Double complex mutations involving<i>F8</i>and<i>FUNDC2</i>caused by distinct break-induced replication

Sheen, Campbell R.; Jewell, Ursula R.; Morris, Christine M.; Brennan, Stephen O.; Férec, Claude; George, Peter M.; Smith, Mark; Chen, Jian‐Min

doi:10.1002/humu.20591

Cited by 56 publications

(60 citation statements)

References 47 publications

(48 reference statements)

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“…In such cases, the DNA repair mechanism is not always a simple event. Several groups recently reported complex rearrangements that at first glance seem to be generated in a mechanistically simple way but after detailed molecular analysis revealed more complex rearrangements potentially due to alternative DNA repair mechanisms (Balciuniene et al 2007;Gotter et al 2007;Potocki et al 2007;Sheen et al 2007) or replication errors ).…”

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confidence: 99%

Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair

Bauters¹,

Esch²,

Friez³

et al. 2008

Genome Res.

122

124

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Recurrent submicroscopic genomic copy number changes are the result of nonallelic homologous recombination (NAHR). Nonrecurrent aberrations, however, can result from different nonexclusive recombination-repair mechanisms. We previously described small microduplications at Xq28 containing MECP2 in four male patients with a severe neurological phenotype. Here, we report on the fine-mapping and breakpoint analysis of 16 unique microduplications. The size of the overlapping copy number changes varies between 0.3 and 2.3 Mb, and FISH analysis on three patients demonstrated a tandem orientation. Although eight of the 32 breakpoint regions coincide with low-copy repeats, none of the duplications are the result of NAHR. Bioinformatics analysis of the breakpoint regions demonstrated a 2.5-fold higher frequency of Alu interspersed repeats as compared with control regions, as well as a very high GC content (53%). Unexpectedly, we obtained the junction in only one patient by long-range PCR, which revealed nonhomologous end joining as the mechanism. Breakpoint analysis in two other patients by inverse PCR and subsequent array comparative genomic hybridization analysis demonstrated the presence of a second duplicated region more telomeric at Xq28, of which one copy was inserted in between the duplicated MECP2 regions. These data suggest a two-step mechanism in which part of Xq28 is first inserted near the MECP2 locus, followed by breakage-induced replication with strand invasion of the normal sister chromatid. Our results indicate that the mechanism by which copy number changes occur in regions with a complex genomic architecture can yield complex rearrangements.

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mentioning

confidence: 99%

Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair

Bauters¹,

Esch²,

Friez³

et al. 2008

Genome Res.

122

124

View full text Add to dashboard Cite

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“…18,19 SRS models have been proposed to explain the origin of complex genomic rearrangements involving deletions seen in a small but significant fraction of cystic fibrosis (Ϸ1.5% of known CFTR gene lesions) and hemophilia A patients. 35,36 For the complex double deletion described in the present study, we suggest a mutational mechanism invoking SRS in trans during DNA replication, which features annealing of single-stranded nascent leadingstrand DNA to lagging strand DNA with minimal homology.…”

Section: Discussionmentioning

confidence: 75%

A Complex Double Deletion in LMNA Underlies Progressive Cardiac Conduction Disease, Atrial Arrhythmias, and Sudden Death

Marsman

Bardai

Postma

et al. 2011

Circ Cardiovasc Genet

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Background— Cardiac conduction disease is a clinically and genetically heterogeneous disorder characterized by defects in electrical impulse generation and conduction and is associated with sudden cardiac death. Methods and Results— We studied a 4-generation family with autosomal dominant progressive cardiac conduction disease, including atrioventricular conduction block and sinus bradycardia, atrial arrhythmias, and sudden death. Genome-wide linkage analysis mapped the disease locus to chromosome 1p22-q21. Multiplex ligation-dependent probe amplification analysis of the LMNA gene, which encodes the nuclear-envelope protein lamin A/C, revealed a novel gene rearrangement involving a 24-bp inversion flanked by a 3.8-kb deletion upstream and a 7.8-kb deletion downstream. The presence of short inverted sequence homologies at the breakpoint junctions suggested a mutational event involving serial replication slippage in trans during DNA replication. Conclusions— We identified for the first time a complex LMNA gene rearrangement involving a double deletion in a 4-generation Dutch family with progressive conduction system disease. Our findings underscore the fact that if conventional polymerase chain reaction–based direct sequencing approaches for LMNA analysis are negative in suggestive pedigrees, mutation detection techniques capable of detecting gross genomic lesions involving deletions and insertions should be considered.

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“…An example of transposition of a large fragment from a distant site into the recombination site was reported in the coagulation factor F8 gene located on chromosome Xq28, and the 263-kb duplicated region was shown to have originated 5.2 Mb apart from the inserted site. 28 These suggest that the insertion of a large genomic fragment into a far distant region can be a cause of disease.…”

Section: Discussionmentioning

confidence: 99%

Insertion of the IL1RAPL1 gene into the duplication junction of the dystrophin gene

et al. 2009

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Duplications of one or more exons of the dystrophin gene are the second most common mutation in dystrophinopathies. Even though duplications are suggested to occur with greater complexity than thought earlier, they have been considered an intragenic event. Here, we report the insertion of a part of the IL1RAPL1 (interleukin-1 receptor accessory protein-like 1) gene into the duplication junction site. When the actual exon junction was examined in 15 duplication mutations in the dystrophin gene by analyzing dystrophin mRNA, one patient was found to have an unknown 621 bp insertion at the junction of duplication of exons from 56 to 62. Unexpectedly, the inserted sequence was found completely identical to sequences of exons 3-5 of the IL1RAPL1 gene that is nearly 100 kb distal from the dystrophin gene. Accordingly, the insertion of IL1RAPL1 exons 3-5 between dystrophin exons 62 and 56 was confirmed at the genomic sequence level. One junction between the IL1RAPL1 intron 5 and dystrophin intron 55 was localized within an Alu sequence. These results showed that a fragment of the IL1RAPL1 gene was inserted into the duplication junction of the dystrophin gene in the same direction as the dystrophin gene. This suggests the novel possibility of co-occurrence of complex genomic rearrangements in dystrophinopathy.

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Double complex mutations involvingF8andFUNDC2caused by distinct break-induced replication

Cited by 56 publications

References 47 publications

Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair

Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair

A Complex Double Deletion in LMNA Underlies Progressive Cardiac Conduction Disease, Atrial Arrhythmias, and Sudden Death

Insertion of the IL1RAPL1 gene into the duplication junction of the dystrophin gene

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