Inheritance Patterns

Question 1

Describe the characteristics of the autosomal dominant inheritance pattern.

Answer 1

• most individuals have an affected parent (not everybody due to cases of new mutations or incomplete penetrance)
• males and females are equally likely to inherit the allele and be affected
• the risk for each child of an affected parent is 1/2
• if an unaffected individual’s siblings/children are not affected, and they do not carry the mutation, then they cannot pass it on to their own offspring

Question 2

What is penetrance?

Answer 2

Penetrance is the percentage of individuals who carry the mutation AND develop symptoms of the disorder - many dominant disorders show age-dependent penetrance.

Question 3

List and describe some features of autosomal dominant inheritance patterns.

Answer 3

VARIABLE EXPRESSIVITY: It is the variation in the severity/symptoms of the disorder between individuals with the same mutation.

NEW MUTATION RATE: the de novo mutation rate varies considerably between AD conditions

SOMATIC MOSAICISM: new mutations arising at an early stage in embryogenesis - present in only some tissues/cells

GERM-LINE MOSAICISM (gonadal mosaicism): new mutation arises during oogenesis or spermatogenesis - mutation must be present in a variable proportion of gametes; can be transmitted to offspring

ANTICIPATION: the worsening of disease severity in successive generations - characteristically occurs in triplet repeat disorders

Question 4

Describe the characteristics of autosomal recessive inheritance.

Answer 4

• manifest in homozygous/compound heterozygous form
• carriers (heterozygous) not affected
• both sexes affected
• male to female and female to male transmission
• usually, one generation affected
• may be consanguinity (eg. cousin marriages)

Question 5

What is the difference between compound heterozygote and homozygote?

Answer 5

Compound Heterozygote:

• two mutations are in the same gene
• the mutations are different

Compound Homozygote:

• two mutations are in the same gene
• they are identical mutations
• (may suggest consanguinity)

Question 6

List some features of autosomal recessive inheritance.

Answer 6

• the traits are often found in clusters of siblings, but not in parents and offspring
• the recurrence risk is 1/4 for each sibling of an unaffected person
• the carrier probability is 2/3 for unaffected siblings of the affected person
• all offspring of the affected person are obligate carriers

Question 7

Describe how the difference in sex chromosomes affects X-linked inheritance.

Answer 7

Women have 2 X chromosomes.

• thus, they have two copies of X-linked genes, giving slight protection
• they can be homozygous or heterozygous for these disorders

Men have one X and one Y chromosome.

• thus, they only have a single copy of X-linked genes
• they are said to be hemizygous

Question 8

How is X-linked inheritance recessive or dominant?

Answer 8

X-linked inheritance can be:

RECESSIVE:

• women are carriers + unaffected
• no male to male transmission

DOMINANT:

• women are affected
• males more severely affected/lethal

Question 9

Describe the characteristics of X-linked recessive inheritance.

Answer 9

• X-linked genes are never passed from father to son
• all daughters of affected males are obligate carriers
• children of carrier females have a 50% chance of inheriting the mutant allele

Skewed X-Inactivation: normally, the majority of genes on one of a woman’s X-chromosomes are inactivated (it’s generally random, but ~10% of women have uneven or skewed X-inactivation)

Manifesting Carriers: some women have some symptoms in X-linked recessive conditions (eg. cardiomyopathy in DMD)

Question 10

Define a pathogenic mutation.

Answer 10

A mutation is a change in genetic material.
A pathogenic mutation (pathogenic variant) results in an altercation of the function of the gene product and can cause a disease phenotype.

Question 11

List the types of mutations and where they are found.

Answer 11

Types of mutations:

• substitutions (point mutations)
• deletions
• insertions

Found in:

• coding DNA
• non-coding DNA (such as promoters and introns)

Question 12

What is a silent/synonymous substitution?

Answer 12

It when there is a nucleotide change that doesn’t change the amino acid made.

Question 13

How do we determine the impact of an amino acid substitution?

Answer 13

• physicochemical similarity between the two amino acids
• functional role of the specific domain of the protein
• phylogenetic conservation of the original amino acid amongst a diverse species