Autosomal Dominant Disorders

Question 1

what are the 5 classifications of gene disorders?

Answer 1

Single gene disorder
Multifactorial gene disorder
Chromosomal gene disorder
Somatic gene disorder
Mitochondrial gene disorder

Question 2

what is a single gene disorder?

Answer 2

mutations in a single gene that are responsible for causing a loss of function. This directly leads to a condition.

Question 3

what are the 3 types of single gene disorders?

Answer 3

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

Question 4

what is a multifactorial gene disorder?

Answer 4

Variants in many genes which then interact with environmental factors to cause alteration in function. This may increase your susceptibility to a disease.

Question 5

what is a chromosomal gene disorder?

Answer 5

imbalance in genetic material (e.g. due to extra chromosome copy) which causes alterations in gene dosage.

Question 6

what is a somatic gene disorder?

Answer 6

These cause cancer when there is an inactivation of both alleles of a gene involved.

Question 7

what is a mitochondrial gene disorder?

Answer 7

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

Question 8

define dominant

Answer 8

describes any trait expressed in a heterozygote

Question 9

what is an autosomal dominant condition?

Answer 9

only need one copy of the gene to express condition
autosome = non - sex cell

Question 10

describe this pedigree of an autosomal dominant condition?

Answer 10

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

Question 11

what is the chance of passing an autosomal dominant condition to children?

Answer 11

50% chance of each child getting condition if a parent is heterozygous

Question 12

what happens to the allele when someone has an autosomal dominant condition

Answer 12

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

Question 13

what determines whether or not an autosomal condition presents itself as dominant or recessive?

Answer 13

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.

1. half amount of a structural proteins or receptors produced => body can’t cope => get clinical effects (dominant mode of inheritance)
   OR
2. 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.

Question 14

what is an example of an autosomal dominant condition?

Answer 14

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

Question 15

how do you diagnose a single gene disorder by examining the DNA?

Answer 15

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)

Question 16

state the 5 exceptions to rules of autosomal dominant inheritance

Answer 16

Variation in expression
reduced/incomplete penetrance
new mutation
anticipation
mosaicism

Question 17

why would family members experience variation in symptoms of a condition?

Answer 17

Family members have different number & severity of symptoms due to the genetic condition.
This is potentially caused by modifications to phenotype by other genes in their body.
e.g Neurofibromatosis type 1 (NF1)
Symptoms: café au lait patches (6 or more may indicate NF1) and multiple neurofibromas (benign tumour that grows along nerves)

Question 18

describe this family tree
consider the variation in expression in the family

Answer 18

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

Question 19

now describe a continuation of the family tree
consider the variation in expression in the family

Answer 19

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

Question 20

what is penetrance?

Answer 20

the extent to which a particular gene or set of genes is expressed in the phenotypes of individuals carrying it, measured by the proportion of carriers showing the characteristic phenotype

Penetrance can make a person appear not to have an autosomal dominant condition when in fact they have the genotype.
This results in incorrect probabilities given for chances of passing a condition on to a child.

Question 21

what are the 3 types of penetrance?

Answer 21

complete penetrance
incomplete penetrance
age dependant penetrance

Question 22

what is complete penetrance?

Answer 22

everyone with the pathogenic mutation shows at least one manifestation of genetic condition

Question 23

what is incomplete penetrance?

Answer 23

not all people with pathogenic mutation show manifestations of the genetic condition (i.e. no signs or symptoms)

Question 24

what is age dependant penetrance?

Answer 24

a delay in the onset of symptoms of a genetic disease

Question 25

what is an example of a condition that shows penetrance?

Answer 25

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.

Question 26

what does this graph show for age dependent penetrance?

Answer 26

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).

Question 27

what is an example of a condition that shows age dependent penetrance?

Answer 27

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.

Question 28

what is a new mutation?

Answer 28

mutation not present in either parent but was present in either egg or sperm.

Question 29

what is an example of a new mutation?

Answer 29

Achondroplasia causes short stature 80% of the time this occurs due to a new mutation

Question 30

what do chances of new mutations increase with?

Answer 30

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

Question 31

what is anticipation?

Answer 31

Caused by unstable, expanding trinucleotide repeat mutation within a gene If the no. of repeats within a gene is above the upper limit it causes a genetic disorder.

Question 32

what are the chances of anticipation in future generations? why?

Answer 32

In successive generations: - age of onset of genetic condition is lowered and/or - severity of phenotype is increased This is because these repeats are unstable in meiosis so can get bigger (more repeats) when passed on from one affected individual to their child. In myotonic dystrophy the repeats are unstable in maternal meiosis - so when females produce eggs they pass on a greater number of repeat units so children may be more severely affected and have an earlier onset

Question 33

how does unstable repeats relate to Huntingtons disease?

Answer 33

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)

Question 34

what is an example of a condition that is caused by anticipation?

Answer 34

Myotonic dystrophy Autosomal Dominant Muscle weakness Impaired muscle contraction after relaxation (myotonia) Usual age of onset 20's-30s Congenital myotonic dystrophy- severely affected infants with respiratory problems

Question 35

when does Mosaicism occur?

Answer 35

The genetic change occurs after fertilisation (unlike others above)

Question 36

what are the two types of Mosaicism and how is the mutation passed to children?

Answer 36

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

Question 37

what is an example of gonadal mosaicism?

Answer 37

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)

Question 38

what are autosomal recessive conditions?

Answer 38

Only manifests when an individual inherits two copies of the altered allele

Question 39

what alleles would a carrier of an ARC have?

Answer 39

heterozygous – 1 copy of normal allele and 1 copy of altered allele