Single Gene Disorders Flashcards
What are the classifications of genetic disorders
Single gene disorders
Multi factorial diseases
Chromosome disorders
Mitochondrial disorders
Somatic mutations
What are single gene mutations
Mutations in single genes often causing loss in function
Leads directly to disease
Types of single gene disorders
Dominant - heterozygotes with one copy of the altered genes
Recessive - homozygotes wit two copies of altered gene
X linked recessive - males with one copy of altered gene on X chromosome
Exceptions to Mendels rules in autosomal dominant inheritance
Variance in expression
Penetrance
New mutations
Anticipation
What do majority of mutations in autosomal dominant disorders cause?
Loss of function of the allele
Dominant disorders cause cell to cope with half of the amount of gene product. Examples of this:
50% Structural protein/ receptor clinical effect
50% enzyme - body can cope so no clinical effect
What is Marfans syndrome?
Autosomal dominant condition
Affects skeletal system, heart and eyes
Caused by fibrillins gene on chromosome 15
How can there be diagnosis using DNA
Allows determination of sequence/ copy number variant
Determines whether normal variant or pathogenic (harmful)
What is genotype-phenotype analysis
Sequencing of affected family member to confirm the mutation
What is polymorphism
the presence of two or more variant forms of a specific DNA sequence that can occur among different individuals or populations
How to determine whether a mutation is cause of disease in a family and not just polymorphism
Segregation studies - see whether family members that are clinically affected have same mutation
Genetic testing - see if member with mutation will develop disease
Clinical effects of neurofibromatosis
Skin cafe au last patches
Multiple neurofibroma
Example of a disease with variation of expression
Neurofibromatosis type 1
Exception of Mendels rules of autosomal dominance
Family members have different signs of the same disease
Cant predict severity of the disease
What disease demonstrates age related penetrance
Huntingtons disease
Breast cancer BRCA1
Is NF1 completely penetrant
Yes
If individual has affected gene NF1 always expressed
What is Huntington’s disease
Progressive neurological disorder
Involuntary movements
Dementia
Psychiatric disturbance
What is age dependant penetrance
Delay in onset of a genetic disease
The older they are without signs the less likely they are to develop disease
What is incomplete penetrance
Not everyone who has gene will develop disease e.g. some cancers
What is Achondroplasia
New mutation that causes the disorder in 80% patients
Which disease are new mutations increase with paternal age
Marfan
Achondroplasia
How does a chance of new mutation increase with paternal age
Higher mutation rates in males are likely to be related to greater number of germ cell divisions
What is myotonic dystrophy
Autosomal dominant
Muscle weakness
Impaired muscle contraction after relaxation (myotonia)
Usual age of onset 20s-30s
What is anticipation
- In successive generations age of onset is reduced and/ or severity of the phenotype is increased
- Unstable & expanding trinucleotide repeat mutation
- Severity/ age of onset may correlate with number of repeats
What is an example of anticipation
Myotonic dystrophy
Huntingtons
(Disorders of the nervous system)
Examples of intragenic triplet repeats causing dominant disease
Myotonic dystrophy - CTG
Huntington disease - CAG
What is an intragenic triplet repeat disorders
Number of triplet repeats above the upper normal limit cause the disease
What is the usual gene repeats for huntingtons disease?
11-34 CAG repeats = 11-34 glutamine residues in protein
Above 34 glutamine residues causes progressive cell death
Anticipation in Huntingtons disease:
Runs of more than 34 CAG repeats in HD gene expand further (during male meiosis) causing earlier age of onset in children of men with HD allele
What is mosaicism?
Mutation after fertilisation
Present in somatic/ germline cells
What is osteogenesis imperfecta
Brittle bone disease
Severe cond. not inherited because baby dies
What causes osteogenesis imperfecta
Father has mutation in gonads
Patch of Gonadal stem cells with gene mutuion arisen from error in cell while gonad was being populated
Gamete has effected genes
How to recognise autosomal recessive disease from pedigree
Cant follow disease through pedigree
See siblings affected - horizontal transmission
Equal incidence of males and females
May be evidence of consanguinity (parents have common ancestor)
What is consanguinity?
Parents have shared common ancestor
Doesn’t cause genetic condition but increases likelihood of parents being carriers of autosomal recessive condition in family
What is X linked recessive inheritance
One copy of an altered gene on the X chromosome
Causes disease in males
Cause females to be carriers
The results for offspring if mother is a carrier of X linked and father unaffected
Unaffected daughter
Carrier daughter
Unaffected son
Affected son
Available options for mother who is carrier of x linked disease
Postpone pregnancy
No further pregnancies - adoption
Further pregnancies - accept risk, prenatal diagnosis if available, egg donation, preimplantation diagnosis if available
What is an example of x linked disease
Duchenne muscular dystrophy
Progressive muscle weakness (cardiac and respiratory)
Decreases life span
How may female carriers of X linked disease be affected
Can show mild symptoms of X linked disease
- mild muscle aches and pain
- myalgia
- cardiac muscle abnormalities
What causes females to show X linked recessive traits
Skewed X inactivation
Turner syndrome
Homozygous for a recessive trait - carry X linked mutation on both X chromosomes
X autosome translocations
What is skewed X inactivation
Random X inactivation in female embryo
Should be equal paternal and maternal X
But data can become skewed and more mutated X present which causes mild symptoms
Results for offspring if father is affected with X linked recessive inheritance but mother unaffected
All daughters Unaffected carriers
All sons Unaffected
What does the pedigree for X linked dominant disease look like
Similar to autosomal dominance
But excess of affected females
No male to male transmission (sons inherit X from mother)
Uncommon diseases
How many DNA bases and genes in mitochondria
16,600 DNA bases
37 genes
What is mitochondrial inheritance
Exclusively maternal inheritance
Description of maternal pedigree
May think its autosomal dominance
All offspring of affected mother will have condition
Males don’t pass on condition - sperm don’t mass on mitochondrial genes
The number of mitochondria in egg cells
100,000
The number of mitochondria in sperm cells
100
The number of genes and DNA bases in nucleus
3,200 million DNA bases
24 chromosomes
Examples of mitochondrial DNA disorders
Kearns-Sayre syndrome
MELAS
Mode of Inheritance of haemophilia
X linked recessive
