Clinical Cytogenetics Microdeletions Flashcards
How can genetic crossing over result in a diseased phenotype ?
Mismatch of low-copy repeats at breakpoints can cause the insertion or deletion of a critical region that contains the genes for a specific phenotype
What are some of the consequences of inaccurate crossing over ?
Name 3 things
Microdeletions which will give rise to a partial monosomy
Micro-duplications- which will give rise to a small trisomy
Subtelomeric rearrangements which are terminal rearrangements, mostly
microdeletions, at chromosome ends)
Can a micro-deletion be detected in the traditional methods ? FISH etc. ?
Name 2 things
No because they are too small for reliable detection by routine methods.
Limited resolution of routine chromosome analysis ( banded chromosomes ) Interstitial and terminal deletions less than 5 Mb cannot be detected reliably
What causes Prader Willi Syndrome?
A deletion encompassing 15q12 (15q11-13) in 70% of patients
What can cause a change in copy number ?
Recombination between miscopied repeats will lead to a change in copy number.
What tools do you have in your genetic arsenal to diagnose one of these problems
FISH
Standard Karyotype ( limited resolution )
Chromosomal Microarray analysis (CMA)
Array Comparative Genome Hybridization (aCGH)
How does CGH work ?
Comparative genome hybridization. You combine a patients DNA with control DNA and apply it to a microarray and evaluate relative copy number across a genome.
**A micro-deletion or micro-insertion will give a deviation in the ratio of patient to control DNA … boom, ya I said it
What is the drawback to CGH ?
CMA will provide you with precise information about the amount of genomic material relative to a reference genome but not the nature of the rearrangement.
What can FISH do that CGH cannot ?
FISH can provide you with information about the type of rearrangement and possible recurrence risks
Describe the power of FISH ( not you hannah haha)
FISH can analyze both interphase and metaphase genes that have been hybridized with markers, which is a powerful tool in identifying both insertions and deletions.
FISH can utilize a marker specific for a gene and can measure dosage gain of that particular gene.
What are the advantages of HGC ?
Detects chromosomal imbalances identified by traditional karyotyping in addition to imbalances that karyotyping cannot detect.
What is the major disadvantage of aCGH?
2 things
It will not pick up balanced array problems
Normal array results do not rule out any problems
Abnormal results have unclear clinical implications
Why would you test the parents of a child who has a genetic abnormality that you, the clinician, think is due to a micro-insertion or micro-deletion
You can determine if the DNA dosage problem is a inherited or is new
Assists in evaluating the recurrent risks
Assists in clarifying whether DNA dosage alteration in the patient is causative of the patients clinical findings
What are the pros of CMA ?
It is a very sensitive detection system of genomic imbalances
Analysis is genome wide
What are the CONS of CMA ?
It cannot detect balanced rearrangements
Results are frequently ambiguous and complex
It is expensive and has potential accessibility issues
The methodology is not standardized
