Genetic Testing in Medicine + Public Health - Prof. Robertson

Question 1

Diagnosing CF

Answer 1

CFTR regulates sweat chloride levels – sweat has elevated Cl- ions and so sweat test can be used to diagnosis
* in milder CF cases - sweat tests borderline abnormal and often normal
* Babies can be difficult to sweat test
* Expensive and difficult to apply to a population

Why not just genotype people?
* LOTS of CF variants
* 80% of CF alleles are in ΔF508
* But other 20% made up of >1050 mutations – difficult to do genetic testing b/c there are so many different variants that cause CF

INSTEAD: lean back to sweat test combined with ΔF508 screening
* gets large pool of CF patients diagnosed

Question 2

The variable expressivity of CF is determined by

Answer 2

• The CFTR mutations
• Variants at modifer loci
• Environment

CF is not a “monogeneic” dosorder but is mendelian

Question 3

Marfan syndrome - genetics

Answer 3

mendelian
* major causitive gene (FBN1) – encodes fibrillin
* LARGE gene - testing examines the whole gene
* Mutations are “private” no “founders” – point mutations are most common
* No mutation found in convinicing cases
* PROBLEM: phenocopies and allelic heterogeneity

Question 4

Duchenne Muscular Dystrophy

Answer 4

• X-linked recessive mendelian disorder
• Muscular weakness and deterioration
• milder allelic variant: Becker Muscular Dystrophy (reading frame is left intact - in duchenne reading frame is changed)
• 1/3 due to new mutations (maybe no family history)
• 2/3 individuals have a deletion or duplication disrupting the gene – readily detected
• 1/3 individuals have harder to find small scake mutations

in new mutations - gonadal mosaicism in mother 2/3

Question 5

Duchenne’s Muscular Dystrophy and Gonadal Mosaicism

Answer 5

2/3 of mothers to de novo muscular dystrophy patients are carriers - 6-7% are gonadal mosaics
* Proportion of germ maternal germ cells harbour mutation that is absent in blood
* The ability to detect the scenario and measure it clinically is zero
* Recurrance risk is high (but variable)

Question 6

Next Gen Sequencing in Prenatal diagnosis

Answer 6

• There is free fetal DNA in maternal blood
• Measure alleles (such as sex, rhesus antigen)
• Aneuploidy assessment (By targeted assay or massively parallel sequencing)
• Theoretically extend to whole fetal genome
• BUT – ethical questions ?!

Question 7

Mendelian Inheritance Patterns can feature

Answer 7

• Clinical complexity
• Phenotypic Pleiotropy (single gene causing multiple seemingly unrelated effects)
• Mutational Complexity