A Douglas, U Maye, K Hood & PJ Howard
Merseyside and Cheshire Regional
Genetics Laboratories, Liverpool Women's Hospital, UK.
Presented at the ECA meeting in Paris, 2001.
Introduction
Telomere Function
Human Telomeres loose a small amount of telomeric DNA after each cell division.
There is a correlation between Telomere shortening and cellular ageing
Maintaining a critical Telomere length is important for stability
Falling below a critical length signals senescence
Telomere length is maintained by Telomerase activity
Telomere Rearrangements
Small rearrangements of Telomeric regions generally contain a high density of genes
These rearrangements can be difficult if not impossible to detect using conventional Cytogenetics
When unbalanced they may result in phenotypes ranging from mild to severe
7-23% of cases with IMR have been shown to have Cryptic Telomeric Rearrangements (CTR)
depending on patient selection and laboratory techniques used
Case 1 del(1)(p36.22)
Fig. 1.Karyotype - Conventional Cytogenetics
(Click on image to enlarge)
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Karyotypes
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Case 1:
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46,XY, del(1)(p36.22).ish del(1) telomere 1 (1p-, 1qx2)
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Case 2:
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46,XX,der(1)t(1;3)(p36.2;q27.1)pat .ish der(1)t(1;3) telomere 1(1p-, 1qx2), telomere 3 (3px2, 3qx3), (wcp1 -)
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Case 3:
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46,XY, del(3)(p26.2)inv(3)(p25.2p26.2) .ish del(3)inv(3) telomere 3 (3p-, 3qx2) (wcp3+)
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Case 4:
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46,XX, del(9)(p24) .ish telomere 9 (9p-, 9qx2)
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Case 5:
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46,XX, del(10)(p14) .ish telomere 10 (10p-, 10qx2),22q11.2 (TUPLE 1 x2)
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Case 7:
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46,XX .ish del(17)(p13.3) telomere 17 (17p-, 17qx2)
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De Vries Checklists
Family history of mental retardation
Compatible with Mendelian inheritance
Incompatible with Mendelian inheritance
Prenatal onset growth retardation
Postnatal growth abnormalities
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Score1
Score2
Score2
Score2
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For each of the following 1 point (Max 2)
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Microcephaly, macrocephaly, short /tall stature
> 2 facial dysmorphic features
Non-facial dysmorphism and Congen. Abnor.
For each anomaly 1 point ( Max 2 )
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Score2
Score2
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Using De Vries Checklist
One of the abnormal cases in this study (case 4 - del(9p)), would have been missed, if
we had used De Vries scoring system with the recommended cut off score of 3 or more,
giving a sensitivity of 100% for the cases studied by De Vries’ group. Nevertheless, testing for subtelomeric rearrangements is an important tool in IMR, but
current cost of testing is expensive, therefore some means of preselection must be used
and this checklist allows the majority of abnormal cases to be picked up. We are therefore recommending to our clinicians that they use this checklist as a guide
but are not precluding any cases that they feel are definitely suggestive of a
chromosomal abnormality.
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Polymorphism
One case out of 50 showed a deletion polymorphism of 18p using the Cytocell probe
system.On repeating the test using Vysis probe system, a very small signal was
detected.This polymorphism has not been previously described by Knight et al. (2q, XpYp)
Fig 2. Polymorphism.
Discussion
Subtelomeric studies were carried out on 50 cases of which 7 were abnormal (14%).
Of these 7 cases, HR GTG banding subsequently (with hindsight) detected 5.
Polymorphism was detected in only one case (18p).
Cross-hybridisation was detected in our studies for regions previously reported by
Knight et al (i.e. 11p with 17p, 15q with 1q).
In 3 out of 50 cases cross-hybridisation of 8p with 7p (not previously reported) was
also detected.
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Case 3: del(3)inv(3)
Using Telomere 3 from the Cytocell Probe System:
3p = Green
3q = Red
(Click on images to enlarge)
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Case 9: del(17)(p13.3)
Using Mix 8 from the Vysis Probe System:
8p = Green, 8q - Red
17p = Green + Red, 17 cen Aqua
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Conclusion
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