Autosomal Reciprocal Translocations

Epidemiology and Etiology:

• Common (~1:625 in general population)
• Some sites are prone to translocations:
• Sequence similar to another part of the genome
• rcp(11;22)(q23;q11) is the most common known human reciprocal translocation
• most translocations are unique, present in only a single family
• paternal origin in most de novo balanced translocations (26 of 27 in one study)
• associated with increased paternal age
• may arise during pre-meiotic mitotis rather than meiosis
• attributeable to much larger number of repeated cycles of premeiotic cell division undergone by male germ cells by comparison with female germ cells
• paternal origin in 8/8 t(11;22) patients in one study
• Mechanisms:
• Non-homologous end joining (NHEJ):
• Double stranded break followed by aberrant joining of non-homologous ends
• Thought to be the predominant mechanism
• Non-allelic homologous recombination (NAHR):
• Thought to be less important mechanism
• rare balanced t(4;8)(p16;p23)
• all de novo unbalanced cases studied had a maternal origin demonstrated to be mediated by a common inversion polymorphism involving olfactory receptor gene clusters
• secondary DNA structures:
• hairpin-shaped secondary structures predicted to be formed by AT-rich palindromic sequences
• DNA sequences that contain two inverted regions complementary to each other
• Susceptible to nucleases that produce double-stranded breaks
• Implicated in recurring t(11;22), and one other translocation, a t(17;22) in a family with NF type I
• Mechanisms proposed for cancer translocations (not mutually exclusive):
• Illegitimate V(D)J or class switch recombination
• Not restricted to sites of normal recombination
• NAHR between repetitive sequences
• Not much evidence for this as a major mechanism in cancer
• Repetitive sequences implicated:
• Alu
• LINE
• DNA topoisomerase II subunit exchange
• Implicated in t-AML after therapy with topo II inhibitors
• Etoposide
• Teniposide
• Daunorubicin
• Doxorubicin
• Topoisomerase II normally causes DSBs followed by relegation to facilitate strand passage
• The topo II inhibitors block this process leading to apoptosis
• Possibly the topoisomerase II molecules could swap partners to bring two non-homologous ends together.
• Aberrant NHEJ following DSB at regions of the genome predisposed to DSB
• Defects in the NHEJ mechanism (as in NBS) predispose to translocations
• Regions of the genome proposed to be predisposed to DSB:
• Purine / pyrimidine repeat regions
• Formation of a left-handed helical structure called Z-DNA
• Preferentially located in internucleosomal regions (maybe due to the Z-DNA structure)
• May be predisposed to DSB due to internucleosomal position (not bound to histone)
• Scaffold / matrix attachment regions (S/MARs)
• These regions are targeted for DSB during apoptosis
• Hypothesis that cells may accumulate these DSBs during an aborted apoptosis
• Preferential DNA topoisomerase II cleavage sites
• Spatial proximity of

Common sites:

Gross features:

Histologic features:

Broad estimates of range of risk for unbalanced offspring of a translocation parent:

(percentages are in terms of abnormal liverbirths as a proportion of all livebirths)

Ascertainment of family:	2:2 segregation Adjacent Male or Female	3:1 segregation Tertiary tri/mono Female	3:1 segregation Tertiary tri/mono Male
Liveborn aneuploid	5-30%	1-3%	1%
Other	0-5%	0-1% (almost zero)	0-1% (almost zero)

· See p. 87 of Gardner for chromosome-specific risk

Molecular features:

Other features:

• Nomenclature:
• Translocated segments – portion of chromosomes exchanged
• Centric segments – portion of chromosomes containing centromeres
• Derivative chromosomes – the rearranged chromosomes
• Double segment exchange
• Both segments exchanged are of substantial size
• Single segment exchange
• One of the segments is telomeric and likely contains no genes
• Whole arm translocation
• Breakpoints right at or actually within the centromere
• Telomere fusion (very rare)
• Fusion at the telomeres of complete, or nearly complete chromosomes
• Quadrivalent
• The four chromosomes with segments in common come together in meiosis I
• When entering metaphase, the four components are only attached still at the tips, forming a ring
• Pachytene configuration – cross-shaped configuration the chromosomes must assume in pachytene stage of meiosis I
• Risk of unbalanced chromosomes in child:
• Risk must be estimated for each individual translocation
• Determine possible viable segregation outcomes (see below)
• Check the literature for that particular imbalance to see if it is possible
• Can use a resource with empirical risk for individual chromosome segments
• If the patient’s family is large enough, do a segregation analysis to derive a “private” recurrence risk.
• Risk ranges from 0-30% (higher risks are rare)
• Some translocations are associated with a high risk (up to 20%)
• malformed and mentally retarded child
• many translocations have an intermediate risk (5-10%)
• t(11;22)(q23;q11) (most common reciprocal translocation)
• only 3:1 segregation with tertiary trisomy is viable
• 3.7% risk of liveborn aneuploid child for a female carrier
• 0.7% risk for a male carrier
• some have a low risk (1% or less) – but higher rate of infertility / infecundity
• the great majority of double-segment imbalances would be expected to be lethal in utero
• some have no reproductive significance
• consider 4 factors in risk assessment:
• mode of ascertainment (history)
• the type of segregation predicted to result in potentially viable gametes
• the sex of the transmitting parent
• the assessed imbalance of potentially viable gametes
• see table above for consideration of first 3 of these factors
• some translocations can have their own peculiar segregation characteristics
• the propensity for a particular segregation outcome may reflect a particular geometry of the quadrivalent, and wheterh it forms a ring or a chain
• the least imbalanced, least monosomic of the imbalanced gametes is the one most likely to produce a viable conceptus
• usually only malsegregations resulting in partial trisomies are viable
• if the tranlocated segments are small in genetic content (1-2% of total haploid autosomal length (HAL), adjacent-1 is the most likely type of malsegregation to produce a viable conceptus
• if the centric segments are small in genetic content, adjacent-2 is the most likely type to produce a viable conceptus
• usually only possible for translocations involving acrocentrics and chromosome 9
• if one of the whole chromosomes in the quadrivalent is small in genetic content, 3:1 disjunction is the most likely viable conceptus
• if the translocated and centric segments both have large genetic content, no mode of segregation would be viable
• see tables 4-3, 4-4, and 4-5 in Gardner for chromosome specific risk
• if more than one segregation mode could give rise to viable offspring, add the risks together to obtain a risk of either
• adjacent-1 segregation of a double-segment translocation:
• hard to deterimine as each is unique, but generally risk is very low due to lethal imbalance
• estimate is half of the lower of the two single segment abnormalities (likely an overestimate of risk)
• asymmetric segregation in meiosis II is very rare
• 3:1 segreagation
• risk of interchange trisomy (for 13, 18, or 21) is 0.5% risk for female, less in male
• types of segregation in meiosis I:
• alternate segregation
• normal or balanced result
• adjacent-1 (71% of malsegregations in offspring)
• unbalanced result
• most frequent mode of malsegregation in children of translocation heterozygotes
• most likely viable segregation when translocated segments of both chromosomes are small
• adjacent-2 (4% of malsegregations in offspring)
• unbalanced result
• uncommon
• most likely viable segregation when centric segments of both chromosomes are small
• tertiary aneuploidy (2.5% of malsegregations in offspring)
• tertiary trisomy
• gamete receives two normal chromosomes plus one derivative
• tertiary monosomy
• gamete receives only one derivative chromosome (and no normal chromosomes)
• most likely viable segregation when quadrivalent is “lop-sided” (p. 68)
• interchange aneuploidy
• interchange trisomy
• gamete receives two derivative chromosomes and one normal chromosome
• interchange monosomy
• gamete receives one normal chromosome and no derivative chromosomes
• general phenotype of autosomal imbalance:
• major dysmorphogenesis involving multiple body systems
• globally disordered brain function
• infertility / infecundity
• 20-30% risk of miscarriage (15% in background population)
• gametogenic arrest may occur if the mechanics of gamete formation are disturbed too much (infrequent)
• particularly those involving an acrocentric chromosome
• males more susceptible
• breakpoints very close to the tip of a chromosome arm are more likely to lead to formation of a chain configuration which is associated with spermatogenic arrest
• in the case of a karyotypically balanced translocation:
• vast majority have no associated phenotype
• ascertainment by abnormal phenotype increases the risk
• inherited:
• same phenotype as the parent is expected
• risk of UPD
• very low (likely <1%)
• de novo:
• 6.1% overall risk of abnormal phenotype (amniotic fluid) (Warburton 1991)
• risk of cryptic unbalanced defect
• low (“a percent or so”)
• up to 25% by aCGH when ascertainment is abnormal phenotype
• risk of unmasking a recessive allele
• very low (likely <1%)
• risk of UPD
• very low (likely <1%)
• risk of malignancy:
• rcp(11;22) carriers may have an increased risk of breast CA
• t(3;8) may have increased risk of renal cancer
• t(3;6) may have increased risk of hematologic malignancy
• breakpoints at vital loci
• the great majority are not at vital loci
• Mendelian disorders

References:

· Gardner RJM, Sutherland GR. Chromosome abnormalities and genetic counseling. Oxford University Press; 2004.

· Thomas NS, Morris JK, Baptista J, et al. De novo apparently balanced translocations in man are predominantly paternal in origin and associated with a significant increase in paternal age. J Med Genet. 2009:jmg.2009.069716.

· Warburton D. De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am J Hum Genet. 1991;49(5):995-1013.

· Ohye T, Inagaki H, Kogo H, et al. Paternal origin of the de novo constitutional t(11;22)(q23;q11). Eur J Hum Genet. 2010. Available at: http://www.ncbi.nlm.nih.gov.myaccess.library.utoronto.ca/pubmed/20179746 [Accessed March 12, 2010].

· Aplan PD. Causes of oncogenic chromosomal translocation. Trends Genet. 2006;22(1):46-55.