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