Genetic Disease Flashcards
What is a multifactorial genetic disorder?
Interaction of genes (genetic predisposition) AND environmental factors E.g. type II diabetes
What is a single gene disorder?
A mutation in a single gene –> Mendelian inheritance E.g. cystic fibrosis
What is a chromosomal disorder?
An imbalance or rearrangement in chromosome structure e.g. deletion
What is a mitochondrial disorder?
A mutation in mitochondrial DNA
What is a somatic mutation?
Mutation within gene in a define population of cells that results in disease e.g. breast cancer
What are the single gene modes of inheritance?
- Autosomal dominant 2. Autosomal recessive 3. X-linked 4. Mitochondrial
How many chromosomes does each cell have?
46 (23 pairs –> diploid)
How many chromosomes do gametes contain?
23 chromosomes with 1 copy of each gene
What is an autosomal dominant inheritance disorder?
“Autosomal” means that the gene in question is located on one of the numbered, or non-sex, chromosomes. “Dominant” means that a single copy of the disease-associated mutation is enough to cause the disease.
What type of genetic disease is Huntingtons, Marfan’s Syndrome and Myotonic dystrophy?
Autosomal dominant
What are autosomal dominant diseases typically caused by?
Structural proteins, receptors, transcription factors Can also be caused by chromosome deletions and duplications (e.g. 22q11 deletion syndrome)
Explaining autosomal inheritance
AA = healthy
Aa = affected (one copy of mutation / one normal gene)
Chance of affected offspring 2/4 = 1/2 = 50%
Chance of unaffected offspring 2/4 = 1/2 = 50%
What does penetrance mean?
The frequency with which a specific genoptype is expressed by those individuals that possess it
- May alter with age e.g. Huntington disease by 80 years 100% penetrance
What is incomplete penetrance?
Not all relatives who inherit the mutation develop the disorder; e.g. BRCAI mutations 80% life time chance of developing breast cancer
What does expressivity mean?
Variation in expression - the extent to which a heritable trait is manifested by an individual
What does anticipation mean?
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 increase in the severity of symptoms.
- Myotonic dystrophy
- Huntington’s disease
What is new dominant / de novo mutation?
A new mutation that has occurred during gametogenesis or in early embyronic development
- Parents not affected (mutation not detected in their blood cells)
- Child is first to be affected in family
What is an autosomal recessive inheritance?
Both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene
- Offspring have lower risk of being affected
- Can be asymptomatic carriers
- Gene mutations, not chromosomes
Explanation of autosomal recessive
- Affected individuals are homozygous or compound heterozygous (both alleles affected but with different mutations)
- Risk of affected offspring: 1/4 = 25% (aa)
- Risk of unaffected offspring being carrier 2/3
What type of genetic disorders are cystic fibrosis, many metabolic disorders, haemachromatosis, sicke cell disease
What is X-linked inheritance?
A copy of a gene located on the X chromosome has a genetic variant or mutation
- Males affected (more severely than females)
- Females may be unaffected, mildy through to fully affected
- Cannot have male to male transmission (e.g man cannot transmit X-linked condition to his sons)
Explanation of X-linked inheritance with carrier mother - Duchenne Muscular dystrophy
- Carrier mother and normal father
- 1/4 normal girl (XX)
- 1/4 carrier girl (Xx)
- 1/4 normal boy (XY)
- 1/4 affected boy (xY)
Explanation of X-linked inheritance with carrier father - Haemophilia
- All daughters are carriers (Xx)
- All sons are unaffected (XY) as there is no male to male transmission
Most X-linked carrier females are asymptomatic or havemilk symptoms but can have significant symptoms.
What are the 2 main factors influencing expression of phenotype?
- X inacitvation
- XL dominnant vs XL recessive inheritance
Often cannot preduct a female phenotype accurately on prenatal testing
What is X-inactivation / lyonisation?
The process of random inactivation of one of the X chromosomes in cells with more than one X chromosome.
- Occurs in early embryogenesis
- Random - which X is silenced
What is purpose of X-inactivation?
Compensates for presence of double X gene
What is skewed X-inactivation?
When inactivation of one X chromosome is favoured over the other, leading to an uneven number of cells with each chromosome inactivated
What can skewed X-inactivation lead to?
A significant phenotype / tissue variability etc
Does skewed X-inactivation have more effect on skin or muscle?
Muscle - random preference for X chromosome with the mutation to be active in crucial tissue group e.g. muscle in Duchenne Muscular Dystrophy
X linked recessive examples
- Red green colour blindness
- Haemophilia
- Duchenne Muscular dystrophy
X-linked dominant examples
- Rett synrdome: lethal in males, phenotype only in females
- Fragile X syndome - females are asymptomatic to fully symptomatic due to X-inactivation pattern
Why are mitochondrial diseases always related in the maternal line?
Sperm head doesn’t have any mitochondria –> all our mitochondria are inherited from other mother
Symbols for family pedigree
Circle: Female
Square: Male
Line through: Deceased
Colour symbol in: Person is affected with disorder
Symbols joined together through middle: Partnership
Symbols joined up and across top: Siblings
Diagram for different parents / step brothers
Line through partnership for broken up
Extra symbols for family pedigree
Triangle with line through: Therapeutic abortion
Diamond with line through: Stillborn baby of unknown sex (diamond due to not knowing sex of baby)
Triange: Miscarriage
Additional symbols
- Dot inside circle/square: Asymptomatic carrier of recessive gene mutation (Aa)
- View diagram: Twins and non-identical twins
- Diamond: unknown sex
- Double line between partners: Consanguineous couple (incest) –> DON’T ASSUME THIS DOESN’T EXIST
What do the symbols labelled 1-5 mean?
1) Consanguineous relationship
2) Identical twins, non identical twins
3) Spontaneous abortion
4) Therapeutic abortion
5) Sex unknown (e.g. foetus)
What is the most likely inheritance pattern?
Autosomal dominant
What is the most likely inheritance pattern?
Autosomal recessive
What is the most likely inheritance pattern?
X-linked recessive
What is the most likely inheritance pattern?
Mitochondrial
What is the most likely inheritance pattern?
X-linked dominant
What is the most likely inheritance pattern?
Chromosomal translocation
What does the arrow pointing to Gary mean?
Gary is the proband, the person serving as a starting point for the genetic study of a family
1) What is the risk that Sarah’s new baby will have cystic fibrosis?
2) What is the risk that Matthew is a carrier?
3) If Matthew is indeed a carrier, what does the risk to Claire’s pregnancy depend on?
4) What factors may influence the carrier status of his partner?
5) If the carrier frequency in the population is 1 in 20, what is the risk for Claire’s pregnancy?
1) 1/4
2) Assuming either mum or dad could be carriers, the risk is 1 in 2 (although, strictly, the risk could be slightly higher or lower because of the small chance that both or carriers, or that the mutation may be de novo).
3) The probability that Claire is a carrier
4) The population frequency of CF and hence the carrier frequency, also the mutation frequency of the gene in the population
5) Risk of Matthew x Risk of Claire x Risk of affected child = 1/2 x 1/20 x 1/4 = 1/160
1) What do you think the inheritance pattern is?
2) What is the chance that any child of Jenny and Kevin may be affected?
3) What is the chance for a male child of Jenny and Kevin being affected?
4) What is the risk for Nathan’s children in the future?
5) If Martin were the only affected male in the family, how would this alter Jenny’s risk of being a carrier, and why?
6) What investigations would you do?
1) X-linked recessive
2) Carrier frequency = 1/2 (due to carrier mother and normal father), risk of transmitting mutant X = 1/2, chance of having a boy = 1/2 (only boys affected) –> 1/2 x 1/2 x 1/2 = 1/8
3) Carrier risk x risk of transmitting mutant X = 1/2 x 1/2 = 1/4
4) Population risk only. His father Bill (regardless of clinical status) cannot have transmitted an X-linked mutation to Nathan.
5) It would decrease it. Her mother Edith would no longer be an obligate carrier. (i.e. Martin could have Duchenne due to a new mutation.) The exact risk depends on the proportion of cases that are new mutations.
6) Array CGH - A small number of boys have a large X chromosome deletion leading to Duchenne; these boys may have other abnormalities as well, as a result of a contiguous gene syndrome (contiguous gene deletions around the DMD gene)
Mutation testing of DMD gene
1) What is the inheritance pattern?
2) What is Mark’s risk of having the mutation causing this disease?
3) What is Lucy’s genetic status?
4) What is Harry’s genetic status?
5) What would you say is the likely status of Robert?
6) What investigations could you offer in this family?
7) Who would you want to take samples from?
1) Autosomal dominant
2) 50%
3) 50% risk
4) Harry does not have an increased risk since he is not a blood relative of Patricia
5) Since Geoffrey has no polyps at 52, he (and therefore also Robert) is unlikely to have the APC mutation. (The gene is >99% penetrant by 40y.)
6) As well as colonoscopy in at-risk individuals (second decade onwards), one could look for mutations in the APC gene
7) From an affected individual (e.g. Patricia or Sandra) for initial purposes of identifying the mutation. Once identified, samples from at-risk individuals can then be tested to see if they have inherited the mutation.
1) What is the inheritance pattern?
2) What is the risk that Tim will have a child with deafness and diabetes?
3) What is the risk of Jade having a child with deafness or diabetes?
4) What is the risk of Amber being affected? What further investigations would you do?
1) This pedigree shows a pattern typical of mitochondrial inheritance (sometimes referred to as maternal inheritance). All the offspring of an affected mother are affected, but none of those of an affected father.
2) No risk
3) Since this condition is maternally inherited, Jade will not have a mitochondrial mutation, because it is her father that is affected. Will not have a child with this disorder
4) Very high risk - she should be seen and advised, followed by mutation screening for the mitochondrial mutation and other tests as appropriate, such as audiology
