Faculty Opinions recommendation of Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements.

Background: Large genomic rearrangements (LGR) in BRCA1 consisting of deletions/duplications of one or several exons have been found throughout the gene with a large proportion occurring in the 5′ region from the promoter to exon 2. The aim of this study was to better characterize those LGR in French high-risk breast/ovarian cancer families. Methods: DNA from 20 families with one apparent duplication and nine deletions was analyzed with a dedicated comparative genomic hybridization (CGH) array, high-resolution BRCA1 Genomic Morse Codes analysis and Sanger sequencing. Results: The apparent duplication was in fact a tandem triplication of exons 1 and 2 and part of intron 2 of BRCA1, fully characterized here for the first time. We calculated a causality score with the multifactorial model from data obtained from six families, classifying this variant as benign. Among the nine deletions detected in this region, eight have never been identified. The breakpoints fell in six recurrent regions and could confirm some specific conformation of the chromatin. Conclusions: Taken together, our results firmly establish that the BRCA1 5′ region is a frequent site of different LGRs and highlight the importance of the segmental duplication and Alu sequences, particularly the very high homologous region, in the mechanism of a recombination event. This also confirmed that those events are not systematically deleterious.

Download Full-text

Hi-C as a molecular rangefinder to examine genomic rearrangements

Seminars in Cell and Developmental Biology ◽

10.1016/j.semcdb.2021.04.024 ◽

2021 ◽

Author(s):

Kyukwang Kim ◽

Mooyoung Kim ◽

Yubin Kim ◽

Dongsung Lee ◽

Inkyung Jung

Keyword(s):

Genomic Rearrangements

Download Full-text

Integrated CNV-seq, karyotyping and SNP-array analyses for effective prenatal diagnosis of chromosomal mosaicism

BMC Medical Genomics ◽

10.1186/s12920-021-00899-x ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Na Ma ◽

Hui Xi ◽

Jing Chen ◽

Ying Peng ◽

Zhengjun Jia ◽

...

Keyword(s):

Prenatal Diagnosis ◽

Sex Chromosome ◽

Snp Array ◽

Genomic Rearrangements ◽

Chromosomal Mosaicism ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Low Level ◽

Autosomal Aneuploidy ◽

Number Variation

Abstract Background Emerging studies suggest that low‐coverage massively parallel copy number variation sequencing (CNV-seq) more sensitive than chromosomal microarray analysis (CMA) for detecting low-level mosaicism. However, a retrospective back-to-back comparison evaluating accuracy, efficacy, and incremental yield of CNV-seq compared with CMA is warranted. Methods A total of 72 mosaicism cases identified by karyotyping or CMA were recruited to the study. There were 67 mosaic samples co-analysed by CMA and CNV-seq, comprising 40 with sex chromosome aneuploidy, 22 with autosomal aneuploidy and 5 with large cryptic genomic rearrangements. Results Of the 67 positive mosaic cases, the levels of mosaicism defined by CNV-seq ranged from 6 to 92% compared to the ratio from 3 to 90% by karyotyping and 20% to 72% by CMA. CNV-seq not only identified all 43 chromosomal aneuploidies or large cryptic genomic rearrangements detected by CMA, but also provided a 34.88% (15/43) increased yield compared with CMA. The improved yield of mosaicism detection by CNV-seq was largely due to the ability to detect low level mosaicism below 20%. Conclusion In the context of prenatal diagnosis, CNV-seq identified additional and clinically significant mosaicism with enhanced resolution and increased sensitivity. This study provides strong evidence for applying CNV-seq as an alternative to CMA for detection of aneuploidy and mosaic variants.

Download Full-text

Rearrangements of the Williams–Beuren syndrome locus: molecular basis and implications for speech and language development

Expert Reviews in Molecular Medicine ◽

10.1017/s146239940700035x ◽

2007 ◽

Vol 9 (15) ◽

pp. 1-16 ◽

Cited By ~ 83

Author(s):

Lucy R. Osborne ◽

Carolyn B. Mervis

Keyword(s):

Language Development ◽

Language Impairment ◽

Short Term Memory ◽

Relative Strength ◽

Genomic Rearrangements ◽

Speech And Language ◽

Human Speech ◽

Hyperactivity Disorder ◽

Low Copy Repeats ◽

Speech And Language Development

AbstractThe Williams–Beuren syndrome (WBS) locus on human chromosome 7q11.23 is flanked by complex chromosome-specific low-copy repeats that mediate recurrent genomic rearrangements of the region. Common genomic rearrangements arise through unequal meiotic recombination and result in complex but distinct behavioural and cognitive phenotypes. Deletion of 7q11.23 results in WBS, which is characterised by mild to moderate intellectual disability or learning difficulties, with relative cognitive strengths in verbal short-term memory and in language and extreme weakness in visuospatial construction, as well as anxiety, attention-deficit hyperactivity disorder and overfriendliness. By contrast, duplication results in severely delayed speech and expressive language, with relative strength in visuospatial construction. Although deletion and duplication of the WBS region have very different effects, both cause forms of language impairment and suggest that dosage-sensitive genes within the region are important for the proper development of human speech and language. The spectrum and frequency of genomic rearrangements at 7q11.23 presents an exceptional opportunity to identify gene(s) directly involved in human speech and language development.

Download Full-text

Competitive PCR-High Resolution Melting Analysis (C-PCR-HRMA) for large genomic rearrangements (LGRs) detection: A new approach to assess quantitative status of BRCA1 gene in a reference laboratory

Clinica Chimica Acta ◽

10.1016/j.cca.2017.04.026 ◽

2017 ◽

Vol 470 ◽

pp. 83-92 ◽

Cited By ~ 10

Author(s):

Angelo Minucci ◽

Elisa De Paolis ◽

Paola Concolino ◽

Maria De Bonis ◽

Roberta Rizza ◽

...

Keyword(s):

High Resolution ◽

High Resolution Melting ◽

Brca1 Gene ◽

High Resolution Melting Analysis ◽

Genomic Rearrangements ◽

Reference Laboratory ◽

Competitive Pcr ◽

New Approach ◽

Large Genomic Rearrangements ◽

Melting Analysis

Download Full-text

Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations

Acta Endocrinologica ◽

10.1530/eje-14-1154 ◽

2015 ◽

Vol 172 (6) ◽

pp. 803-811 ◽

Cited By ~ 32

Author(s):

Maya B Lodish ◽

Bo Yuan ◽

Isaac Levy ◽

Glenn D Braunstein ◽

Charalampos Lyssikatos ◽

...

Keyword(s):

Copy Number ◽

Molecular Mechanisms ◽

De Novo ◽

Genetic Defect ◽

Molecular Cytogenetics ◽

Case Series ◽

Sporadic Case ◽

Genomic Rearrangements ◽

Clinical Presentations ◽

Depth Analysis

ObjectiveWe have recently reported five patients with bilateral adrenocortical hyperplasia (BAH) and Cushing's syndrome (CS) caused by constitutive activation of the catalytic subunit of protein kinase A (PRKACA). By doing new in-depth analysis of their cytogenetic abnormality, we attempted a better genotype–phenotype correlation of theirPRKACAamplification.DesignThis study is a case series.MethodsMolecular cytogenetic, genomic, clinical, and histopathological analyses were performed in five patients with CS.ResultsReinvestigation of the defects of previously described patients by state-of-the-art molecular cytogenetics showed complex genomic rearrangements in the chromosome 19p13.2p13.12 locus, resulting in copy number gains encompassing the entirePRKACAgene; three patients (one sporadic case and two related cases) were observed with gains consistent with duplications, while two sporadic patients were observed with gains consistent with triplications. Although all five patients presented with ACTH-independent CS, the three sporadic patients had micronodular BAH and underwent bilateral adrenalectomy in early childhood, whereas the two related patients, a mother and a son, presented with macronodular BAH as adults. In at least one patient,PRKACAtriplication was associated with a more severe phenotype.ConclusionsConstitutional chromosomalPRKACAgene amplification is a recently identified genetic defect associated with CS, a trait that may be inherited in an autosomal dominant manner or occurde novo. Genomic rearrangements can be complex and can result in different copy number states of dosage-sensitive genes, e.g., duplication and triplication.PRKACAamplification can lead to variable phenotypes clinically and pathologically, both micro- and macro-nodular BAH, the latter of which we speculate may depend on the extent of amplification.

Download Full-text

Multiple Fates of L1 Retrotransposition Intermediates in Cultured Human Cells

Molecular and Cellular Biology ◽

10.1128/mcb.25.17.7780-7795.2005 ◽

2005 ◽

Vol 25 (17) ◽

pp. 7780-7795 ◽

Cited By ~ 179

Author(s):

Nicolas Gilbert ◽

Sheila Lutz ◽

Tammy A. Morrish ◽

John V. Moran

Keyword(s):

Genetic Instability ◽

Noncoding Rnas ◽

Human Cells ◽

Genomic Rearrangements ◽

U6 Snrna ◽

Human Dna ◽

Cultured Human Cells ◽

Repair Pathways ◽

Genomic Locations ◽

Host Parasite

ABSTRACT LINE-1 (L1) retrotransposons comprise ∼17% of human DNA, yet little is known about L1 integration. Here, we characterized 100 retrotransposition events in HeLa cells and show that distinct DNA repair pathways can resolve L1 cDNA retrotransposition intermediates. L1 cDNA resolution can lead to various forms of genetic instability including the generation of chimeric L1s, intrachromosomal deletions, intrachromosomal duplications, and intra-L1 rearrangements as well as a possible interchromosomal translocation. The L1 retrotransposition machinery also can mobilize U6 snRNA to new genomic locations, increasing the repertoire of noncoding RNAs that are mobilized by L1s. Finally, we have determined that the L1 reverse transcriptase can faithfully replicate its own transcript and has a base misincorporation error rate of ∼1/7,000 bases. These data indicate that L1 retrotransposition in transformed human cells can lead to a variety of genomic rearrangements and suggest that host processes act to restrict L1 integration in cultured human cells. Indeed, the initial steps in L1 retrotransposition may define a host/parasite battleground that serves to limit the number of active L1s in the genome.

Download Full-text