Historical and Clinical Perspectives on Chromosomal Translocations

Abstract

Chromosomal translocations, rearrangements involving the exchange of segments between chromosomes, were documented in humans in 1959. The first accurately reported clinical phenotype resulting from a translocation was that of Down syndrome. In a small percentage of Down syndrome cases, an extra 21q is provided by a Robertsonian translocation chromosome, either occurring de novo or inherited from a phenotypically normal parent with the translocation chromosome and a balanced genome of 45 chromosomes. Balanced translocations, including both Robertsonian and reciprocal translocations, are typically benign, but meiosis in germ cells with balanced translocations may result in meiotic arrest and subsequent infertility, or in unbalanced gametes, with attendant risks of miscarriage and unbalanced progeny. Most reciprocal translocations are unique. A few to several percent of translocations disrupt haploinsufficient genes or their regulatory regions and result in clinical phenotypes. Balanced translocations from patients with clinical phenotypes have been valuable in mapping disease genes and in illuminating cis-regulatory regions. Mapping of discordant mate pairs from long-insert, low-pass genome sequencing now permits efficient and cost-effective discovery and nucleotide-level resolution of rearrangement breakpoints, information that is absolutely necessary for interpreting the etiology of clinical phenotypes in patients with rearrangements. Pathogenic translocations and other balanced chromosomal rearrangements constitute a class of typically highly penetrant mutation that is cryptic to both clinical microarray and exome sequencing. A significant proportion of rearrangements include additional complexity that is not visible by conventional karyotype analysis. Some proportion of patients with negative findings on exome/genome sequencing and clinical microarray will be found to have etiologic balanced rearrangements only discoverable by genome sequencing with analysis pipelines optimized to recover rearrangement breakpoints.

Overview of Cytogenetic Technologies

“…In the case of referral indication being an abnormal ultrasound, the percentage increased to 5.2% [52]. While current array-based technologies may be too expensive for routine applications, it is hypothesized that in the near future, with the introduction of massive whole-genome parallel sequencing, complete mapping of the genomic changes in malignant cells can be achieved [34]. A decrease in the cost of these technologies will probably occur with the use of automation and wider application.…”

Analysis of balanced reciprocal translocations in patients with subfertility using single-molecule optical mapping

“…Balanced reciprocal translocations (BRTs) are common chromosomal structural rearrangements formed by random de novo breakage and rejoining of two or more chromosomes and occur in approximately 0.2% of newborns [1,2]. While most translocations are de novo in origin, some individuals inherit familial forms.…”

“…The main issues that plague couples where one partner is a translocation carrier is a high probability of reproductive failure due to biased formation of unbalanced gametes, which typically result in either implantation failure or miscarriage of an established fetus [2]. In some cases, if the unbalanced translocation is compatible with fetal development, a child can be born with a chromosome disease syndrome.…”

Temporal-Spatial Visualization of Endogenous Chromosome Rearrangements in Living Cells

“…Large-scale chromosomal rearrangements occur in various genetic disorders and cancers (1). For example, chromosome duplications cause Down syndrome and Patau Syndrome (2,3), and many cancers including chronic myelogenous leukemia and Burkitt's lymphoma are correlated with large-scale chromosomal translocations (4,5).…”