Decoding NF1 Intragenic Copy-Number Variations

Hsiao, Meng-Chang; Piotrowski, Arkadiusz; Callens, Tom; Fu, Chuanhua; Wimmer, Katharina; Claes, Kathleen; Messiaen, Ludwine

doi:10.1016/j.ajhg.2015.06.002

Cited by 26 publications

(26 citation statements)

References 71 publications

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“…[5][6][7][8][9][10] Although we cannot completely rule out the possibility of two independent two-step events, we suggest that both aberrations can be traced back to a shared primary Alu retrotransposition event. This interpretation is based on (i) identity of the region harboring the presumed integration; (ii) involvement of AluYb8 as one of the most active Alu subfamilies; 16 (iii) presence of a classical L1-endonuclease site; 16 (iv) the sequence representing the potential target site duplication to be of the typical size of 16 bp; 16 and (v) the rarity of the haplotype on which both variants reside.…”

Section: Discussionmentioning

confidence: 99%

“…4 Meanwhile, a few disease-associated deletions that harbor Aluderived sequence insertions have been reported, including in the BRCA-1, CHD7, NF1, PMM2, GLA, and LPL genes. [5][6][7][8][9][10] Mechanistic interpretations referred to the one-step AMD concept, 8 or alternatively suggested a two-step scenario in which an Alu insertion precedes the actual deletion event. 10 The present study reports on the characterization of two distinct Alu insertion-associated deletions in the SPAST gene, alterations of which cause hereditary spastic paraplegia type SPG4 (OMIM 604277).…”

Section: Introductionmentioning

confidence: 99%

“…[5][6][7][8][9][10] Mechanistic interpretations referred to the one-step AMD concept, 8 or alternatively suggested a two-step scenario in which an Alu insertion precedes the actual deletion event. 10 The present study reports on the characterization of two distinct Alu insertion-associated deletions in the SPAST gene, alterations of which cause hereditary spastic paraplegia type SPG4 (OMIM 604277). 11 Haplotyping as well as detailed analysis of the sequences involved was used to trace the probable history of the corresponding alleles, and to unravel the likely mutational mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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A polymorphic Alu insertion that mediates distinct disease-associated deletions

et al. 2016

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Large deletions that are associated with insertions of Alu-derived sequence represent a rare, but potentially unique class of alterations. Whether they form by a one-step mechanism or by a primary insertion step followed by an independent secondary deletion step is not clear. We resolved two disease-associated SPAST deletions, which involve distinct exons by long range PCR. Alu-derived sequence was observed between the breakpoints in both cases. The intronic regions that represent the targets of potentially involved Alu retrotransposition events overlapped. Microsatellite-and SNP-based haplotyping indicated that both deletions originated on one and the same founder allele. Our data suggest that the deletions are best explained by two-step insertion-deletion scenarios for which a single Alu retrotransposition event represents the shared primary step. This Alu then mediated one of the deletions by non-homologous end joining and the other by non-allelic homologous recombination. Our findings thus strongly argue for temporal separation of insertion and deletion in Alu insertion-associated deletions. They also suggest that certain Alu integrations confer a general increase in local genomic instability, and that this explains why they are usually not detected during the probably short time that precedes the rearrangements they mediate.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A polymorphic Alu insertion that mediates distinct disease-associated deletions

et al. 2016

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“…7,9,43,44 Analyses of the breakpoints of these deletions show that all of them involve Alu elements suggesting that they were mainly generated by NAHR (Supplementary Table S8). Still, as a recent study on the genetic mechanisms responsible for intragenic gross deletions inactivating the NF1 gene suggests that FoSTeS/MMBIR is an underestimated cause of this type of gene alterations, 22 it may be worthwhile to test whether also RBM may have a role for the high frequency of non-recurrent (intragenic) deletions affecting the PMS2 gene.…”

Section: Resultsmentioning

confidence: 98%

“…18,20,21 Up to now, complex PMS2 alterations thought to result from RBM have not been described, but analysis of rearrangements in other genes has shown that RBMs are probably still under-recognised as molecular mechanism underlying (mainly complex) genomic, genic and exonic rearrangements. 18,22 Here, we describe a chromosomal rearrangement inactivating the PMS2 gene in an individual with CMMRD syndrome. Thorough characterisation of this complex rearrangement involving sequences of the inverted 100-kb LCR and a human endogenous retrovirus (HERV) element on 7p22.1 renders strong evidence that it results from a RBM.…”

Section: Introductionmentioning

confidence: 96%

PMS2 inactivation by a complex rearrangement involving an HERV retroelement and the inverted 100-kb duplicon on 7p22.1

et al. 2016

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Biallelic PMS2 mutations are responsible for more than half of all cases of constitutional mismatch repair deficiency (CMMRD), a recessively inherited childhood cancer predisposition syndrome. The mismatch repair gene PMS2 is partly embedded within one copy of an inverted 100-kb low-copy repeat (LCR) on 7p22.1. In an individual with CMMRD syndrome, PMS2 was found to be homozygously inactivated by a complex chromosomal rearrangement, which separates the 5'-part from the 3'-part of the gene. The rearrangement involves sequences of the inverted 100-kb LCR and a human endogenous retrovirus element and may be associated with an inversion that is indistinguishable from the known inversion polymorphism affecting the ~0.7-Mb sequence intervening the LCR. Its formation is best explained by a replication-based mechanism (RBM) such as fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR). This finding supports the hypothesis that the inverted LCR can not only facilitate the formation of the non-allelic homologous recombination-mediated inversion polymorphism but it also promotes the occurrence of more complex rearrangements that can be associated with a large inversion, as well, but are mediated by a RBM. This further suggests that among the inversion polymorphism on 7p22.1, more complex rearrangements might be hidden. Furthermore, as the locus is embedded in a common fragile site (CFS) region, this rearrangement also supports the recently raised hypothesis that CFS sequence motifs may facilitate replication-based rearrangement mechanisms.

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High Frequency of Pathogenic Rearrangements in SPG11 and Extensive Contribution of Mutational Hotspots and Founder Alleles

et al. 2016

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Biallelic loss-of-function mutations in SPG11 cause a wide spectrum of recessively inherited, neurodegenerative disorders including hereditary spastic paraplegia (HSP), amyotrophic lateral sclerosis, and Charcot-Marie-Tooth disease. By comprehensive screening of three large cohorts of HSP index patients, we identified 83 alleles with "small" mutations and 13 alleles that carry large genomic rearrangements. Including relevant data from previous studies, we estimate that copy number variants (CNVs) account for ∼19% of pathogenic SPG11 alleles. The breakpoints for all novel and some previously reported CNVs were determined by long-range PCR and sequencing. This revealed several Alu-associated recombination hotspots. We also found evidence for additional mutational mechanisms, including for a two-step event in which an Alu retrotransposition preceded the actual rearrangement. Apparently independent samples with identical breakpoints were analyzed by microsatellite PCRs. The resulting haplotypes suggested the existence of two rearrangement founder alleles. Our findings widen the spectra of mutations and mutational mechanisms in SPG11, underscore the pivotal role played by Alus, and are of high diagnostic relevance for a wide spectrum of clinical phenotypes including the most frequent form of recessive HSP.

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Decoding NF1 Intragenic Copy-Number Variations

Cited by 26 publications

References 71 publications

A polymorphic Alu insertion that mediates distinct disease-associated deletions

A polymorphic Alu insertion that mediates distinct disease-associated deletions

PMS2 inactivation by a complex rearrangement involving an HERV retroelement and the inverted 100-kb duplicon on 7p22.1

High Frequency of Pathogenic Rearrangements in SPG11 and Extensive Contribution of Mutational Hotspots and Founder Alleles

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