Apparently balanced structural chromosome rearrangements (ABSCRs) and abnormal phenotype

Written	2009-03	Jean Marie Rival
		Medical genetic service, CHU Nantes, France

Live birth prevalence of ABSCRs is estimated around 0,8%-1%. 15-20 % of which occur de novo, and 80-85 % are inherited.
Most individuals with ABSCRs have a normal phenotype. However, the risk for abnormalities exists. It is relatively low in inherited cases, but high in de novo cases (Table 1).

TABLE 1: Patients with an apparently balanced chromosome rearrangement
		Risk of an abnormal phenotype*
Familial cases
ascertained through	MR/MCA**	10-15%
	sterility	3%
De novo cases		50%

*Risk: proband excluded in familial cases
**MR: mental retardation, MCA: major congenital abnormalities

De novo rearrangements represent a challenge in prenatal diagnosis given that the risk of malformations and learning disabilities is about 5-10%.
In patients with an abnormal phenotype, ABSCRs host “cryptic” chromosomal rearrangements (more often deletions, rarely duplications), uncovered by molecular cytogenetics techniques, mainly the array CGH (Table 2).

TABLE 2: Patients with an abnormal phenotype
	Cryptic imbalance
Familial cases	25%
De novo cases	33%*
*In de novo cases with complex ABSCRs (with more than 3 breakpoints), imbalance was found in 90 %

Conversely, patients with a normal phenotype and ABSCRs were found to carry no imbalance.
The majority of de novo imbalances have a paternal chromosome origin.
ABSCRs breakpoints were compared in patients with normal and abnormal phenotype:
- No significant differences were found in GC contents, nor in the number of CpG islands, the number of genes, exons and genes disrupted, the number of segmental duplications and copy number variants in the 200 Kb window around and within the breakpoints.
- Only the number of breakpoints in G-bands versus R-bands was statistically significant (p < 0.01): patients with one or both breakpoints within R-bands had more often an abnormal phenotype.
- The proportion of gene disruption (at the breakpoints) was similar in patients with normal and abnormal phenotypes. However, genes implicated in biological processes of the nervous system, genes for transcription/regulation of transcription or signal transduction/signalling, and genes associated with known Mendelian diseases were more frequently disrupted in patients with an abnormal phenotype.

A molecular analysis of 18 breakpoints in patients with an abnormal phenotype revealed 11 microdeletions (deletions of 1 to 16 bp), 6 insertions (2-17 bp), 2 duplications (3 and 13 bp) and 3 multiples sequences changes.
The oligonucleotide composition of the breakpoints was studied. Alternating purine-pyrimidine sequences, polypurine or polypyrimidine tracts were found to be significantly overrepresented in the vicinity of deletions and translocation breakpoints junctions.
Such sequences are prone to form non B-DNA configurations (triplex, tetraplex, cruciform, slipped or Z-DNA).They are detected for example near the breakpoints of the recurrent t(11;22).
These structures are likely to slow down or arrest the replication fork processing. Serial steps of intra and/or inter chromosomal replication slippage can explain complex genome rearrangements.
The initial breakage event involved in many constitutional and somatic translocations is thought to be the result of stalled DNA replications.
A single DNA strand lesion -rather than a double stand break- as the initiating damage that causes replication fork stalling, may be the mechanism involved in this process.

Rival JM

Atlas of Genetics and Cytogenetics in Oncology and Haematology 2009-03-01

Apparently balanced structural chromosome rearrangements (ABSCRs) and abnormal phenotype