6. INHERITANCE PATTERNS

Question 1

What are the four modes of Mendelian inheritance?

Answer 1

1. Autosomal Dominant
2. Autosomal Recessive
3. X-linked
4. Y-linked

Question 2

*What is autosomal dominant inheritance?

Answer 2

• Autosomal dominant disorders only require one copy of the gene so they manifest in the HETEROZYGOUS FORM
• Individuals with one copy will therefore be affected
• 50% chance that offspring will be affected if one parent is affected
• Both sexes can be affected
• Most affected individuals will have a parent who is affected but not always, could be due to new mutations arising or penetrance

Question 3

What are 6 features of autosomal dominant inheritance?

Answer 3

1. Penetrance
2. Variable Expressivity
3. De novo mutation rate
4. Somatic Mosaicism
5. Germ-line Mosaicism
6. Anticipation

Question 4

What is penetrance?

Answer 4

• Penetrance refers to the percentage of individuals who have the mutation go on to develop symptoms
• Reduced penetrance = not everyone with genotype develop symptoms
• 100% penetrance = almost always develop symptoms
• Age-dependent penetrance is characteristic of autosomal dominant disorders

Question 5

What is variable expressivity?

Answer 5

• Variable expressivity refers to the symptoms of a disorder differing between individuals

Question 6

What is mosaicism & what are the two types of mosaicism?

Answer 6

• Mosaicism is when the genetic make up of two or more cells differ in an individual as a result of error in mitosis
  1. Somatic mosaicism
  2. Germ-line mosaicism

Question 7

What is somatic mosaicism & germ-line mosaicism?

Answer 7

• Somatic mosaicism occurs during the early stages of embryogenesis. Only the daughter cells that arise from the mutated cell will be affected
• Germ-line mosaicism occurs during oogenesis/spermatogenesis. A variable proportion of gametes will be affected, the mutations can be passed on to offspring but this due to random chance

Question 8

What is autosomal recessive inheritance?

Answer 8

• Autosomal recessive disorders require two copies of the gene in order to be affected
• It can manifest as HOMOZYGOUS or COMPOUND HETEROZYGOUS
• Individuals with only one copy of the gene are considered to be carriers
• Autosomal recessive disorders only tend to affect one generation & can be characteristic of consanguinity (cousin marriages)

Question 9

What’s the difference between compound heterozygote & homozygote (autosomal recessive inheritance)?

Answer 9

• Compound heterozygote - inherit two different mutations of the same gene. Two mutations of the same gene that aren’t identical
• Homozygote = two mutations of the same gene that are identical. May be characteristic of consanguinity

Question 10

What are the genotypes for X-linked disorders for men & women?

Answer 10

• Women have two X chromosomes so can be HOMOZYGOUS or HETEROZYGOUS
• Men only have one X chromosome so they can only be HEMIZYGOUS

Question 11

What are the characteristics of recessive X-linked inheritance?

Answer 11

• Women are carriers & are unaffected, due to X-inactivation

- There is no male to male transmission as men cannot pass on an X chromosome to their sons

Question 12

What are the characteristics of dominant X-linked inheritance?

Answer 12

• Women can be affected as they only need one copy, so X inactivation an still mean an X with dominant gene is active
• Men are more severely affected

Question 13

Why does X inactivation lead to manifesting carriers?

Answer 13

• In women, one of the X chromosomes will be inactivated in some cells whilst others will have both active. Most of the time the X chromosome with the mutation will be inactivated
• HOWEVER, some women will have SKEWED X INACTIVATION where the X chromosome without the mutation is inactivated meaning that the X chromosome with the mutation can is active.
• This can lead to manifesting carriers

Question 14

What are the three main types of mutation?

Answer 14

1. Substitution
2. Deletion
3. Insertion

Question 15

*What is a silent mutation?

Answer 15

• A silent/synonymous mutation leads to an base change without changing the AA. This is because more than one codon codes for an AA.

Question 16

What is missense & nonsense point mutation?

Answer 16

• A base substitution or SNP that is pathogenic is known as a point mutation
• MISSENSE = a base change resulting in an AA which can change he structure and/or function of the protein. Therefore protein can be non-functioning or malfunctioning
• NONSENSE = a base change leads to a stop codon, which means that the protein is prematurely truncated or shortened

Question 17

What are the two types of deletions/insertion mutations?

Answer 17

1. In-frame = deletion or insertion - multiple of 3

2. Frame-shift = deletion or insertion - not a multiple of 3

Question 18

What is the difference between an in-frame mutation & a frameshift mutation?

Answer 18

• In-frame mutations tend to be harmless as they don’t change the reading frame
• HOWEVER, frame shift mutations shift/change the reading frame affecting the codons & therefore the AA
• A change in the primary structure (AA sequence) of the protein can affect the 3D structure & it’s function
• Frameshift mutations can lead to a malfunctioning protein.