Patterns of inheritance

Question 1

What are the classic mendelian models of inheritance?

Answer 1

Autosomal Dominant
Autosomal Recessive
X-linked
Y-linked

Question 2

Describe the autosomal dominant allele.

Answer 2

• Manifests in heterozygous form, meaning only one mutated allele needed to inherit condition
• Multiple generations affected
• Most will have affected parent (not all due to new mutations and incomplete penetrance)
• 50% risk of transmission to offspring
• if an affected individual’s siblings/children are not affected and they do not carry the mutation, they cannot pass it on to their offspring

Question 3

give some features of autosomal dominant inheritance.

Answer 3

Penetrance
Variable Expressivity
New mutation rate
Somatic (post-zygotic) mosaicism
Germ-line (gonadal) mosaicism
Anticipation

Question 4

Define penetrance.

Answer 4

% of individuals who carry the mutation (genotype) AND develop symptoms of the disorder (phenotype)

-many dominant disorders show age-dependent penetrance, e.g. the older a person is, the more likely they are to develop the condition if carrying a susceptible genotype

Question 5

Describe the autosomal recessive allele.

Answer 5

• manifested only in homozygous/compound heterozygous form (both mutated alleles have to be present to inherit the disorder)
• carriers not affected
• usually one generation affected
• may be consanguinity (e.g. cousin marriages)
• e..g. Cystic fibrosis (manifests in homozygous and compound heterozygous form)

Question 6

Describe Reduced/Incomplete penetrance.

Answer 6

Not all individuals with a mutant genotype show the mutant phenotype

e.g. person with mutation does not develop symptoms of disorder

Question 7

Give some features of autosomal recessive inheritance.

Answer 7

• trait found in clusters of siblings but not in parents and offspring
• recurrence risk= 25% for each sibling of affected person
• carrier probability= 2/3 for unaffected siblings of affected person
• all offspring of affected person are obligate carriers

Question 8

Define variable expressivity.

Answer 8

Individuals with the same genotype may have different phenotypes

e.g. variation in the symptoms of disorder in individuals with the same mutation (neurofibromatosis 1)

Question 9

What is X-linked inheritance?

Answer 9

A pattern of inheritance in which a recessive gene is carried on the X chromosome, so males are more likely to be affected because they are hemizygous (one X and Y chromosome)

Recessive X-linked:

• women are carriers + unaffected (unless skewed X inactivation)
• no male to male transmission

Dominant X-linked:

• women are affected
• males are more severely affected/lethal

Question 10

Give some features of X-linked Recessive inheritance.

Answer 10

• X-linked genes never passed from father to son (sons get X from mother)
• All daughters of affected males are obligate carriers (daughters get one X from father)
• Children of carrier females have a 50% chance of inheritance mutant allele

Question 11

Somatic (Post-zygotic) Mosaicism

Answer 11

new mutation arising at early stage in embryogenesis

- present in only some tissues/cells
- some cells will contain mutation, but majority don’t
e. g. Trisomy 21

Question 12

Are women not affected by X-linked recessive disorders?

Answer 12

The EXPECTED is that women are not affected by X-linked recessive disorder, however this is not always the case due to skewed X-inactivation

Question 13

What is Germ line (gonadal) Mosaicism?

Answer 13

new mutation arises during oogenesis or spermatogenesis

-mutation present in variable proportion of gametes and can be transmitted to offspring

Question 14

What is Skewed X inactivation?

Answer 14

occurs when the inactivation of one X chromosome is favoured over the other, leading to an uneven number of cells with each chromosome inactivated

causes manifesting carriers, with symptoms of X-linked recessive conditions e.g. cardiomyopathy in DMD

Question 15

What is meant by anticipation?

Answer 15

worsening of disease severity in successive generations

-occurs in triplet repeat disorders (e.g. Huntington’s Disease)

Question 16

What is Y-linked inheritance?

Answer 16

• mutation is always and only passed from fathers to sons

- example is a form of hirsutism between fathers and sons (hairy ears)

Question 17

What does a pathogenic mutation cause?

Answer 17

Alteration of the function of the gene product and can cause a disease phenotype

Question 18

What are the different types of mutation?

Answer 18

substitution, deletion, insertion

Question 19

Where can mutations be found?

Answer 19

Coding DNA

Non-coding DNA (e.g. promoters and introns)

Question 20

What is a Silent/Synonymous Base Substitution

Answer 20

This is a mutation where a nucleotide changes without the amino acid changing due to the degenerate code

-silent mutations are caused by mismatch repair system not functioning properly

Question 21

What is a Point Mutation- Missense/Non-synonymous?

Answer 21

A mis-sense mutation is when a base substitution causes for a change in amino acid

incorrect amino acid may produce malfunctioning protein (if amino acid very different then more likely to be pathogenic, but if very similar it might not have an impact on protein)

Question 22

What is a Point Mutation- Nonsense/Non-synonymous?

Answer 22

A nonsense mutation is when there is a premature stop codon resulting in a truncated protein

Can cause removal of functional parts of protein and shortening of protein

However, mRNA strand can sometimes be degraded by nonsense mediated decay

Question 23

What is a frameshift mutation?

Answer 23

mutation that involves the insertion or deletion of a nucleotide in the DNA sequence

Question 24

Which mutations are most likely to be pathogenic?

Answer 24

Nonsense mutations and frameshift mutations