Week 8 Flashcards
Types of genetic disorders
Single gene disorders
Multi factorial diseases
Chromosome disorders
Mitochondrial disorders
Somatic mutations
What’s are single gene disorders
Mutations in single genes often causing loss of function
This directly leads to a condition
Multi factorial diseases
Variants in genes which then interact with environmental factors causing alteration of function (also called common complex disorders). This may increase susceptibility of disease
Chromosome disorders
Chromosomal imbalance causes alteration in gene dosage
Mitochrondrial disorders
Generally affect organ systems with high energy requirement
Mutation in mtDNA
Where are genes controlling function and structure of mitochrondria found
In both mitochondrial and nuclear DNA
What are somatic mutations
Cause cancer. Inactivation of both alleles of a gene involved in growth
Types of single gene disorder
Dominant- heterozygotes with one copy of the altered gene have the condition
Recessive-homozygotes with 2 copies of altered gene have the condition
X-linked recessive- males with one copy of altered gene on the x-chromosome have the condition
Autosomal dominant conditions
Variation in expression
Penetrance
New mutations
Anticipation
Penetrance
Refers to the likelihood that a clinical condition will occur when a particular genotype is present
Anticipation definition
A phenomenon in which the signs and symptoms of some genetic conditions tend to become more severe and/or appear at an earlier age as the disorder is passed from one generation to the next
Autosomal dominant inheritance
Affected people in each generation
Males and females affected
All forms of transmission seen
In this condition, everyone who inherits the altered gene shows clinical signs
Segregation pattern
50% chance of passing on genetic condition if one parent is heterozygous
Most mutations cause loss of function of an allele
Some mutations can cause gain of function but majority of mutations in autosomal dominant disorders cause loss of function of allele
So the allele does not code for a viable protein so doesn’t have its intended effect
The majority of mutations in autosomal recessive disorders abolish action of the allele
Dominant or recessive pattern of inheritance?
Depends on how the cell copes with effectively half the amount of gene product
When one allele is working normally and one allele inactive (heterozygous, only half the amount of gene product is produced)
Half amount of structural proteins or receptors produced. Body cant cope, get clinical effects (dominant mode of inheritance)
Half amount of an enzyme is produced, body can cope, no clinical effect (recessive mode of inheritance)
So need both copies of the gene to be wiped out to abolish production of enzyme to produce an effect
Marfan syndrome
Autosomal dominant condition
Mutation of fibrillin
Affects eyes, heart and skeletal muscle
Regular cardiac screening required for effected individuals risk of aortic aneurysm
Tall and long arm span with deformity of chest wall
Diagnosis of single gene disorder using DNA
The aim is to determine a sequence/copy number variant
You start with sequencing the genome of a person & compare it to a normal person
Look for differences
The check whether the difference is a normal variant or whether it is pathogenic
E.g. if its a nonsense mutation then it’s likely to cause a harmful effect, possibly condition
You should see if variant is present in all effected family members and not present in all non-affected
Once you have found the cause of the genetic condition then you can offer predictive genetic testing to families to see who’s affected and who’s not §
Exceptions to Mendel’s rules in autosomal dominant inheritance
Neurofibromatosis type 1
Autosomal dominant
Patches on skin
Multiple neurofibroma
Variation in expression
Family member have different number and severity of symptoms due to genetic condition
Potentially caused by modifications to phenotype by other genes in their body
Very important clinically in autosomal dominant disorders
Complete Penetrance
Everyone with the pathogenic mutation shows at least one manifestation of genetic condition
Incomplete Penetrance
Not all people with pathogenic mutation show manifestations of the genetic condition
Age dependent Penetrance
A delay in the onset of symptoms of a genetic disease
Huntington disease
Demonstrates age related penetrance
-autosomal dominant inheritance
-progressive neurological disorder: involuntary movements, dementia, psychiatric disturbance
Delayed onset in signs of genetic disease (age-dependent penetrance)
How huntingtons demonstrates age-dependent penetrance
A delay in the onset of a genetic disease
50% of people with mutation have developed signs by age 50
Likely to have children by then, still 50% chance of passing on mutated allele
This is incomplete penetrance as not 100% of population with genotype have signs for genetic disease
Age dependent penetrance of breast cancer in women who have a mutation in one allele of BRCA1
If other allele in a cell mutates you have two mutated copies of BRCA1 so this cell becomes cancerous example of a somatic mutation
Risk of cancer in people who mutation in one allele is higher as only need one more allele to mutate
Chance of developing breast cancer increases with age as you’re more likely to develop a mutation. More opportunities for mutation to occur
New mutation
Mutation not present in either parent but was present egg or sperm
Achondroplasia
Causes short stature
Due to number of germ cells divisions
Each sperm at age 15 is result of 30 prior cell divisions
A spermatogonium is left after each division to maintain stock
The older the father, the more DNA has been replicated. Increased chance of copying errors & subsequent mutations occurring or there’s a higher chance of being exposed to mutagens
So new mutations increase with paternal age
Myotonic dystrophy
Autosomal dominant
Muscle weakness
Impaired muscle contraction after relaxation (myotonia)
Usual age of onset 20-30s
Congenital myotonic dystrophy- severely affected infants with respiratory problems
Anticipation
In successive generations: age of onset reduced and/or the severity of the phenotype is increased
This is because there repeats are unstable in meiosis so can get bigger when passed on from one affected individual to their child
Unstable expanding trinucleotide repeat mutation within a gene. If the no. Of repeats within a gene is above upper limit it causes a genetic disorder
Severity/age of onset may correlate with number of repeats
Huntington disease- a triplet repeat disease
Usual gene 11-34 CAG repeats= 11-34 glutamine residues in protein
>34 glutamine residues protein aggregates in brain cell causes progressive cell death
Runs of >34 CAG repeats in HD gene expand further causing earlier age of onset in children of men within HD allele- anticipation
Mosaicism
The genetic change occurs after fertilisation
Somatic: genetic mutation in one of the early cells derived from zygote. This mutated cell the divides passing on the mutation. This results in a clustered population of affected and in affected cells
Gonadal:mutation in gametes and confined to glands (parent unaffected) results in population of affected and unaffected gamete: up to 50% chance of fertilisation by affected gamete
Severe osteogenesis imperfecta (brittle bone disease)
Example of gonadal mosaicism
Autosomal dominant inheritance
Mutation affects bones and CT due to lack of type I collagen fibres. Results in multiple fractures in utero baby wouldn’t survive
Autosomal recessive disease
Only manifests when an individual inherits 2 copies of altered allele
Individuals only affected in one generation
Can’t follow disease through the pedigree
See siblings affected ‘horizontal transmission’
Equal incidence of males and females
May be evidence of consanguinity- 2 parents are related
Determining probability in autosomal recessive conditions
Say mother is carrier, probability =1
Chance of new partner being a carrier obtained from frequency of condition in population =1/22. This is unless partner has a family history for same condition
Chance mother passing on allele 1/2, chance of affected pregnancy is therefore 11/2214=1/88
11/44=1/88
Can do a genetic test on foetus during pregnancy to see if child will be affected
Hardy-Weinberg principle
Suppose a normal gene has 2 common alleles
P+q=1
In next generation alleles combine at random
AA - PP=P^2
Aa or aA — pq or qp=2pq
Or aa — qq=q^2
Carrier rate = 2pq=2(1-q)q=2q-2q^2
Applications of Hardy-Weinberg
Both his parents must be carriers so he must be Aa aA or AA. 2/3 risk of being carrier
Chance of partner being carrier 1/22 assuming no family history
Chance of child with CF= 2/3 *1/22 *1/4
Can estimate carrier frequency of AR disease in population with hardy-Weinberg
Frequency of disease aa is 1/2000
F=q^2=1/2000
so q=1/44
Know that p+q=1 therefore p=43/44
Carrier frequency=2pq= 243/441/44
Hardy Weinberg equilibrium
The relative proportions of each genotype will remain constant in subsequent generations
Holds true if:
Random mating
Infinitely large population
No preferential selection of genotypes
No new alleles
Consanguinity
Shown by double parallel line on pedigree diagram
Consanguineous- where 2 people are related by blood share a common ancestor
Doesn’t cause genetic condition but if there is a recessive genetic condition in family its more likely for 2 parents who are both carriers to come together & give birth to affected child. Both parents heterozygotes for same recessive
X-linked recessive inheritance
Refers to the pattern of inheritance of genes located on sex chromosomes
Male: one copy of an altered gene on the X chromosome causes the disease in a male. Hemizygote
Female: an altered gene on one of the X chromosome pair = carrier status in a female heterozygote
Duchenne muscular dystrophy
Degenerative muscle disorder
Present in infancy- delayed walking, waddling and risks of cardio-myopathy
Gower’s manoeuvre- climb onto legs to stand up due to proximal muscle weakness
Progressive, no cure
Sons can’t be a carrier, daughters cant be affected if only parent is carrier, either carrier or unaffected
Available options for mother if they’re a carrier for X-linked disease
Postpone pregnancy
No further pregnancies- adoption
Further pregnancies: accept risk, prenatal diagnosis if available, egg donation, preimplantation diagnosis if available
Sequencing of the dystrophin gene
Codes for dystrophin protein
Part of protein complex that links myofibrils to cytoskeleton important in skeletal muscle
There can be a large deletion in affected people so gene wont code for protein
Tracking inheritance of gene causing Duchenne muscular dystrophy through family
In DMD and other x linked recessive conditions female carriers may show mild symptoms of x linked disease
E.g. mild muscle aches and pains, cardiac muscle abnormality
Carriers of DMD may also have increased levels of CK (creatine kinase) compared to unaffected females
Ck is a muscle enzyme released by damaged muscles
Males with DMD have very high CK levels
Female carriers may show mild symptoms of X-linked disease
Due to x inactivation in early embryo
In each cell 1 copy of X chromosome is randomly inactivated. Clonal expansion
Skewed x inactivation
Turner syndrome- where females have only one copy of X chromosome
Why do some females show x-linked recessive traits
Skewed x inactivation
Turner syndrome (45,X)
Homozygous for a recessive trait
X; autosome translocations
- X chromosome involved in the translocation survives preferentially to maintain functional disomy of the autosomal genes
X-linked recessive inheritance: father affected
Daughters carriers, son unaffected
Phenotype more severe in males
Multiple generations and both males and females are affected
Excess of affected females, males usually die
No male to male transmission
Mitochondrial inheritance
37 exclusive genes
Exclusively maternally inherited
Egg cells 100000 mitochondria
Sperm cells 100 mitochondria, actively expelled from fertilised egg
Mitochondrial mutations affect organs with high energy demand e.g. cause stroke, affect vision
MELAS-mitochondrial encephalopathy with lactic acidosis &stroke, severe
Kearns-Sayre syndrome KSS-chronic progressive external opthalmoplegia. Droopy eyelids, improper extraocular movements. Neuromuscular disorder
Variation in the genome
Can lead to altered effects of a protein or control of genes
How it affects health and disease depends on its type and where it is
DNA sequence variants
Varying effects on health depending on where they occur and whether they alter the function of essential genes and/or their controlling elements
What is Mendelian inheritance
Caused by mutation in a single nuclear gene
Classical inheritance patterns: dominant/recessive, autosomal/X-linked
What is Non-Mendelian inheritance
Polygenic inheritance
Multi factorial (common complex)
Maternal inheritance (mitochondrial)
Inheritance of common complex disorders
Condition due to the interaction of variants within your genes with one another (increasing your susceptibility) and the environment
You can inherit common complex disorder either via Mendelian inheritance or Non-Mendelian inheritance
Generally only one organ system affected
Environmental factors important in both
Mendelian conditions
Hypercholesterolaemia
Marfan syndrome
Cystic fibrosis
Sickle cell disease
Duchenne muscular dystrophy
-genetic component highlighted by pedigree pattern and recurrence risk
Common conditions
Coronary heart disease
Diabetes mellitus
Hypertension
Cerebrovascular disease (stroke)
Schizophrenia
Breast and bowel cancers
Some congenital abnormalities
-genetic component suggested by clustering of cases in some families but no obvious inheritance pattern
Differences between Mendelian and common conditions
Mendelian conditions and common conditions give different observed patterns of recurrence within families
The effect of environment is more important for common conditions but also important for Mendelian conditions
Identifying genetic and environmental influences
By observational studies of the incidence of diseases in different groups of people
They tell us how variations in a common complex condition can be due to genetic influences or environmental influences
How is evidence gathered
Familial clustering- working out the relative incidence in the family compared with the incidence within general pop.
Twin studies- incidence in monozygotic twins compared with dizygotic twins
Adoption studies- incidence of disease in monozygotic twins adopted into different families. Impact of moving to new environment may alter disease susceptibility
Population and migration studies- incidence of disease in a population of a particular ancestry when they move to a new geographical area
Comparing MZ/DZ twins
MZ twins share all same genes and environment
DZ twins share 50% genes and environment
Determining incidence of a disease in twins helps delineate whether there are genetic and environmental components
Risks to family members
Often increased where a relative has a common complex disorder
Probabilities of recurrence of common complex condition are calculated by observing no. Of relatives with same condition in studied families
Polygenic inheritance
Polygenic=many genes
Large number of genetic factors, each making only a small additive contribution to the final phenotype
Typically polygenic inheritance is the basis for continuous traits (blood pressure, height) which follow a normal distribution in the population
How can genetic and environmental factors combine to produce a liability to a multi factorial condition
Multi factorial inheritance= controlled by polygenes (genetic predisposition) and environmental factors
Liability curve made up of genetic and environmental factors
Individual start at different liability depending on genetic susceptibility
Above a certain threshold liability a person will develop multi factorial disorder
The probability of a relative having a multi factorial disease is higher because they’re more likely to share genes (and environment) in common so increase their liability
Magnitude of Recurrence risk in other family members
The further away you get from individual affected by a multi factorial condition in family tree the lower the recurrence risk is. Because the further away you are the fewer genetic factors you have in common
What is empiric risk
The chance that a disease will occur in a family, based on experience with the diagnosis, past history and medical records rather than theory
Must apply to studied population
observed recurrence risk after one baby with NTD in UK pop is ~4%, 1/25
How did we find genes for Mendelian disorders
Used families
Identified by: a pedigree pattern indicative of a known mode of inheritance, the diagnosis of a single gene disorder with a known mode of inheritance
Compare common markers in families to try and deduce specific gene. Perform linkage studies to see which bits of chromosomes have been inherited by all affected people in family. If you have multiple families with same condition you can look at specific area of genome all affected people have in common to find relevant gene
How are genetic components of common conditions identified
Genes for common disorders have to be identified through association studies in large populations
Association studies rely on fact that people with same condition share a particular DNA pattern
What are SNPs
Single -nucleotide polymorphism
Genetic markers used in genome-wide association study (GWAS)
They are changes of a single base in a particular DNA sequence (in genes or non-coding sequences)
The physical locations of SNPs are known
Identifying genetic components of common complex conditions
Through genome-wide association studies
Thousands of people, split into control group and affect group
Test up to 500000 SNPs in each person by microarray analysis
Compare SNP patterns 1st between members of same group to create average then compare 2 groups
Look for SNPs more/ less common in affected group than control. SNP may be factor that influences susceptibility to a disease
Relative risks associated with susceptibility loci
Most relative risks associated with particular SNP genotypes are usually low: may increase or decrease risks, may have variable effects in different combinations
Therefore other genes and environmental factors involved
In future clinical practice, SNPs associated with several genes maybe used together to give estimated of susceptibility
Changes picked up using SNP library: may be direct effect, may be indirect association/ marker for nearby major genetic influence
100000 genome project
Government announced plans to sequence the full genomes of up to 100000 NHS patients: cancer, rare inherited diseases, infectious diseases
This can influence management of conditions
Genetic variants can alter drug response and cause adverse effects, new therapies can be developed based on genomic info of an individual or disease itself. Want to use genomic info to tell people risk of developing disease
The impact of genetic testing on motivation to stop smoking
Asked 180 smokers (without family history of crohns)
Crohn’s disease affects gut, tends to run in families and is more common in smokers
Symptoms include: abdominal pain, diarrhoea, fever, loss of appetite, weight loss. The symptoms are so serious that some people cannot work or go out
If offered genetic test: pop.Sample- shown ‘their’genetic results, expressed motivation to quit smoking, more motivated if bigger risk. Real family members- offered real genetic testing, actual, individualised risk- same behaviour with and without genetic test
To personalise treatment and surveillance we can use genomic information
To sub-classify their disease
To assess their susceptibility
To predict their response to drugs
To choose best treatment
