Genetic Descriptors

Question 1

What is the definition of a genetic disease?

Answer 1

A pathological condition of a part, organ, or system of an organism resulting from various causes, such as infection, genetic defect, or environmental stress, and characterised by an identifiable group of signs or symptoms.

Question 2

What is the spectrum of genetic diseases that contribute to a phenotype?

Answer 2

Mendelian (single gene) —————————> multifactorial
(many genes +
environmental)

PKU Reduced Digenic Hursch- Chron’s MS
Penetrance RP sprung Disease

Mendelian are individually rare, but when grouped equate to 1% disorders
Multifactorial risk is 5% by age 25, 60% lifetime risk

Question 3

What are the features of autosomal dominant inheritance?

Answer 3

Affected males and females appear in each generation of the pedigree.

Affected mothers and fathers transmit the phenotype to both sons and daughters.

Approx equal numbers of affected and unaffected, both males and females

Autosomal dominant conditions with reduced penetrance means the disorder is not fully penetrant so can skip generations - this is very common.

Question 4

What are common autosomal dominant conditions and their frequencies?

Answer 4

Familial hypercholesterolaemia (1/500)
Adult polycystic kidney disease (1/1000)
Neurofibromatosis Type 1 (1/2500)
Huntington’s disease (1/3000)
Myotonic dystrophy (1/7000)
Familial adenomatous polyposis (1/8000)

Question 5

Describe autosomal recessive inheritance

Answer 5

The disease appears in male and female children of unaffected parents.

Both parents have one recessive gene, but two are required (with no dominant genes) to cause disease, so in their children they will both pass one on.

There may be no family history of the disease at all, but often occur in a large multiply inbred kindred

Question 6

What are common autosomal recessive conditions?

Answer 6

Haemochromatosis (1/500)
Cystic fibrosis (1/2000)
Phenylketonuria (1/10 000)
SCA (1/250)
Thalassaemia (1/150)
Tay Sach’s disease (1/1000)

Question 7

Describe X-linked recessive inheritance.

Answer 7

Many more males than females show the disorder.

All the daughters of an affected male are “carriers”.

None of the sons of an affected male show the disorder or are carriers.

Question 8

Describe X-linked dominant inheritance.

Answer 8

Affected males pass the disorder to all daughters but to none of their sons.

Affected heterozygous females married to unaffected males pass the condition to half their sons and daughters.

Question 9

What are common X-linked disorders and their frequency in boys?

Answer 9

Duchenne / Becker muscular dystrophy (1/3000)
Retinitis pigmentosa (1/3500)
Fragile X (1/4000)
Haemophilia A (1/5000)
Haemophilia B (1/30 000)

Question 10

What is Y-linked transmission and what are some Y-linked conditions?

Answer 10

The main Y gene is called the SRY gene, which is the master gene that specifies maleness and male features.

Only men have a Y chromosome and so the Y is only passed from father to son.

The Y chromosome is relatively small and contains very few genes, there are relatively few Y-linked disorders.

List of Y-Linked Diseases:

Male Infertility
Excessive hair on the ear pinna (Hypertrichosis pinnae)
A form of Retinitis pigmentosa
Colour blindness
XYY syndrome

Question 11

Describe mitochondrial inheritance.

Answer 11

Mitochondria divide in response to the energy needs of the cell

Mitochondrial DNA is replicated in response to the energy needs of the cell – not linked to the cell cycle

Mutations in the mitochondrial genome can result in genetic disorders.

Egg has about 100,000 molecules of mtDNA and sperm 100–1500 mtDNAs

Sperm mitochondria enter the egg during fertilization but are lost soon after

This means your mitochondria all come from your mother

Mitochondrial disorders are therefore maternally inherited, are transmitted to children of both sexes and are often very variable in their expression (depends on the number that have been translated an the number that have been passed on)

Question 12

What are the types of point mutations?

Answer 12

Truncating (shorter protein,or non at all)
- deletions
- nonsense (premature stop codon)
- frameshift (deletions or insertions that alter the triplet reading frame)
- splice site mutations (affect splicing of exons and introns by
abolishing or creating a new splice site - leads to premature stop
codon,by creating an altered reading frame and almost always
leads to loss of function)

Non-truncating (change in AA sequence)
- missense (replace one amino acid with another, outcome depends on
how different the new amino acid is - has it gone polar to non-polar?
and how important that amino acid is for the function of the gene
product)
- Synonymous Mutation (no replacement of AA even though there’s a
single base pair change, mutation results in replacement of one amino
acid with the same now)
- Expansion of Trinucleotide Repeats (eg (CAG)n -rare - can be unstable
and their expansion can cause disease, if expansions occurs within a
coding region the properties of the protein can be altered, if expansions
occurs within the regulatory region of a gene, gene expression
can be altered)

Question 13

A single base pair change may have no genetic consequence whatsoever, but on the other hand, it may cause a dominant lethal disorder. Why? Which is more likely?

Answer 13

Non coding region? May lead to an AA that is totally different, or may lead to loss of a crucial AA. 1/8 base pairs are a variant that cause no issues.

Question 14

A single base pair deletion may cause a dominant lethal disorder, whereas a larger deletion may have a minor effect or no genetic consequence at all. Why?

Answer 14

A single base deletion may change the whole reading base pair, changing all consiqent AAs. But a large one may lose a non-important AA, or be in a non-coding region.

Question 15

What are the effects of mutations on proteins?

Answer 15

Loss of functional phenotypes is mostly recessive:
- Most genes code for enzymes
- Half normal amounts are sufficient
- Not rate limiting - less enzyme doesn’t mean the function can’t
continue
- Regulatory compensation
Can be dominant (rare):
- Half normal amounts are not sufficient
- Rate limiting step
- Structural protein

Gain of functional phenotype only occurs with very specific DNA sequence changes:
- limited spectrum of mutations
- only one or a few mutations are seen in affected people
- Gain of function very seldom means a mutations causes a protein to
gain an entirely new function instead often cause inappropriate gene
expression (too high levels, failure to respond to controls =
expressed at wrong time, in wrong place, or in response to wrong
signals, or produce a toxic protein product, eg Huntington’s
caused by trinucleotide repeat)

Question 16

What are the features of Huntington’s disease?

Answer 16

Autosomal dominant 
Late onset (typically 40’s) Neurodegenerative disorder
Involuntary movements
Memory loss 
Apathy
Changes in personality and mood 
depression and anxiety, seizures
Mutations in HD gene (trinucleotide repeats)

Example of a dynamic mutation:
- Repeats are unstable, tend to expand
- The size of expansion is often correlated with the severity of symptoms
and/or with onset at younger age

This is an example of a condition with anticipation:
A phenomenon whereby the symptoms of a genetic disorder become apparent at an earlier age and are more severe from one to the next generation.