Pelizaeus-Merzbacher disease caused by a duplication-inverted triplication-duplication in chromosomal segments including the PLP1 region

Shimojima, Keiko; Mano, Toshiyuki; Kashiwagi, Masayuki; Tanabe, Takuya; Sugawara, Midori; Okamoto, Nobuhiko; Arai, Hiroshi; Yamamoto, Toshiyuki

doi:10.1016/j.ejmg.2012.02.013

Cited by 31 publications

(39 citation statements)

References 9 publications

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“…30,[44][45][46][47][48] In most cases, the triplicated segment is inverted relative to the tandem duplication, and this conformation is known as DUP-TRP/INV-DUP. Breakpoint analysis of six DUP-TRP-DUPs in our study revealed that half of the triplications are in direct orientation and half are inverted relative to the duplication (Table S7).…”

Section: Duplications With Common Breakpointsmentioning

confidence: 98%

Next-Generation Sequencing of Duplication CNVs Reveals that Most Are Tandem and Some Create Fusion Genes at Breakpoints

Newman

Hermetz

Weckselblatt

et al. 2015

The American Journal of Human Genetics

142

127

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Interpreting the genomic and phenotypic consequences of copy-number variation (CNV) is essential to understanding the etiology of genetic disorders. Whereas deletion CNVs lead obviously to haploinsufficiency, duplications might cause disease through triplosensitivity, gene disruption, or gene fusion at breakpoints. The mutational spectrum of duplications has been studied at certain loci, and in some cases these copy-number gains are complex chromosome rearrangements involving triplications and/or inversions. However, the organization of clinically relevant duplications throughout the genome has yet to be investigated on a large scale. Here we fine-mapped 184 germline duplications (14.7 kb-25.3 Mb; median 532 kb) ascertained from individuals referred for diagnostic cytogenetics testing. We performed next-generation sequencing (NGS) and whole-genome sequencing (WGS) to sequence 130 breakpoints from 112 subjects with 119 CNVs and found that most (83%) were tandem duplications in direct orientation. The remainder were triplications embedded within duplications (8.4%), adjacent duplications (4.2%), insertional translocations (2.5%), or other complex rearrangements (1.7%). Moreover, we predicted six in-frame fusion genes at sequenced duplication breakpoints; four gene fusions were formed by tandem duplications, one by two interconnected duplications, and one by duplication inserted at another locus. These unique fusion genes could be related to clinical phenotypes and warrant further study. Although most duplications are positioned head-to-tail adjacent to the original locus, those that are inverted, triplicated, or inserted can disrupt or fuse genes in a manner that might not be predicted by conventional copy-number assays. Therefore, interpreting the genetic consequences of duplication CNVs requires breakpoint-level analysis.

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Section: Duplications With Common Breakpointsmentioning

confidence: 98%

Next-Generation Sequencing of Duplication CNVs Reveals that Most Are Tandem and Some Create Fusion Genes at Breakpoints

Newman

Hermetz

Weckselblatt

et al. 2015

The American Journal of Human Genetics

142

127

View full text Add to dashboard Cite

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“…Type II triplications lie within larger duplications and may or may not involve SDs at breakpoints (Figure 3c). In most type II CNVs, the triplicated segment is inverted relative to the duplications, a structure known as DUP-TRP/INV-DUP (Figure 4) [69–73]. …”

Section: Complex Chromosome Rearrangementmentioning

confidence: 99%

Human Structural Variation: Mechanisms of Chromosome Rearrangements

2015

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Chromosome structural variation (SV) is a normal part of variation in the human genome, but some classes of SV can cause neurodevelopmental disorders. Analysis of the DNA sequence at SV breakpoints can reveal mutational mechanisms and risk factors for chromosome rearrangement. Large-scale SV breakpoint studies have become possible recently owing to advances in next-generation sequencing (NGS) including whole-genome sequencing (WGS). These findings have shed light on complex forms of SV such as triplications, inverted duplications, insertional translocations, and chromothripsis. Sequence-level breakpoint data resolve SV structure and determine how genes are disrupted, fused, and/or misregulated by breakpoints. Recent improvements in breakpoint sequencing have also revealed non-allelic homologous recombination (NAHR) between paralogous long interspersed nuclear element (LINE) or human endogenous retrovirus (HERV) repeats as a cause of deletions, duplications, and translocations. This review covers the genomic organization of simple and complex constitutional SVs, as well as the molecular mechanisms of their formation.

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“…Replication-based mechanisms with potential iterative template switches either coupled or not with non-homologous end joining (NHEJ) underlie the formation of these inverted triplications embedded in duplications, frequently consisting of, at least, two breakpoint junctions (jct1 and jct2) generated in one single event. 13 DUP-TRP/INV-DUP was reported in 20% of the MECP2 CNV gains at Xq28, 13 at the PLP1 locus at Xq22, 14,15 at VIPR2 at 7q36, 16 and at 15q13.3. 17 We investigated the mechanism underlying CGRs found in association with segmental AOH in five families.…”

Section: Introductionmentioning

confidence: 97%

Absence of Heterozygosity Due to Template Switching during Replicative Rearrangements

Carvalho

Pfundt

King

et al. 2015

The American Journal of Human Genetics

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We investigated complex genomic rearrangements (CGRs) consisting of triplication copy-number variants (CNVs) that were accompanied by extended regions of copy-number-neutral absence of heterozygosity (AOH) in subjects with multiple congenital abnormalities. Molecular analyses provided observational evidence that in humans, post-zygotically generated CGRs can lead to regional uniparental disomy (UPD) due to template switches between homologs versus sister chromatids by using microhomology to prime DNA replication-a prediction of the replicative repair model, MMBIR. Our findings suggest that replication-based mechanisms might underlie the formation of diverse types of genomic alterations (CGRs and AOH) implicated in constitutional disorders.

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Pelizaeus-Merzbacher disease caused by a duplication-inverted triplication-duplication in chromosomal segments including the PLP1 region

Cited by 31 publications

References 9 publications

Next-Generation Sequencing of Duplication CNVs Reveals that Most Are Tandem and Some Create Fusion Genes at Breakpoints

Next-Generation Sequencing of Duplication CNVs Reveals that Most Are Tandem and Some Create Fusion Genes at Breakpoints

Human Structural Variation: Mechanisms of Chromosome Rearrangements

Absence of Heterozygosity Due to Template Switching during Replicative Rearrangements

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