Autosomal Dominant Disorders Flashcards
what are the 5 classifications of gene disorders?
Single gene disorder
Multifactorial gene disorder
Chromosomal gene disorder
Somatic gene disorder
Mitochondrial gene disorder
what is a single gene disorder?
mutations in a single gene that are responsible for causing a loss of function. This directly leads to a condition.
what are the 3 types of single gene disorders?
Dominant Gene Disorder: heterozygotes with one copy of faulty allele have the condition.
Recessive Gene Disorder: homozygotes with two copies of altered gene have the condition
X-linked recessive – males with one copy of altered gene on the X-chromosome have the condition
what is a multifactorial gene disorder?
Variants in many genes which then interact with environmental factors to cause alteration in function. This may increase your susceptibility to a disease.
what is a chromosomal gene disorder?
imbalance in genetic material (e.g. due to extra chromosome copy) which causes alterations in gene dosage.
what is a somatic gene disorder?
These cause cancer when there is an inactivation of both alleles of a gene involved.
what is a mitochondrial gene disorder?
mutation in mtDNA. This affects organ systems with high energy requirement
Genes controlling function and structure of mitochondria are found in both mitochondrial and nuclear DNA
define dominant
describes any trait expressed in a heterozygote
what is an autosomal dominant condition?
only need one copy of the gene to express condition
autosome = non - sex cell
describe this pedigree of an autosomal dominant condition?
Affected people in each generation
Males and females are affected
All forms of transmission e.g. the father or mother can be affected and pass it on to both daughter or son.
Male = square Female = circle
what is the chance of passing an autosomal dominant condition to children?
50% chance of each child getting condition if a parent is heterozygous
what happens to the allele when someone has an autosomal dominant condition
Most mutations causing an autosomal dominant condition directly cause a loss of function of the allele
The allele does not code for a viable protein so does no have its intended effect
E.g. a mutation of one allele can results in only half the number of LDL receptors on the cell membrane being present in familial hypercholesterolaemia
Very rarely mutations can cause a gain of function for the allele
what determines whether or not an autosomal condition presents itself as dominant or recessive?
Whether an autosomal condition presents as dominant or recessive depends on whether the body can cope with losing half the function of that gene.
i.e. when one allele is working normally and one allele inactive (heterozygous) only half the amount of gene product is produced.
- half amount of a structural proteins or receptors produced => body can’t cope => get clinical effects (dominant mode of inheritance)
OR - half the amount of an enzyme is produced => body can cope => NO clinical effect (recessive mode of inheritance)
So you need both copies of the gene to be wiped out to abolish production of enzyme to produce an effect.
what is an example of an autosomal dominant condition?
Marfan Syndrome
- mutation in gene for fibrillin
- Tall and long arm span with deformity of chest wall
- Affects eyes, heart & skeletal muscle
- Regular cardiac screening is required for effected individuals - risk of aortic aneurysm
how do you diagnose a single gene disorder by examining the DNA?
aim: determine a sequence/copy number variant that directly causes the condition.
1. start with sequencing the genome of a person and compare it to a normal person.
2. look for differences.
3. check whether the difference is a normal variant or whether it is pathogenic (cause condition)
e.g. if it is a nonsense mutation then it is likely to cause a harmful effect, possibly the condition.
4. see if this variant is present in all effected family members and not present in non-affected family members.
5. Once you have found the cause of the genetic condition then you can offer predictive genetic testing to families to see who is effected and who is not (contain altered allele or not)
describe this family tree
consider the variation in expression in the family
James has just been diagnosed with an NF1 (autosomal dominant condition)
Looking at the family tree initially both parents are not affected (don’t carry the mutated gene)
Therefore, this mutation must have occurred within James therefore the chance of further affected children is low
now describe a continuation of the family tree
consider the variation in expression in the family
However further examination of the family results in the findings that both James’s mother and grandfather are also affected but they didn’t realise as they had mild manifestation of the condition.
Therefore, now the chance of having another child with the same condition has gone to 50%.
However, we can’t predict how severely affected the new born child will be.
Therefore, NF1 shows variation in expression
NF1 is completely penetrant
what is an example of a condition that shows penetrance?
Huntington’s disease
Autosomal dominant inheritance
Symptoms: involuntary movements, dementia or psychiatric disturbance.
There is a delayed onset in signs of the genetic disease (age-dependent penetrance)
Symptoms often don’t develop until approx. 40 yrs. old - likely to have had children by then - still 50% chance of passing on mutated allele
This is Incomplete penetrance as not 100% of the population with the genotype have signs for genetic disease
photo:
III:1 has a ¼ chance of developing Huntington Disease.
If the mother is then diagnosed (50% chance) the child has a 50% chance of having Huntington’s Disease.
what does this graph show for age dependent penetrance?
A: probability of showing signs (increases with age)
B: probability of having condition if you have not showed signs by age
So, the older you are and have not developed signs the less likely you are to have condition. (e.g. if person not genetically tested).
what is an example of a condition that shows age dependent penetrance?
Breast cancer (BRCA1 mutation)
The baseline risk of developing cancer increases with age.
If a person is heterozygous for the BRCA1 mutation all their cells already have a faulty allele.
If the other allele in one of the cells mutates as well you now have two mutated copies of BRCA1 so this cell becomes cancerous (form a tumour) -somatic mutation.
The chance of developing breast cancer increases with age as you are more likely to develop a mutation
More opportunities for a mutation to occur e.g. via cell division but also as you age your DNA becomes more unstable.
The risk of breast cancer is much higher in women that already have one BRCA1 gene mutation as they only need one more allele to mutate to cause the cancer. The rest of the population require two alleles in the same cell to be mutate which is much less likely to happen.
what do chances of new mutations increase with?
New mutations increase with paternal age (age of father of child)
This is due to number of germ cell divisions.
Each sperm at age of 15 is the result of 30 prior cell divisions
A spermatogonium is left after each division to maintain stock
The older the father, the more the DNA has been replicated - increased chance of a copying errors and subsequent mutations occurring or there is a higher chance of being exposed to mutagens
how does unstable repeats relate to Huntingtons disease?
In Huntington disease the repeat is unstable in paternal meiosis
man who is affected passes on a large number of repeats to child.
Huntington’s: (refer to pic)
what are the two types of Mosaicism and how is the mutation passed to children?
Somatic: genetic mutation in one of the early cells derived from the zygote
This mutated cell then divides passing on the mutation. This results in a clustered population of affected and unaffected cells
Gonadal: mutation in the gametes and confined to gonads (parent unaffected)
Results in a population of affected an unaffected gamete
Up to a 50% chance of fertilisation by the affected gamete
what is an example of gonadal mosaicism?
Autosomal dominant inheritance
Mutation affects bones & CT due to a lack of type I collagen fibres
It results in multiple fractures in utero - baby wouldn’t survive
Because it is so severe child does not survive so the condition is passed on by unaffected parents (due to mutation in gonads)
