Modes of Inheritance Flashcards
What are the 6 types of inherited disorders?
- Autosomal dominant
- Autosomal recessive
- X-linked dominant
- X-linked recessive
- Y-linked
- Mitochondrial
What are autosomes?
Chromosomes not involved in determining sex (1-22)
What are autosomal dominant alleles?
Only 1 inherited for phenotype
Why are brown eyes dominant?
Even just 1 active OCA-2 gene —> enough melanin produced for brown eyes
What is the chance of an autosomal dominant affected parent having an affected child?
1/2
What type of pedigree pattern do autosomal dominant disorders have?
Vertical
How do autosomal dominant alleles change a phenotype? (3)
- Gain-of-function
- Dominant negative effect
- Haploinsufficient
What is a gain-of-function effect?
Gene makes protein with new function
What is a dominant negative effect?
Mutated gene produces protein that can’t bind properly (eg. dimers/multimers produced)
What is a haploinsufficient effect?
Loss of 1 allele copy —> not enough protein produced
What are 2 examples of autosomal dominant disorders?
- Huntington’s disease
- Hypertrophic cardiomyopathy
What are the 5 symptoms of Huntington’s disease?
- Difficulty concentrating
- Depression
- Stumbling
- Involuntary jerking
- Swallowing issues
When do Huntington’s disease symptoms usually start?
Age 30-50
What mutation causes Huntington’s disease?
CAG repeats —> multiple glutamines in huntingtin protein
Why does the CAG expansion cause Huntington’s?
Abnormal huntington protein aggregates in cells —> toxic to neurones —> cell death
How does hypertrophic cardiomyopathy affect the heart? (4)
- Thick heart muscles
- Reduced heart chamber volume
- Stiffer heart walls
- Sudden cardiac death
What type of genetic disorder is Huntington’s disease?
Autosomal dominant
What type of genetic disorder is hypertrophic cardiomyopathy?
Autosomal dominant
What is the most common mutation leading to cardiomyopathy?
MYH7 gene (β-myosin heavy chain)
- Also MYBPC3 —> mutated myosin binding protein c
Why does MYH7 mutation lead to hypertrophic cardiomyopathy?
Decreased ATPase activity —> reducing sliding velocity —> weaker cardiac muscle —> compensatory cardiac muscle growth
What happens to cardiac function in hypertrophic cardiomyopathy?
Reduced
Why does hypertrophy occur in hypertrophic cardiomyopathy?
Compensatory (weaker muscle)
What are carriers?
Those with 1 copy of recessive disorder allele —> can pass on disorder but don’t have it
What are autosomal recessive alleles?
Need 2 copies for phenotype
How do autosomal recessive alleles change a phenotype?
Loss-of-function
What is the chance of an autosomal recessive affected child having an affected sibling?
1/4
What type of pedigree pattern do autosomal recessive disorders have?
Horizontal
What increases the risk of autosomal recessive diseases in a family?
Cosanguineous marriages
What do cosanguineous marriages lead to and why?
Increased risk of autosomal recessive disorders in children
- Smaller gene pool
What symbol represents disease gene frequency?
q
How do you calculate the risk of having an affected child via q?
1/q^2
How do you calculate the risk of having an affected 1st cousin of an affected child via q?
1/(q/16)
How does the prevalence of an autosomal recessive disease affect the risk of inheritance in cosanguineous marriages?
Less prevalent (rarer) —> higher risk
What is an example of an autosomal recessive disease?
Cyctic fibrosis
What type of disease is cystic fibrosis?
Autosomal recessive
What are the 4 symptoms of cystic fibrosis?
- Failure to thrive
- Impaired airway defence
- Prone to respiratory infections
- Digestive issues
Which mutations cause cystic fibrosis?
CFTR gene mutations (chromosome 7) —> codes for chloride ion channel
What is the result of CFTR gene mutations in cystic fibrosis?
Defective chloride ion channels (loss-of-function)
What are the sex chromosomes?
Chromosomes determining individual’s sex
- Females —> XX
- Males —> XY
How many genes do X chromosomes contain?
1000-1300
How many proteins do X chromosomes code for?
850
How many genes do Y chromosomes contain?
850
How many proteins do Y chromosomes code for?
50-70
Which sex do X-linked disorders mainly effect and why?
Males
- Only need 1 copy —> effectively dominant
How are males with X-linked disorders connected?
Via females
∴ affected son may have affected maternal uncle
What is the chance of an X-linked affected son having an affected brother?
1/2
What is the chance of an X-linked affected son having a carrier sister?
1/2
What will daughters of an X-linked affected male all be?
Carriers
What are 2 examples of X-linked disorders?
- Haemophilia (rec)
- X-linked hypophosphatemia (dom)
What type of disease is haemophilia?
X-linked recessive
What type of disease is X-linked hypophosphatemia?
X-linked dominant
What causes haemophilia?
Issues with clotting factors VIII or IX
What is the main symptom of haemophilia?
More/worse bleeds
Do female carriers of X-linked disorders ever display symptoms?
Sometimes
- If unaffected X chromosome inactivated
What are X-linked recessive disorders?
Need all X chromosomes affected for phenotypes
- more common in males
What are the 5 symptoms of X-linked hypophosphatemia?
- Rickets (vit D resistant)
- Growth effects
- Lower serum phosphorus
- Osteomalacia
- Fractures/pseudofractures
Which mutation leads to X-linked hypophosphatemia?
PHEX gene
Why does a PHEX mutation lead to X-linked hypophosphatemia?
FGF21 overproduced —> inhibits kidney phosphate reabsorption + retention
Which sex do Y-linked disorders affect?
Males
What is the chance of a Y-linked affected father having an affected son?
1 —> all
What pedigree pattern do Y-linked disorders display?
Vertical
What is an example of a Y-linked disorder?
Retinitis pigmentosa
What type of disease is retinitis pigmentosa?
Y-linked
What is the main symptom of retinitis pigmentosa?
Sight loss
Which mutation causes retinitis pigmentosa?
RPY gene
Why does a RPY mutation cause retinitis pigmentosa?
Retina cells produce defective protein
What is the main difference between the inheritance of X-linked recessive vs dominant disorders?
- Recessive —> more males
- Dominant —> more females
What is mitochondrial endosymbiosis?
Mitochondria once existed as bacteria —> taken up by eukaryotic cells
Why is mitochondrial disease inheritance different from other diseases?
Mitochondria have own DNA
What are most mitochondrial diseases caused by?
Mitochondrial DNA mutations (90%)
Why can some mitochondrial diseases be caused by mutations in nuclear genes?
Some autosomal/sex chromosome genes code for mitochondrial proteins
What type of inheritance do mitochondrial diseases display and why?
Maternal
- Mitochondria inherited from mother
What is the chance of a mitochondrial affected mother having an affected child?
1 —> all
What pedigree pattern do mitochondrial disorders display?
Vertical
Are mitochondrial conditions consistent within a family?
No —> very variable
What is heteroplasmy?
Multiple types of mitochondrial DNA within an individual’s cells
Why do mitochondrial diseases have so much variability?
Heteroplasmy
- Some normal + some affected mitochondria
- Each mitochondria must pass affected DNA threshold
- Each cell must pass affected mitochondria threshold
How do mitochondria replicate?
Binary fission
What can happen to mutated mitochondrial genes during mitochondrial replication?
Gained or lost
∵ random segregation
What does the severity of a mitochondrial disease depend on?
Number of affected mitochondria
Why may mitochondrial diseases develop over time?
Accumulation of mutant mitochondria to pass threshold
Which functions are commonly affected by mitochondrial diseases? (2)
- Motor
- Nerve
What is an example of a mitochondrial disorder?
LHON (Leber’s hereditary optic neuropathy)
What is the main symptom of LHON and why?
Visual loss in young adulthood
- Degeneration of optic nerve and retina
Which sex is more commonly affected by LHON?
Males
