Ken's Notes

Double stranded break followed by aberrant joining of non-homologous ends
84% of de novo, non-recurrent, cytogenetically visible interstitial deletions are paternally derived

Terminal deletions:

Recurrent terminal deletions:
Non-recurrent terminal deletions:

Most terminal deletions have non-recurrent breakpoints
Non-homologous end joining (NHEJ):

70% of de novo non-recurrent, cytogenetically visible terminal deletions are paternally derived

Double-stranded DNA break followed by “telomere healing”

“telomere healing” mechanism

Addition of a new (TTAGGG)n sequence at or near the deletion breakpoint
Telomerase synthesizes the new telomere after binding to a telomerase recognition site in the vicinity of the deletion breakpoint

NAHR:

Telomere-associated repeats (TARs) may be involved
Some terminal deletions have been demonstrated to actually be derivative chromosomes from a translocation event

They have telomeric and subtelomeric sequences from another chromosome

Some terminal deletions (7-20%) are actually interstitial deletions as demonstrated by molecular techniques
Fragile sites

Ex. FRA11B in Jacobsen (but not all cases have this breakpoint)

“bouqet” association of telomeres at meiosis

Short and long-arm telomeric regions of a chromosome come to be in contact allowing subtelomeric exchange
Submicroscopic intrachromosomal rearrangemement

Common sites:

“hot spots”

Some regions have a propensity to the formation of deletions
Low-copy repeat (LCR) duplicons in these regions
15q11-q13
22q11
16p13.3 (Rubinstein-Taybi)

Same spot as t(8;16)(p11;p13.3) in AML

9p23

Multiple hot spots at this site

Gross features:

Histologic features:

Immunophenotype:

Marker:	Sensitivity:	Specificity:

Molecular features:

Other features:

If the rearrangement occurs during meiosis or postzygotic mitosis:

Assume recurrence risk no different from the general population

Some euchromatic deletions that have been associated with a benign phenotype:

5p14
11p12
11q14
13q21
16q21

References:

· Gardner RJM, Sutherland GR. Chromosome Abnormalities and Genetic Counseling. 2nd ed. Oxford University Press, USA; 1996.

· 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.