Evidence for Correlation of Fragile Sites and Chromosomal Breakpoints in Carriers of Constitutional Balanced Chromosomal Rearrangements

Abstract

A molecular cytogenetic study of 251 cases with balanced chromosomal rearrangements detected due to infertility of unclear origin or in prenatal diagnostics with a later normal outcome was done. Balanced translocations (127 cases), inversions (105 cases), insertions (three cases), balanced complex rearrangements (four cases), or derivative chromosomes leading to no imbalance (12 cases), were studied by multicolor banding (MCB) and/or subcentromeric multicolor fluorescence in situ hybridization (subcenM-FISH). Five-hundred and twenty-nine break-events were characterized by molecular cytogenetics. Only 150 of these were unique breakpoints, the remainder were observed between two and 10 times. According to the results obtained, there was cytogenetic co-localization of fragile site (FS) in ~71% of the studied 529 break-events. Nine selected cases with evidence for breakpoints within FS were further analyzed by FS-specific bacterial artificial chromosome (BAC) probes; only one did not show a co-localization. Further detailed molecular analysis will be necessary to characterize the mechanisms and genetic basis for this phenomenon.

Recombinant Chromosomes Resulting From Parental Pericentric Inversions—Two New Cases and a Review of the Literature

“…Overall, here an up to date review of pericentromeric inversion based viable recombinants is provided. Considering also recent new insights into influence of chromosomal rearrangements on interphase architecture (keyword: topologically associated domains = TADs) (Schrank and Gautier, 2019), as well as of overlap of evolutionary conserved breakpoints (important in speciation) and breakpoints observed in clinical cases (Liehr et al, 2011), the importance of gross cytogenetic aberrations to provide a better understanding of general principles of the human genome is highlighted.…”

Comprehensive characterization of evolutionary conserved breakpoints in four New World Monkey karyotypes compared to Chlorocebus aethiops and Homo sapiens

“…This finding is consistent with previous reports that 64% human chromosomal bands that contain evolutionary breakpoints presented in seven mammalian species ( Ruiz-Herrera et al, 2006 ). Thus, there must be some ‘breakpoint prone regions’ in the mammalian genomes, which may be used by evolution as well as in human diseases ( Liehr et al, 2011 ). These regions seem to correlate by large means especially with human FS (Supplementary Table S2) ( Mrasek et al, 2010 ).…”

Prenatal diagnosis of a de novo interstitial deletion of 11q (11q22.3 → q23.3) associated with abnormal ultrasound findings by array comparative genomic hybridization

“…In a proportion of patients with Jacobsen syndrome (terminal 11q deletions) the breakpoints cluster in chromosomal subband 11q23.3 [ 20 - 22 ], a breakage-prone region which encompasses both the folate sensitive rare fragile site FRA11B and the aphidicolin inducible common fragile site FRA11G [ 20 , 23 - 25 ]. In our case, the deleted region maps at 11q22.3 → q23.3, the breakpoint is on the proximal side of FRA11G and FRA11B , indicating that the co-localization fragile site could have caused instability and constitutional chromosomal rearrangements in vivo [ 23 , 26 ]. Aphidicolin inducible common fragile sites do not break at defined sequences but in breakage-prone regions up to 10 Mb where the break is most likely to appear [ 25 , 27 , 28 ].…”