7. Inheritance Patterns

Question 1

Key for pedigree drawing

Answer 1

• Males are squares
• Females are circles
• Partners have a line between them
• Siblings have a line above them
• Line down for children
• Affected people are shaded
• Carriers have dots in
• Double line joins union of consanguineous couple (share the same blood)
• Unknown sex are diamonds
• P stands for pregnant
• SB stands for stillborn
• Non-identical twins have an incomplete triangle above them - identical twins have a complete triangle above them
• Triangle shows miscarriage
• Triangle with a line through it shows therapeutic abortion

Question 2

What are the 4 ways of inheritance?

Answer 2

1) Autosomal dominant
2) Autosomal recessive
3) X-Linked
4) Y-Linked

Question 3

Autosomal dominant inheritance. Main points.

Answer 3

• Manifest in HETEROZYGOUS form
• Multiple generations affected
• Both sexes affected
• Male to female & female to male transmission
• Most will have an affected parent
• 50% risk to offspring

Question 4

What are the characteristics of inheritance patterns autosomal dominant (AD)?

Answer 4

• 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.
• Risk for each child of an affected parent is ½.
• If an affected individual’s siblings/children are not affected, and they do not carry the mutation they cannot pass it on to their own offspring.

Question 5

Features of autosomal dominant inheritance

Answer 5

• Many dominant disorders show age-dependant penetrance
• Variable expressivity
• de novo mutation rate varies considerably between AD conditions
• Somatic mosaicism is present in only some tissues/cells
• Mutation present in variable proportion of gametes; can be transmitted to offspring
• Anticipation characteristically occurs in triplet repeat disorders (e.g. Huntington’s)

Question 6

What is penetrance?

Answer 6

Percentage of individuals who carry the mutation AND develop symptoms of the disorder

Question 7

What is variable expressivity?

Answer 7

Variation in severity/symptoms of disorder between individuals ( or within the family) with same mutation

Question 8

What is somatic and germ-line mosaicism (gonadal mosaicism)?

Answer 8

• Somatic mosaicism: new mutn arising at early stage in embryogenesis
• Germ-line mosaicism (gonadal mosaicism): new mutn arises during oogenesis or spermatogenesis

Question 9

What is anticipation of a disease?

Answer 9

Worsening of disease severity in successive generations

Question 10

Autosomal recessive inheritance. Main points.

Answer 10

• Manifest in HOMOZYGOUS/ COMPOUND HETEROZYGOUS form
• Carriers (heterozygote) not affected
• Both sexes affected
• Male to female and female to male transmission
• Usually one generation affected
• May be consanguinity - e.g. cousin marriages
• 25% affected, whilst 50% carriers

Question 11

What is the difference between compound heterozygote and homozygote?

Answer 11

• In homozygote, there are 2 identical mutations in the same gene
• In compound heterozygote, there are 2 different mutation in the same gene.
- The outcome is the same as both copies are still not functioning properly. e.g. in cystic fibrosis.
- This is seem more often than homozygous

Question 12

Features of autosomal recessive inheritance

Answer 12

• Trait often found in clusters of siblings but not in parents & offspring.
• 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 13

X-linked inheritance

Answer 13

• Women have two X chromosomes
     - Two copies of X-linked genes
     - Can be homozygous or heterozgous
• Men have one X and a Y 
     - Only a single copy of X-linked genes
     - Hemizygous
• Can be recessive (mostly)
     - Women are carriers + unaffected
     - No male to male transmission
• Can be dominant
     - Women are affected
     - Males more severely affected/lethal

Question 14

Aspects of x-linked recessive inheritance

Answer 14

• 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 mutant allele.

• SKEWED X-INACTIVATION: normally the majority of genes on one of a woman’s X-chromosomes are inactivated
- the active mutated X chromosome is the one expressing all the proteins
• MANIFESTING CARRIERS: some women have some symptoms in X-linked recessive conditions e.g. cardiomyopathy in DMD.

Question 15

Y-linked inheritance

Answer 15

Always and only passed from fathers to sons

Question 16

What is a mutation? What are the different types? and where are they found?

Answer 16

• Mutation: a change in the genetic material
• A pathogenic mutation (pathogenic variant) results in an alteration of the function of the gene product and can cause a disease phenotype
• Depending on the type of mutation – can present as dominant or recessive

• Types:
     - Substitutions (point mutations)
     - Deletions 
     - Insertions
• Found in:
     - Coding DNA
     - Non-coding DNA (such as promoters and introns)

Question 17

What is a missense and nonsense mutation?

Answer 17

• Missense = a point mutation with leads to a change in AA (a type of nonsynonymous substitution)
• Nonsense = when the codon is changed into a stop codon

Question 18

Impact of amino acid substitution

Answer 18

• Physicochemical similarity between the two aminoacids
• Functional role of the specific domain of the protein
• Phylogenetic conservation of original aminoacid amongst diverse species

Question 19

What is the different between in-frame mutations and frameshift muations?

Answer 19

• In-frame is indels (insertion/deletions) of nucleotides that is divisible by 3 (doesn’t change the frame)
• Frameshift mutations are indels of nucleoties that is not divisible by 3.

• Frameshift indels and nonsense mutations are more likely to be pathogenic.