Week 8

Question 1

Types of genetic disorders

Answer 1

Single gene disorders
Multi factorial diseases
Chromosome disorders
Mitochondrial disorders
Somatic mutations

Question 2

What’s are single gene disorders

Answer 2

Mutations in single genes often causing loss of function
This directly leads to a condition

Question 3

Multi factorial diseases

Answer 3

Variants in genes which then interact with environmental factors causing alteration of function (also called common complex disorders). This may increase susceptibility of disease

Question 4

Chromosome disorders

Answer 4

Chromosomal imbalance causes alteration in gene dosage

Question 5

Mitochrondrial disorders

Answer 5

Generally affect organ systems with high energy requirement
Mutation in mtDNA

Question 6

Where are genes controlling function and structure of mitochrondria found

Answer 6

In both mitochondrial and nuclear DNA

Question 7

What are somatic mutations

Answer 7

Cause cancer. Inactivation of both alleles of a gene involved in growth

Question 8

Types of single gene disorder

Answer 8

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

Question 9

Autosomal dominant conditions

Answer 9

Variation in expression
Penetrance
New mutations
Anticipation

Question 10

Penetrance

Answer 10

Refers to the likelihood that a clinical condition will occur when a particular genotype is present

Question 11

Anticipation definition

Answer 11

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

Question 12

Autosomal dominant inheritance

Answer 12

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

Question 13

Most mutations cause loss of function of an allele

Answer 13

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

Question 14

Dominant or recessive pattern of inheritance?

Answer 14

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

Question 15

Marfan syndrome

Answer 15

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

Question 16

Diagnosis of single gene disorder using DNA

Answer 16

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 §

Question 17

Exceptions to Mendel’s rules in autosomal dominant inheritance
Neurofibromatosis type 1

Answer 17

Autosomal dominant
Patches on skin
Multiple neurofibroma

Question 18

Variation in expression

Answer 18

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

Question 19

Complete Penetrance

Answer 19

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

Question 20

Incomplete Penetrance

Answer 20

Not all people with pathogenic mutation show manifestations of the genetic condition

Question 21

Age dependent Penetrance

Answer 21

A delay in the onset of symptoms of a genetic disease

Question 22

Huntington disease

Answer 22

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)

Question 23

How huntingtons demonstrates age-dependent penetrance

Answer 23

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

Question 24

Age dependent penetrance of breast cancer in women who have a mutation in one allele of BRCA1

Answer 24

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

Question 25

New mutation

Answer 25

Mutation not present in either parent but was present egg or sperm

Question 26

Achondroplasia

Answer 26

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

Question 27

Myotonic dystrophy

Answer 27

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

Question 28

Anticipation

Answer 28

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

Question 29

Huntington disease- a triplet repeat disease

Answer 29

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

Question 30

Mosaicism

Answer 30

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

Question 31

Severe osteogenesis imperfecta (brittle bone disease)

Answer 31

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

Question 32

Autosomal recessive disease

Answer 32

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

Question 33

Determining probability in autosomal recessive conditions

Answer 33

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 1*1/22*1*4=1/88 1*1/44=1/88 Can do a genetic test on foetus during pregnancy to see if child will be affected

Question 34

Hardy-Weinberg principle

Answer 34

Suppose a normal gene has 2 common alleles P+q=1 In next generation alleles combine at random AA - P*P=P^2 Aa or aA — pq or qp=2pq Or aa — q*q=q^2 Carrier rate = 2pq=2(1-q)q=2q-2q^2

Question 35

Applications of Hardy-Weinberg

Answer 35

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

Question 36

Can estimate carrier frequency of AR disease in population with hardy-Weinberg

Answer 36

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= 2*43/44*1/44

Question 37

Hardy Weinberg equilibrium

Answer 37

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

Question 38

Consanguinity

Answer 38

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

Question 39

X-linked recessive inheritance

Answer 39

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

Question 40

Duchenne muscular dystrophy

Answer 40

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

Question 41

Available options for mother if they’re a carrier for X-linked disease

Answer 41

Postpone pregnancy No further pregnancies- adoption Further pregnancies: accept risk, prenatal diagnosis if available, egg donation, preimplantation diagnosis if available

Question 42

Sequencing of the dystrophin gene

Answer 42

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

Question 43

Tracking inheritance of gene causing Duchenne muscular dystrophy through family

Answer 43

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

Question 44

Female carriers may show mild symptoms of X-linked disease

Answer 44

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

Question 45

Why do some females show x-linked recessive traits

Answer 45

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

Question 46

X-linked recessive inheritance: father affected

Answer 46

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

Question 47

Mitochondrial inheritance

Answer 47

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

Question 48

Variation in the genome

Answer 48

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

Question 49

DNA sequence variants

Answer 49

Varying effects on health depending on where they occur and whether they alter the function of essential genes and/or their controlling elements

Question 50

What is Mendelian inheritance

Answer 50

Caused by mutation in a single nuclear gene Classical inheritance patterns: dominant/recessive, autosomal/X-linked

Question 51

What is Non-Mendelian inheritance

Answer 51

Polygenic inheritance Multi factorial (common complex) Maternal inheritance (mitochondrial)

Question 52

Inheritance of common complex disorders

Answer 52

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

Question 53

Mendelian conditions

Answer 53

Hypercholesterolaemia Marfan syndrome Cystic fibrosis Sickle cell disease Duchenne muscular dystrophy -genetic component highlighted by pedigree pattern and recurrence risk

Question 54

Common conditions

Answer 54

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

Question 55

Differences between Mendelian and common conditions

Answer 55

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

Question 56

Identifying genetic and environmental influences

Answer 56

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

Question 57

How is evidence gathered

Answer 57

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

Question 58

Comparing MZ/DZ twins

Answer 58

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

Question 59

Risks to family members

Answer 59

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

Question 60

Polygenic inheritance

Answer 60

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

Question 61

How can genetic and environmental factors combine to produce a liability to a multi factorial condition

Answer 61

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

Question 62

Magnitude of Recurrence risk in other family members

Answer 62

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

Question 63

What is empiric risk

Answer 63

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

Question 64

How did we find genes for Mendelian disorders

Answer 64

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

Question 65

How are genetic components of common conditions identified

Answer 65

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

Question 66

What are SNPs

Answer 66

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

Question 67

Identifying genetic components of common complex conditions

Answer 67

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

Question 68

Relative risks associated with susceptibility loci

Answer 68

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

Question 69

100000 genome project

Answer 69

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

Question 70

The impact of genetic testing on motivation to stop smoking

Answer 70

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

Question 71

To personalise treatment and surveillance we can use genomic information

Answer 71

To sub-classify their disease To assess their susceptibility To predict their response to drugs To choose best treatment