Genetic Testing 3: Scanning Flashcards
What is the ratio of new mutations to heritable mutations in DMD?
1 new : 3 heritable
Describe the chief differences between Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD) on histochemistry
DMD: complete/almost complete absence of Dystrophin protein in muscle. (0-5%) quantity
BMD: normal appearing or reduced intensity +/- patchy staining (20-100%) quantity
Describe the differences of deletions (incomplete codon vs entire codon deletions) in DMD and BMD and why they elicit such results
DMD is associated with deletions that alter the reading frame (frameshift). A frameshift mutation is caused by the incomplete deletion of a codon (1-2 base pairs only). This results in a change in the reading frame. This would alter all AAs later translated, thus altering the protein entirely.
BMD is more likely to be associated with frame-neutral deletions (deleted coding sequence = multiple of 3bp). There is no frameshift. This would remove one AA from the protein but not disrupt the reading frame.
Describe the mode of inheritance of the BRCA1 family of hereditary breast cancer and ovarian cancers
Autosomal dominant with reduced penetrance
A frameshift mutations is likely to result in a severely ________ protein which will be degraded.
truncated
Do all the discussed mutations involve introns AND exons?
Yes. With the exception of Deep intron mutations (perhaps ~10kb) that interferes with normal splicing.
Describe the basic concept of gene scanning.
You scan one or more genes, looking for any pathogenic variant, using methodology appropriate for the target.
- sequence gene looking for point mutations/other small mutations
- use a specially designed method such as targeted array for detection of mutations
What are private mutations?
A mutation found in one family to cause a disease. The mutation causing the disease has never been seen before in another family.
What is gene scanning good for?
Useful as an approach for testing in disorders with extensive allelic heterogeneity and where families are likely to carry “private mutations”
A chromosomal microarray scans:
The entire genome
A custom array for a gene, such as DMD, scans:
Only the gene targeted, for deletions and duplications
What is the next step if no deletions or duplications are found in a gene scan?
Next step is to sequence coding region (~14kb), intron/exon junctions, promoter, 5 known deep intronic mutations.
Describe the use of gene sequencing as a scanning approach to genetic testing
A custom array scans a specific gene for large deletions & duplications covering one or more exons.
Should results of uncertain significance (VUS) be used in medical management?
No.
