(2) Categories and impact of genetic disease Flashcards
What are the 3 points of the triangle representing aetiology of disease?
100% environmental
Single gene
Polygenic
For any condition, the balance of genetic and environmental factors can be represented by a point somewhere within the triangle
What type of condition is achondroplasia?
Single gene but different heights
What type of condition is stroke?
Multifactorial with environment and polygenic factors - for some there may be single gene influence (Cadasil)
On a scale from 100% genetic to 100% environmental, what are the characteristics of diseases nearer the 100% genetic end?
- rare
- simple genetics
- unifactorial
- high recurrence rate
On a scale from 100% genetic to 100% environmental, what are the characteristics of diseases nearer the 100% environmental end?
- common
- complex genetics
- multifactorial
- low recurrence rate
Give an example of a 100% genetic disease
Duchenne muscular dystrophy (single gene - mutation in dystrophin gene)
Give an example of a 100% environmental disease
Scurvy
tuberculosis also near this end of the scale
Is osteogenesis imperfecta (OI) more genetic or environmental?
In the middle but nearer the 100% genetic end of the scale
Bone fragility caused by genes, expression different on environment
Give 5 classifications of genetic disorders
- multifactorial/complex
- single gene
- chromosomal
- mitochondrial
- somatic mutations
What are multifactorial/complex genetic disorders?
The interaction of multiple genes (genetic predisposition) in combination with environmental factors eg. type II diabetes, ischaemic heart disease
What is a single gene genetic disorder?
A mutation in a single gene = Mendelian inheritance - AD, AR, XL eg. cyctic fibrosis
What is a chromosomal genetic disorder?
An imbalance or rearrangement in chromosome structure eg. aneuploidy, deletion, translocation
What is a mitochondrial genetic disorder?
A mutation in mitochondrial DNA
What is a somatic mutation genetic disorder?
Mutation(s) within a gene(s) in a defined population of cells that results in disease eg. breast cancer
Not born with the mutation, mutation not found in the blood but found in the tumour
What are the 4 single gene modes of inheritance?
- autosomal dominant
- autosomal recessive
- X-linked
- mitochondrial
What are the characteristics of autosomal dominant (AD) inheritance?
- a trait or disease runs from one generation to the next
- males and females equally affected
- offspring of affected person has a 50% chance of inheriting the mutation
What is the chance of the offspring of an affected parent inheriting an AD disorder?
50% (1 in 2)
Autosomal dominant disordes are usually related to what?
- structural proteins
- receptors
- transcription factors
Give some examples of autosomal dominant disorders that are caused by gene mutations
- myotonic dystrophy
- marfan syndrome
- huntington disease
Give an example of an autosomal dominant disorder that is cause by chromosomal deletion or duplication
22q11 deletion syndrome
Are affected individuals of AD disorders homozygous or heterozygous?
They are heterozygous for the mutation (one copy of mutation/one normal gene)
What does ‘penetrance’ mean?
The frequency with which a specific genotype is expressed by those individuals that possess the mutation, usually given as a percentage.
What is incomplete penetrance?
Not all relatives who inherit the mutation develop the disorder
Give an example of a mutation that has incomplete penetrance
BRCA1 mutations - 80% life time chance of developing breast cancer
Penetrance may alter with which factor?
Age - eg. Huntington disease by 80 years has 100% penetrance
What is ‘expressivity’?
Variation in expression - the extent to which a heritable trait is manifested by an individual
Give 2 examples of genetic diseases that vary in expressivity
- Marfan syndrome = 100% penetrance but some have aortic dilatation, lens dislocation, stretch marks etc, others do not
- BRCA1 mutation = some may have ovarian cancer, some may have breast cancer, some both and some not at all (as it is not 100% penetrant)
What is ‘anticipation’?
The symptoms of a genetic disorder become apparent at an earlier age as it is passed from one generation to the next. In most cases, there is an increased in the severity of the symptoms too
Give 2 examples of genetic disorders that show anticipation
- myotonic dystrophy
- huntington’s disease
What is a new dominant/ de novo mutation?
A new mutation that has occurred during gametogenesis or in early embryonic development
Are the parents of those with new dominant/ de novo mutations affected?
No
The parents are not affected and the mutation is not detected in their blood cells. The child is the first to be affected in the family but can pass the mutation on to their own children
What are the characteristics of autosomal recessive (AR) inheritance?
- disease seen in one generation
- does not tend to pass from one generation to the next and so parents usually unaffected
- offspring of affected individuals has low risk of disease unless in consanguineous relationship
- relatives may be asymptomatic carriers of the disease
- affects males and females equally
- gene mutations, not chromosomes
Are those with autosomal recessive disorders homozygous or heterozygous?
Affected individuals are homozygous or compound heterozygous (two different mutations but they work together to give the disease)
What is the risk of offspring being affected if both parents are carriers of an AR disease?
1/4 (25%)
What is the risk to unaffected offspring being a carrier? (when both parents are heterozygous carriers of AR disorder)
2/3
Give some examples of autosomal recessive disorders
- cystic fibrosis
- many of the metabolic disorder
- haemachromatosis
- sickle cell disease
Who is affected by X-linked inheritance?
- males affected
- females may be unaffected, mildly affected or fully affected
- males usually more severely affected than females
Why is male to male transmission not possible in X-linked disorders?
Fathers pass on their Y chromosome to their son
Daughters all carriers as they definitely get their dad’s X chromosome
Give some examples of X-linked disorders
Gene mutations and chromosome deletions/duplications
- duchenne muscular dystrophy
- fragile X syndrome
- red/green colour-blindness
- haemophilia
What is the chance of a so having haemophilia given that the father is affected with haemophilia?
All sons are unaffected (no male to male transmission)
All daughters are carriers
In XL carrier females, the phenotype is very variable. What are the 2 main factors influencing expression of phenotype?
- X inactivation
- XL dominant vs. XL recessive inheritance
What is another name for X-inactivation?
Lyonisation
What is X-inactivation/lyonisation?
The process of random inactivation of one of the X chromosomes in cells with more than one X chromosome
Compensates for the presence of the double X gene dose
What is a Barr body?
The inactive X chromosome rendered inactive during lyonisation
(the condensed X chromosome)
Is X inactivation normal?
It is normal and occurs when there is 2 or more X chromosomes
Occurs in early embryogenesis
Which X is silenced during X-inactivation?
Random
Does the silenced X chromosome remain inactive?
Once inactivated, an X chromosome remains inactive throughout the lifetime of the cell and all its descendants
Which genes are switched off on the inactivated X chromosome?
Most, but not all genes are switched off on the inactivated X chromosome
What does skewed X-inactivation mean?
There is a random preference for the “normal” X chromosome to be inactivated - significant phenotype
What is tissue variability in terms of X-inactivation?
There is a random preference for the X chromosome with the mutation to be active in crucial tissue group eg. muscle in Duchenne muscular dystrophy
Are XL dominant or XL recessive disorders more common?
XL recessive
XL dominant conditions are rare
Give an example of an XL dominant condition
Rett syndrome
Lethal in males, phenotype only in females
Females only need gene on one of their Xs to show phenotype
What type of inherited disorder is fragile X syndrome?
XL dominant
Females can be asymptomatic to fully symptomatic (due to X-inactivation pattern)
Give 2 XL dominant disorders
- Rett syndrome
- Fragile X syndrome
Give examples of XL recessive disorders
- red-green colour blindness
- haemophilia
- duchenne muscular dystrophy
Are girls affected by XL recessive disorders?
Carrier girls usually unaffected BUT can have significant symptoms because of X-inactivation switching off the normal X
Girls are fully affected if they inherit the mutation from mum and dad
Give examples of mitochondrial inheritance disorders
- maternally inherited diabetes and deafness
Where do we inherit mitochondrial DNA from?
All mitochondrial DNA comes from the egg
The sperm head does not have any mitochondria
All out mitochondria are inherited from our mother
Who is affected by mitochondrial inheritance disorders?
Males and females are affected equally
Rare
How many genes are there within mitochondrial DNA?
27 genes
Every mitochondrion has many copies of each gene
How are offspring affected by mitochondrial inheritance?
An affected mother will give all of her children the mutation
All the children of an affected man will be unaffected
Highly variable expressivity and therefore severity of phenotype between relatives
Why is family history taking important?
- helps make a diagnosis
- helps clarify risk for the patient
- helps understand the patient’s point of view
- helps identify who else may be at risk
- helps understand the patient’s support network
How are males and females represented in a family pedigree?
Female = circle
Male = square
How do you show a person has died in a family pedigree?
Draw a line through the circle/square
What information should you record about each person on a family pedigree?
- name
- maiden name
- date of birth
What does a line through a line connecting two people mean?
The couple has split up
What are 2 questions you shouldn’t forget to ask when taking a family pedigree? (concerning half siblings and step siblings)
- “do the children all have the same dad?” - half siblings
- “ do either of you have any other children from other relationships?” - step siblings
What are 2 questions you shouldn’t forget to ask when taking a family pedigree? (concerning miscarriages)
- “have you had any other pregnancies?”
- “do you know if anyone in the family has had any miscarriages?”
How should you represent a person affected by the condition in question?
Colour in the square/circle
How is a miscarriage (spontaneous abortion) represented in a family pedigree?
Triangle
How is a therapeutic abortion represented in a family pedigree?
Triangle with a line through it
How is a stillborn baby of unknown sex represented?
Diamond with a line through it
How is an asymptomatic carrier of a recessive gene mutation represented in a family pedigree?
A coloured in circle in the middle of the square/circle
What does a double line connecting 2 people mean in a family pedigree?
Consanguineous couple
What is consanguinity?
- couples who are “blood” relatives
- potentially share recessive gene mutations
- seen in all ethnic groups
How does consanguinity change the risk of congenital birth defects?
Risk of congenital birth defects = 5-6% compared to 2-3% in the general population
Given that there is no family history of genetic condition
How is a person of unknown sex represented in a family tree?
A diamond
How are twins represented in a family tree?
(look at image of this slide 33)
What does EDD mean in a family pedigree?
Expected date of delivery
