Fluorescence in situ hybridization characterization of apparently balanced translocation reveals cryptic complex chromosomal rearrangements with unexpected level of complexity

Abstract

The great majority of apparently balanced translocations are associated with multiple miscarriages and normal phenotype. Several mechanisms have been proposed to explain how a small percentage of apparently balanced translocations are associated with abnormal phenotypes. One of the proposed mechanisms that have not been well investigated is that apparently balanced translocations may host 'cryptic' complex chromosomal rearrangements (CCRs). To test this hypothesis, this study investigated 20 non-preselected cases with apparently balanced translocations in order to determine the presence of cryptic CCRs. Multiprobe subtelomeric and whole chromosome paint FISH analyses revealed and further characterized three cryptic CCRs. Two out of three CCRs showed an unexpected level of complexity. The results of this study provided evidence that the link between an apparently balanced rearrangement and the appearance of abnormal phenotype may be partly explained by the presence of cryptic CCRs. The results also suggested that what is reported as apparently balanced translocation by classical cytogenetics may host cryptic CCRs, which could be more common than initially thought. Furthermore, the use of both of the above-mentioned FISH methodologies was absolutely necessary to detect the CCRs.

Molecular cytogenetic characterization of a constitutional complex intrachromosomal 4q rearrangement in a patient with multiple congenital anomalies

“…Looking at apparently balanced translocations, Gribble et al (2005) found in three out of ten cases additional breakpoint complexity at or near the translocation breakpoints. Similar results were obtained by Patsalis et al (2004).…”

“…Since array CGH can only detect imbalanced chromosomal aberrations, other tech-niques are needed to detect balanced chromosomal rearrangements. Whole chromosome painting, M banding FISH (as illustrated for example in this study) and mFISH (Patsalis et al, 2004;Gribble et al, 2005) therefore complement high resolution array CGH and are required for the accurate delineation of the breakpoints involved and the full cytogenetic analysis.…”

Replication timing regulation in adults with chromosomal balance rearrangements

“…At least 100 interphase nuclei were analyzed in each sample. The high SD-cell frequency indicated an asynchronous mode of replication, and the low frequency indicated a synchronous mode (Patsalis et al, 2004).…”

The Cypriot and Iranian National Mutation Frequency Databases

“…1A, Table 1). The Cypriot NMDB includes information for the mutation frequencies of α-thalassemia (Baysal et al, 1995, Kyriakou et al, 2000, β-thalassemia (Baysal et al, 1992), δ-thalassemia (Triffilis et al, 1993), G6PD deficiency (Drousiotou et al, 2004), cystic fibrosis (Deltas, 1998), familial hypercholesterolemia (Xenophontos et al, 2000;Baysal E, personal communication), familial Meditteranean fever (Deltas et al, 2002), GM-1 gangliosidosis type I (Georgiou et al, 2005), Sandhoff disease (Drousiotou et al, 2000), Huntington disease (Christodoulou K., unpublished), Y-linked spermatogenic failure (Ioulianos et al, 2002, achondroplasia (Patsalis PC., personal communication), Fragile X syndrome (Patsalis et al, 1999a(Patsalis et al, , 1999b, Prader-Willi, Angelman, Williams-Beuren and 22q11.2 micro-deletion syndromes (Patsalis PC, personal communication), X-linked ichthyosis, retinoblastoma (Patsalis PC, personal communication) and various rearrangements in chromosomal subtelomeric regions (Sismani et al, 2001, Patsalis et al, 2004, leading to Miller-Dieker lissencephaly (17p), Cri du Chat (5p), Wolf-Hirschhorn syndromes (4p), α-thalassemia, tuberous sclerosis and the adult form of polycystic kidney disease (16p). It should be stated that all the Turkish Cypriot mutation data pertain to the indigenous Turkish Cypriots, based on well-preserved medical records, and none of the data were derived from the settlers from Turkey who immigrated to Cyprus only after Turkey's invasion to Cyprus in 1974.…”