Case 13- mechanism of inheritance Flashcards
Homozygous dominant inheritance
AA x aa –> A A a a –> Aa, Aa, Aa, Aa –> 100% heterozygous. All offspring will develop the dominant phenotype.
One Heterozygous dominant inheritance
Aa x aa –> A a a a –> Aa, Aa, aa, aa –> 50% heterozygous, 50% homozygous recessive. Half of the offspring will develop the dominant phenotype.
2 Heterozygous recessive inheritance
Aa x Aa –> A A a a –> AA, Aa, Aa, aa –> 25% homozygous dominant, 50% heterozygous, 25% homozygous recessive. 25% will develop the recessive phenotype.
Homozygous x Homozygous inheritance
AA x aa –> A A a a –> Aa, Aa, Aa, Aa –> 100% heterozygous. None of the offspring will develop the recessive phenotype but they will all be carriers.
1 Heterozygous recessive X-linked disease
(X^A x Y) x ( X^A x X^a) –> ( X^A x X^A), ( X^A x X^a), ( X^A x Y) (X^a x Y) –> 50% of males will have the disease, 50% of males wont have the disease and 50% of the females will be carriers. Overall, 25% of offspring get the disease.
Two Homozygous recessive X-linked disease
(X^A x X^a) x (Y x X^a) –> (X^A x X^a), (X^a x X^a), (X^A x Y), (X^a x Y) –> 50% of males will have the disease, 50% of males will not have the disease, 50% of females will be carriers and 50% of females will have the disease. Overall, half of all offspring will have the disease.
Why do X-linked diseases affect more men
If the disease is fatal to males it is unlikely that they will live long enough to pass on their genes. This means females are less likely to get the disease as they need two copies of the gene. However, men can get it from female carriers.
Inheritance of mitochondrial DNA
1) It is passed down the maternal line
2) Mutations can form in the mitochondrial DNA
3) During meiosis there is uneven assortment of DNA, some egg cells may contain more mutated DNA and some may contain less
4) During embryo development mutated mitochondrial DNA can divide and become more prominent
5) One child may have 50% mutated mitochondrial DNA and have a severe disease whilst another child may only have 25% mutated mitochondrial DNA and have a mild disease.
Penetrance
Penetrance of an inherited disease is the proportion of people who have a particular mutation who go on to develop the disease.
Expressivity
Variability in the signs/symptoms a particular individual may experience
What influences Penetrance
1) Link between gene and disease, some diseases have a 100% penetrance.
2) Environmental factors/lifestyle
3) Age- Huntington’s is late onset, people may die before they get the disease
Disease which does not have full penetrance
The BRCA1 gene increases your risk of breast cancer
Diseases which have different levels of expressivity
Marfan syndrome as there are variable signs and symptoms. It is a connective tissue disorder
Why do we use family trees?
- Records family history.
- Build a pattern of inheritance.
- Aids diagnosis /investigation /management.
Key rules for family trees
- Use conventional symbols
- 3 generations
- Mark affected/ unaffected/ carrier
- Include abortions/miscarriages
- Indicate individuals seeking advice
Male symbol
Square
Female symbol
Circle
Partners symbol
Connected by line
Separated symbol
Diagonal line through the straight line connecting the partners
Un-identical twins symbol
Upside down V
Identical twins symbol
Triangle
Consultant symbol
Arrow pointing
Proband symbol
First individual with disease. Arrow pointing with P in the corner
With disease symbol
Filled in
Carries (not likely to get disease) symbol
Dot in the middle
Carriers (asymptomatic or presymptomactic) symbol
Line through the centre
How to arrange the family tree
For partners males on the left and females on the right. For siblings eldest on the left and youngest to the right
Miscarriage or abortion symbol
Small triangle
Symbol to indicate death
Put a diagonal line through the person. Add the age they died on the side as well as cause
How to denote close relations between partners i.e. distant cousins
Two horizontal lines between them
Examples of mitochondrial disease
Includes Leber’s Hereditary Optic Neuropathy (LHON) and LHON plus. Leigh’s disease. Pyruvate Dehydrogenase Complex deficiency (PDCD/PDH).
Characteristics of Mitochondrial disease
Can only be passed down the maternal line. If a male has a mitochondrial disease he can not pass it on to his children. Another may not pass the mitochondrial disease to all of her children, it depends how much of the mutated mitochondrial DNA ends up in each egg cell.
Diseases with a dominant pattern of inheritance
1) Huntington’s disease
2) Marfan syndrome
3) Neurofibromatosis
4) Achondroplasia
Huntington’s disease
Mutation in the Huntington gene. Causes disruption in the control of movement as nerve cells die in a region of the brain which controls movement. This causes Choreiform movement. Degenerative disease which gets worse over time. Delayed onset, symptoms occur at 40/50 but gets earlier in subsequent generations. Continuous movement. Dominant inheritance
Marfan syndrome
Due to Fibrillin deficiency. A connective tissue disorder which leads to thin individuals with elongated fingers (Arachnodactyly). Increased risk of Dissecting aortic aneurysms. Dominant inheritance
Neurofibromatosis
An NFI gene mutation. Dysregulation of RAS which is a tumour suppressor, leads to multiple neufibromas (tiny bumps). It is a disorder of the nervous system affecting development of nerve cell tissues. There is an increase tumour risk. Dominant inheritance
Achondroplasia
Lack of bone growth. A mutation in a growth factor receptor gene. Causes dwarfism. Dominant inheritancr
List of diseases with a recessive pattern of inheritance
1) Cystic fibrosis
2) Thalassaemia
3) Phenylketonuria
4) Hartnups disease
Cystic fibrosis
An autosomal recessive disease. A mutation in the CFTR gene resulting in a disruption in sodium/chloride movement. Causes sticky mucus and salty sweat.
Thalassaemia
It is autosomal recessive, there are alpha and beta types. Alpha Thalassaemia involves two genes HBA1 and HBA2. Beta thalassaemia has one gene HBB.
Phenylketonuria
Is autosomal recessive due to a mutation in Phenylalanine hydroxylase. Body can not metabolise the amino acid Phenylalanine. Causes mental disability and a mousy smell as the brain does not receive enough amino acids and becomes damaged, the phenylalanine clogs up the amino acid transporters in the brain. The smell is due to the body trying to metabolise the phenylalanine, the products then produce this smell.
Hartnups disease
Is autosomal recessive and is due to a defect in uptake of neutral amino acids. Results in the malabsorption of Tryptophan. Causes Pellagra (skin rash). Uncontrolled can cause problems in the brain.
Disease with an X-linked pattern of inheritance
1) Haemophilia A
2) Haemophilia B
3) Colour blindness
4) Duchenne muscular dystrophy
Haemophilia A
A factor VIII deficiency. A blood clotting disorder. Leads to haemorrhage and longer PTT. X linked disease.
Haemophilia B
A factor IX deficiency, blood clotting disorder. Leads to haemorrhage and longer PTT. X linked disease
Colour blindness
A mutation of opsin pigment in the cones of the retina. Depending on which genes it can lead to red-green or blue-yellow colour blindness. X linked disease.
Duchenne muscular dystrophy
A mutation for the gene dystrophin. A muscle wasting disease, which affects muscle which connects cytoskeleton’s to the basal lamina. Muscle weakening and muscle wasting. X linked disease. Degenerative.
