inheritance patterns

Question 1

What are the classic Mendelian modes of inheritance?

Answer 1

Autosomal Dominant
Autosomal Recessive
X-linked
Y-linked

Question 2

Autosomal Dominant

Answer 2

• Manifests in heterozygous form, meaning only one mutated allele needed to inherit condition
• Most will have affected parent (not all due to new mutations and incomplete penetrance)
• 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

Features of Autosomal Dominant Inheritance

Answer 3

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

Question 4

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

Autosomal Recessive

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

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

Features of Autosomal Recessive Inheritance

Answer 7

• manifests in homozygous
  form only
• carriers are unaffected
• both parents must be carriers or one parent be affected
• trait found in clusters of siblings but not in parents and offspring

Question 8

Variable Expressivity in autosomal dominant

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

Question 9

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

New Mutation Rate in autosomal dominant

Answer 10

de novo mutation rate varies considerably between autosomal dominant conditions

Question 11

Features of X-linked Recessive inheritance

Answer 11

• 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 12

Somatic (Post-zygotic) Mosaicism in autosomal dominant

Answer 12

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 13

Are women not affected by X-linked recessive disorders?

Answer 13

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 14

Germ line (gonadal) Mosaicism in autosomal dominant

Answer 14

new mutation arises during formation of gametes: oogenesis or spermatogenesis
- mutation present in variable proportion of gametes and can be transmitted to offspring

Question 15

Skewed X inactivation

Answer 15

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 16

Anticipation in autosomal dominant

Answer 16

worsening of disease severity in successive generations

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

Question 17

Y-linked Inheritance

Answer 17

• mutation is always and only passed from fathers to sons

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

Question 18

What does a pathogenic mutation cause?

Answer 18

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

Question 19

Silent/Synonymous Base Substitution

Answer 19

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 20

Missense/Non-synonymous

Answer 20

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 21

Point Mutation- Nonsense/Non-synonymous

Answer 21

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 22

Which mutations are most likely to be pathogenic?

Answer 22

Nonsense mutations and frameshift mutations