Genetic screening

Question 1

What are the 2 main types of genetic variation?

Answer 1

1. Structural
   - Copy number (deletions & duplications)
   - positional (insertions, translocations)
   - orientational (inversions)
2. Sequence level
   - single base substitutions
   - small deletions/duplications
   - repetitive sequence

Question 2

Why do we perform genetic tests, and what samples does it entail?

Answer 2

Aim of detecting genetic alterations associated with disease. Samples include DNA and RNA (direct) or chromosomes, proteins or metabolites (biochemical or immunohistochemical test)

Question 3

Define Cytogenetics

Answer 3

Studies the structure, properties and behaviour of chromosomes

Question 4

Define Molecular genetics, what tests does it generally entail?

Answer 4

Studies the structure and function of genes at a molecular level. Tests typically DNA or RNA based

Question 5

What does Cytogenetics combined with Molecular genetics mean?

Answer 5

That the line between both is blurring - molecular methods can detect cytogenetic abnormalities

Question 6

Can small and large variants be disease causing or not?

Answer 6

Small and large variants may be disease causing or not.

Question 7

Can repetitive elements be disease causing or not?

Answer 7

Repetitive elements such as tandems or interspersed are non disease-causing but may predispose to rearrangements or expansions/contractions

Question 8

What are the causes of genetic variation?

Answer 8

• DNA repair mechanisms
• DNA replication errors (proof-reading or fork stalling)
• Homologous DNA recombination during meiosis
• retrotransposition

Question 9

What is the significance of molecular diagnosis?

Answer 9

• accurate diagnosis
• possible prognosis
• better informed genetic counseling
• prenatal, pre-implantation, pre-symptomatic diagnosis
• appropriate trial treatment/enrolment
• drug interactions

Question 10

What are the consequences of genetic variation?

Answer 10

• no change in phenotype
• alternative phenotypes of no medical consequence
• disease susceptibility
• pathogenic

Question 11

What are some databases of variation?

Answer 11

• “Normal” variation
  
  • ExAC, gnomAD, Exome Variant Server, 1000 genomes, dbSNP
• disease associated variation
  
  • DECIPHER and Human Gene Mutation Data (HGMD)

Question 12

Why does caution need to be taken when calling variation “normal” vs “abnormal”?

Answer 12

As variation occurs between population.

Common variant = “normal” e.g. BRCA2 (not all people with this get breast cancer)

Rare variant = “abnormal”
e.g. Dmd (nonsense mutation)

Question 13

How are DNA sequence changes described?

Answer 13

• with reference to the current versions of the genome
• using the approved gene name
• using internationally recognised nomenclature
• change at the DNA coding level (c)
• change at the amino acid or protein level (p)

Question 14

Why do we need to describe sequence changes in particular ways?

Answer 14

• no of gene landmarks can change
• reference seq and genome are updated regularly
• gene names can change

Therefore, variants can be recognised across laboratories/countries over time

Question 15

Define polymorphism

Answer 15

A variant that is common and normal in population (>1%), therefore presumed benign. Ancient with weak or no effect.

Question 16

Define autosomal dominant

Answer 16

Where the disease gene is on an autosome. At least one individual in each successive generation is affected (exception of incomplete penetrance). Independent of sex.

One copy (het) of the disease allele = disease phenotype - normal allele cannot fully compensate.

Two copies = usually lethal (or more severe).

Question 17

What’s an example of autosomal dominant

Answer 17

Examples include Neurofibromatosis 1 and 2 (NF1 and NF2): growth of tumours (usually non-cancerous) in the NS.

NF1 prevalence 1:35000

NF2 prevalence 1:25000 (risk of early death)

Question 18

Define autosomal recessive

Answer 18

One copy = no phenotype or very mild.

Two copies (hom or compound het) of the disease allele = disease phenotype.

Horizontal transmission (may have affected siblings, but usually not affected earlier generations) - parents usually carriers.

Incidence independent of sex (25% of disease/not getting and 50% carrier)

Question 19

What’s an example of autosomal recessive disease?

What drug has been approved for it?

Answer 19

Spinal muscular atrophy (SMA): progressive muscle wasting disease with loss of motor neurons. Most common cause of infant death (different age onset). Caused by mutations in SMN1 gene

Nusinersen first drug approved for use of SMA.

Question 20

What is an X-linked dominant disease?

Answer 20

Disease gene is on the X chromosome. Males typically more severely affected. Higher prevalence in females as more chance of inheriting an X-linked mutation.

One copy (het/hemizygous) of the disease allele = disease phenotype.

All daughters of affected father will be affected, none of their sons (unless mother also affected).

If mother affected, 50% of her children will be affected.

Question 21

What are the 2 examples of X-linked dominant disease?

Answer 21

Rett syndrome and Fragile X syndrome.

Rett syndrome: neurological disorder of the brain’s grey matter –> deceleration of head growth rate, small hands and feet. Nearly all females. Caused by mutation in MECP2 gene.

Fragile X: intellectual disability, various physical characteristics. Most common single gene cause of autism. Caused by expansions of CGG triplet repeat region in the 5’UTR of the FMR1 gene. Boys usually more affected.

Question 22

What is X-linked recessive disease?

Answer 22

Hemizygous males affected (can be lethal).

For females: 2 copies of disease allele = disease phenotype. 1 copy = no or mild phenotype.

In mothers, 50% chance of sons having disease, 50% of daughters being carriers.

In males, no sons affected. All daughters carriers.

Question 23

What is an example an X-linked recessive disease?

Answer 23

Duchenne muscular dystrophy: progressive skeletal muscle degeneration. Onset = early childhood, survival until early thirties. Affects 1 in 3500 males. Cause: mutations in the dystrophy gene (DMD) –> absence of dystrophin protein

Question 24

What is mitochondrial inheritance?

What do mitochondrial diseases usually affect?

Answer 24

Typically, maternal inheritance where 99.9% of mtDNA is inherited from mother.

Mother passes on disease to all children, father never passes on disease.

Diseases usually affect muscle, nerve and eye

Question 25

What is an example of mitochondrial disease?

Answer 25

Leber’s hereditary optic neuropathy: degeneration of retinal ganglion cells and their exons (vision loss). Primary affects young males. Cause: mutations in mt NADH dehydrogenase genes