVs) like duplications and complex rearrangements. Such information could possibly lead to a better interpretation of the clinical significance of the SV. In this study, the clinical use of mate pair next-generation sequencing was evaluated for the detection and further characterization of structural variants within the genomes of 50 ID/MCA patients. Thirty of these patients carried a chromosomal aberration that was previously detected by array CGH or karyotyping and suspected to be pathogenic. In the remaining 20 patients no causal SVs were found and only benign aberrations were detected by conventional techniques. Combined cluster and coverage analysis of the mate pair data allowed precise breakpoint detection and further refinement of previously identified balanced and (complex) unbalanced aberrations, pinpointing the causal gene for some patients. We conclude that mate pair sequencing is a powerful technology that can provide rapid and unequivocal characterization of unbalanced and balanced SVs in patient genomes and can be essential for the clinical interpretation of some SVs.

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Breakpoint mapping by next generation sequencing reveals causative gene disruption in patients carrying apparently balanced chromosome rearrangements with intellectual deficiency and/or congenital malformations

Cited by 97 publications

References 40 publications

Reconstruction of ancestral chromosome architecture and gene repertoire reveals principles of genome evolution in a model yeast genus

Reconstruction of ancestral chromosome architecture and gene repertoire reveals principles of genome evolution in a model yeast genus

Unbalanced Translocations Involving Chromosome Region 10q25.3q26.3 in Patients with Intellectual Disability and Complex Phenotypes

Mate pair sequencing for the detection of chromosomal aberrations in patients with intellectual disability and congenital malformations

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