Investigating Genetic Disorders

Question 1

What different types of reasons is genetic testing done for? (5)

Answer 1

Diagnostic
Pre-symptomatic
Carrier status
Prenatal
Risk factors

Question 2

What was the largest activity of prenatal genetic testing for?

Answer 2

Common aneuploidies

Question 3

What are the three common things testing for postnatally?

Answer 3

Cytogenetics in malignancy
Genetic risk factors
Molecular testing for rare single gene disorders

Question 4

What are the two types of genetic testing?

Answer 4

Cytogenetic

Molecular

Question 5

What conditions are most commonly (molecular) tested for postnatally? (5)

Answer 5

Fragile X
Cystic fibrosis
Breast cancer
Haemochromatosis
Factor V Leiden

Question 6

What conditions are most commonly (cytogenetic) tested for postnatally? (2)

Answer 6

Solid tumours

Haematological malignancy

Question 7

What conditions are most commonly (molecular) tested for prenatally? (3)

Answer 7

Sickle cell disease
Free fetal DNA - sex
Cystic fibrosis

Question 8

What conditions are most commonly (cytogenetic) tested for prenatally? (2)

Answer 8

Karyotype

Aneuploidy

Question 9

What is a genetic marker?

Answer 9

A marker tags a piece of DNA and can be used to track genes in families or populations.

Question 10

What does SNP stand for?

Answer 10

Single nucleotide polymorphism

Question 11

What is an STR?

Answer 11

Short tandem repeat (microsatellite), highly variable in length.

Question 12

When is a genetic marker polymorphic?

Answer 12

When the frequency of the minor allele in the population is >1%

Question 13

What different types of genetic conditions are there mentioned in this lecture?

Answer 13

Chromosomal abnormalities (e.g. Downs)
Single gene disorders (e.g. sickle cell, CF)
Cancer
Thrombophilia e.g. factor V Leiden

Question 14

What does MAF stand for?

Answer 14

Minor allele frequency

Question 15

What can be said about linked genetic markers?

Answer 15

They are physically close on the chromosome

Question 16

Linked genetic markers mostly stay together through meiosis but can ….?

Answer 16

Cross over in recombination

Question 17

What can linked genetic markers be used to track?

Answer 17

Location of a disease gene

Question 18

What are the three different ways disease genes are identified?

Answer 18

Positional candidates
Functional candidates
Exome sequencing

Question 19

How are positional candidates identified?

Answer 19

Genome wide genetic linkage analysis

Question 20

How are functional candidates identified?

Answer 20

Functional association with previously identified disease genes

Question 21

How are disease genes identified using exome sequencing?

Answer 21

The exome is sequenced and coding variants identified. Using exome sequencing controls and genetic variation databases, the common variants are excluded. This leaves the candidate genes only and so the disease genes can be identified.

Question 22

What is the exome? How much of the genome does it make up?

Answer 22

All the protein coding regions of the genome.

~1.5%

Question 23

What condition is given as an example in this lecture that the disease-causing gene was identified using exome sequencing? What is the gene?

Answer 23

Freeman-Sheldon syndrome (distal arthrogryposis)

MYH3 is the gene

Question 24

How are genetic variants classified on a scale of 1 to 5?

Answer 24

1. Non-pathogenic
2. Unlikely pathogenic
3. Variant of unknown Significance (VoUS)
4. Likely pathogenic
5. Pathogenic

Question 25

How may searching medical literature be useful in classifying a genetic variant?

Answer 25

Can be decisive if there is a clear known precedent

Question 26

How may searching databases be useful in classifying a genetic variant?

Answer 26

Can be decisive e.g. if there is a clear incompatible population frequency (too many people have the variant, can’t be disease causing).

Question 27

When is using in-silico tools acceptable in classifying a genetic variant? When is it not acceptable?

Answer 27

To predict the severity of a variant

To rely solely on these predictions to assign pathogenicity to a previously unclassified variant.