Modes of inheritance

Question 1

What are the four different modes of inheritance?

Answer 1

Autosomal dominant
Autosomal recessive
Y and X-linked
Mitochondrial

Question 2

What is autosomal dominant inheritance? Give examples

Answer 2

Single copy of the dominant alleles is enough for the dominant trait to be expressed
Single allele disease
located on one of the non-sex chromosomes
eg Dark hair over blonde

Question 3

What gene is responsible for brown eyes being dominant?

Answer 3

OCA-2 - controls the amount of melanin in melanocytes

active → High amount of melanocytes → brown eyes

Question 4

What 3 autosomal dominant mutations can occur?

Answer 4

Gain-of-function - gene programs for protein with new better function
Dominant negative effect - interference with the activity of normal proteins reducing activity
Insufficient - Mutant in one gene results in ½ the amount of a protein, this is not enough for normal function

Question 5

What pedigree characteristics does an autosomal dominant trait have?

Answer 5

Males and females equally affected - equal chance of passing it on
Vertical pedigree pattern
Cannot be recessive - affected parents have affected offspring

Question 6

What type of condition is huntingtons disease and what mutation has occurred? What does this result in?

Answer 6

Autosomal dominant mutation of HTT gene (Chr 4) for huntingtin protein - causes expansion of CAG
Altered huntingtin protein aggregates to form toxic protein aggregates which prevent normal nerve cell function

Question 7

What is genetic anticipation?

Answer 7

With every generation, age of onset decreases and severity of symptoms increases

Question 8

What age do symptoms of huntingtins start and what are they?

Answer 8

30-50 years

• difficulty concentrating
• depression
• stumbling
• involuntary jerking (dyskinesias)

Question 9

What type of mutations occur in autosomal recessive disorders?

Answer 9

Loss of function mutations (eg deletions)

Question 10

What are some pedigree features of autosomal recessive disorders?

Answer 10

• parents and children of affected people are normally unaffected
• one or more siblings affected
• Males and females equally affected
• horizontal pedigree pattern

Question 11

What type of genetic disorder is cystic fibrosis? What causes CF and what does this result in?

Answer 11

autosomal recessive - causes mutations in CFTR gene on chromosome 7 which encodes chloride ion channels

Results in defective chloride ion channel → results in impaired airway defence → prone to respiratory infections → digestive issues occur (ie meconium ileus)

Sticky mucus build up outside the cell due to lack of chloride channel

Question 12

Who do X-linked recessive disorders usually affect?

Answer 12

Mainly males - almost dominant
Females can be carriers

Homozygous females have the condition

Question 13

How can you recognise X linked recessive disorders on a pedigree?

Answer 13

Affected boys have affected uncles

Parents and children of affected people are commonly unaffected

Question 14

What is an example of an X-linked recessive condition?
What genes is effected and how does it present?
What can female carriers sometime show?

Answer 14

mutations of genes coding for clotting factors VII (haemophilia A) or IX (haemophilia B)
Partial or complete absence of the affected clotting factor results in impaired clotting

presentation -
Mild/moderate/severe presentations
Easy bruising
Excessive bleeding from cuts that takes a long time to stop
Tendency to bleed into joints and muscles causing pain, swelling and limitation of movement

Female carriers can exhibit subtle signs - fabrys disease

Question 15

Who do X-linked dominant disorders mainly affect?

Answer 15

All daughters and no sons of an affected father are affected
condition milder and more variable in females then males

Question 16

What is hypophosphatemia and how does it present?

Answer 16

mutation of the PHEX gene leading to overproduction FGF21
FGF21 inhibits kidney phosphate resorption
Kidneys can not retain phosphate
Results in vitamin D-resistance rickets

presentation:
Low serum phosphate (lost in urine)
Soft, weak bones (rickets)
bone deformities and high risk of fracture
Bone, joint and muscle pain
Impaired growth

Question 17

How can you distinguish a y-linked disorder in a pedigree?

Answer 17

Affects only males
All sons of an affected father have it
Vertical pedigree pattern

Question 18

What is an example of a y linked condition?

What is the mutation and how does it present?

Answer 18

Retinitis pigmentosa
Mutation in RPY gene causing cells of retina to produce a defective protein

Presentation:
Trouble seeing at night
Decreased peripheral (side) vision (may develop tunnel vision)

Question 19

How are mitochondrial inherited disorders recognised on pedigree?

Answer 19

All mitochondria are inherited from mother so all children of an affected women may be affected
Children of affected men never affected
Vertical pedigree pattern
Variable conditions

Question 20

What is heteroplasmy and what does this mean for mitochondrial inheritance?

Answer 20

Mitochondria have multiple copies of their genome: some normal, some mutant (heteroplasmy)

Different mitochondria will have different number of mutant genomes

Disease only expressed if number of mutant genomes is above a threshold

Question 21

What causes mitochondrial disease variability

Answer 21

divide by binary fission - mtDNA replicates and sorts randomly among mitochondria
Mitochondria then sort randomly among daughter cells

Each daughter cell may receive different proportions of mitochondria carrying normal and mutant mtDNAi
Mitochondria can gain or lose mutant genomes with every cycle of binary fission as a result of random segregation

develops with age due to accumulation of mutant mitochondria

Question 22

What is leben’s Hereditary Optic Neuropathy? What is it caused by and how does it present?

Answer 22

Mitochondrial disease
Mitochondrially inherited mutation leading to degeneration of retinal ganglion cells

Presentation:
Late onset (adult life)
Rapid progressive loss of visual acuity and colour vision
Loss of central vision