Inheritance patterns

Question 1

On a pedigree drawing how are males and females represented?

Answer 1

• Males are represented by squares
• Females represented by circles

Question 2

On a pedigree diagram how are partners represented?

Answer 2

• Partners represented by a line between the two of them

Question 3

On a pedigree diagram how are siblings represented?

Answer 3

• Siblings are represented by a line above them

Question 4

On a pedigree diagram how are carriers and the affected represented?

Answer 4

• Affected people are completely shaded
• Carriers can either be unshaded or have a dot in them

Question 5

On a pedgree diagram how are children represented?

Answer 5

• Children are represented by a line running down from the parents

Question 6

What does this symbol represent on a pedigree diagram

Answer 6

• Represents a consanguineous partenership (Partners are related to each other)

Question 7

What does this symbol represent on a pedigree diagram?

Answer 7

• Indicates that the person is deceased

Question 8

What do these 2 symbols represent on a pedigree diagram?

Answer 8

• Triangle represents spontaneous abortion
• Triangle with the line through it represents therapeutic abortion

Question 9

What do these 2 symbols represent on a pedigree diagram?

Answer 9

• Angular lines, with horizontal line connecting them, running down to siblings of same sex indicates monozygotic twins (identical twins)
• Angular lines, without horizontal line connecting them, which run down to siblings of different sex indicates dizygotic twins (Non-identical twins)

Question 10

What does this symbol represent on a pedigree diagram?

Answer 10

• Represents pregnancy

Question 11

What is autosomal dominant inheritance?

Answer 11

• A form of inheritance in which an individual only needs to have one copy of the mutant allele in order to be affected (herteozygous for the mutant allele).

Question 12

For autosomal dominant inheritance why don’t you usually see people with a homozygous genotype?

Answer 12

• Because usually if a person has both copies of the mutant allele (homozygous for the mutant allele) is in-utero lethal which means the embryo won’t survive the pregnancy

Question 13

What are some of the features of a pedigree diagram showing autosomal dominant inheritance

Answer 13

• Multiple generations affected
• Both sexes affected equally
• Male to female & female to male transmission

Question 14

In autosomal dominant inheritance what is the risk of offspring being affeceted?

Answer 14

50%

Question 15

Most people who are affected by an autosomal dominant disorder will have a parent that is affceted. What are the two exceptions to this rule?

Answer 15

• De novo mutations - New mutation within a persons genome may mean that that person develops an autosomal dominant disorder without either parent being affected
• Incomplete penetrance - Results in offspring not showing any symptoms of the disorder (not showing the phenotypes) despite having inherited the mutant from their parents (they have the genotype).

Question 16

Define the term “penetrance”

Answer 16

The percentage/proportion of individuals who carry the mutation and develop symptoms of the disorder

Question 17

What is age-dependent penetrance?

Answer 17

When the penetrance for a particular disorder increases as individuals get older.

Question 18

What type of penetrance do most autosomal dominant disorder show?

Answer 18

Reduced penetrance

Question 19

What is reduced penetrance?

Answer 19

When individuals who must possess the mutant allele for a particular disorder show absolutely no manifestations/symptoms of that disorder.

Question 20

Apart from reduced penetrance what are some of the other characteristics of autosomal dominant inheritance?

Answer 20

• Variable expressivity - Idea that the severity of symptoms/symptoms themselves can vary between individuals with the same mutation
• New mutation rate - New muation rate (de novo mutation rate) varies between different autosomal dominant disorders
• Somatic mosaicism
• Germ-line mosaicism
• Anticipation - Worsening of disease severity in successive generations

Question 21

Explain the idea of Somatic mosaicism

Answer 21

• Refers to the presence of 2 or more populations of cells with different genotypes within the somatic cells of an individual due to the prescence or absence of a new mutation.
• The new mutation developes at an early stage of embryogenesis.
• Mutation only affects some of the somatic cells so some tissues/cells will reamin unaffected

Question 22

Explain the idea of germline mosaicism (Gonadal mosaicism)

Answer 22

• Refers to the presence of 2 or more populations of cells with different genotypes within the gametes of an individual due to a new mutation
• New mutation develops during oogenesis or spermatogenesis
• Mutation can be passed down to offspring depending on whether the gametes responsible for fertilisation have the mutation or not

Question 23

What is autosomal recessive inheritance?

Answer 23

• A form of inheritance in which an individual needs to have both copies of a mutated allele in order to be affected
• Person can either be homozygous for the mutant allele or be a compound heterozygote

Question 24

What is meant by the term compound heterozygote and how does it compare to being a homozygote

Answer 24

• A person is a compound heterozygote when they have 2 mutations within the same gene but these 2 mutations are different so they have 2 different recessive alleles
• A person is a homozygote when they have 2 mutations within the same gene but these 2 mutations are exactly the same so they have 2 of the same recessive allele

Question 25

What are some of the features of a pedigree diagram showing autosomal recessive inheritance?

Answer 25

• Carriers (heterozygote) not affected
• Both sexes affected
• Male to female and female to male transmission
• Usually one generation affected

Question 26

What are some features of autosomal recessive inheritance?

Answer 26

• Trait often found in clusters of siblings but not in parents & offspring.
• Biological parents of an affected child are usually both heterozygous
• Recurrence risk = 1/4 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 27

What is meant by the term obligate carrier?

Answer 27

Somebody who may be unaffected but must carry a copy of the abnormal gene based on analysis of family history.

Question 28

In autosomal recessive inheritance how can a child still be affected if only one of their biological parents are heterozygous for the mutant allele?

Answer 28

• A new mutation occurs on the gamete inherited from the other parent
• Uniparental isodisomy occurs resulting in the offspring inheriting two copies of the heterozygous parent’s mutated allele

Question 29

What is x-linked inheritance?

Answer 29

• A form of inheritance in which a mutation within a gene on the X-chromosome (X-linked gene) leads to a male developing a disorder

Question 30

Why can females be homozygous/heterozygous for X-linked genes while males can only be Hemizygous?

Answer 30

• Females can be either homozygous or heterozygous because they have two X chromosomes and therefore have two copies of X-linked genes
• Males can only be hemizygous because they have one X and a Y chromosome and so only have a single copy of X-linked genes

Question 31

X-linked inheritance can be dominant or recessive. What are some features of both types of X-linked inheritance?

Answer 31

Dominant

• Women are affected
• Males more severely affected/lethal

Recessive

• Women are carriers and unaffected
• Men are always affected
• No male to male transmission

Question 32

What are some general features of X-linked inheritance?

Answer 32

• X-linked genes 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.

Question 33

What is skewed X-inactivation?

Answer 33

• This occurs when all or most of the genes present on one of the two X chromosomes are silenced.
• The choice of which X chromosome is silenced is generally random but 10% of women have uneven or skewed X-inactivation - when inactivation of one X chromosome is favoured over the other.

Question 34

Explain the concept of manifesting carriers

Answer 34

• When some women have some symptoms in X-linked recessive conditions
• Occurs as a result of X-inactivation silencing the genes on a healthy X-chromosome which would leave all the genes on the unhealthy X-chromosome to be expressed

Question 35

What is Y-linked inheritance?

Answer 35

• When a trait/disorder that is produced by genes located on the Y chromosome are passed down to offspring

Question 36

What are some features of Y-linked inheritance?

Answer 36

• Appears in all sons of males who exhibit that trait
• Is absent from daughters of trait carriers

Question 37

What is the difference between a mutation and a pathogenic mutation?

Answer 37

• Mutation - A change in the structure of a gene
• Pathogenic mutation - A change in the structure of a gene that results in an alteration of the function of the gene product and can cause a disease phenotype

Question 38

What are the different types of mutation?

Answer 38

• Substitutions
• Deletions
• Insertions

Question 39

What are the different types of substitution mutation?

Answer 39

• Synonymous substitution - occurs when a change in a single base doesn’t change the amino acid sequence

Missense substitution - occurs when a change in a single base does change the amino acid sequence therefore changing the protein produced

Nonsense substitution - occurs when a premature stop codon is seen within a DNA sequence resulting in the production of an incomplete protein

Question 40

What is an insertion mutation?

Answer 40

Insertion of a single nucleotide into a DNA sequence

Question 41

What is a deletion mutation?

Answer 41

Deletion of a single nucleotide from a DNA sequence

Question 42

What is meant when it is said that insertions and deletions can occur “in frame” or “in frameshift?”

Answer 42

• In frame - Insertion/deletion of bases in multiples of 3
• Frameshift - Insertion/deletion of bases not in multiples of 3 e.g. deletion of only 2 bases