WEEK 7 Flashcards
What does Mendelian Inheritance refer to?
Single gene disorders
What are the types of single gene disorders?
1) Autosomal dominant
2) Autosomal recessive
3) X-linked recessive
What is autosomal dominant inheritance?
Heterozygotes with one copy of an altered gene have the condition
What is autosomal recessive inheritance?
Homozygotes with two copies of an altered gene have the condition
What is X-linked recessive inheritance?
Males with one copy of altered gene on X-chromosome have the condition
What is a heterozygote?
2 different alleles at locus
What is a homozygote?
2 alleles which are the same at locus
What are autosomal dominant conditions?
Describes any trait expressed in a heterozygote due to everyone who inherits altered gene showing clinical signs
Give three characteristics of autosomal dominant conditions?
1) M+F affected equally
2) Transmitted from one generation to the next (“vertical transmission”)
3) All forms of transmission are observed (M-M, F-F, M-F, F-M)
What is the result of most mutations in autosomal dominant disorders?
Loss of allele function
What is the result of the majority of mutations in autosomal recessive disorders?
Abolish action of allele
What is the result of autosomal dominant/autosomal recessive in a heterozygote?
dominant=clinical signs
recessive=no clinical signs
LOOK AT PEDIGREE DIAGRAM FOR:
AUTOSOMAL DOMINANT CONDITION
What is the aim for diagnosing autosomal dominant mutations using DNA?
To determine a sequence/copy number variant in order to demonstrate mutation in other affected family member/show it isn’t present in unaffected relatives
What are the implications of exceptions to Mendel’s rules in autosomal dominant inheritance?
Causes a person to appear not to have an autosomal dominant condition when they have the genotype
Give five examples of exceptions to Mendel’s rules in autosomal dominant inheritance
1) Variation in expression
2) Reduced penetrance
3) New mutation
4) Anticipation
5) Mosaicism
What is variation in expression?
When other genes modify the phenotype to cause family members to have different signs for the same disease
Give an example of variation in expression
Neurofibromatosis Type 1 causing café au lait skin patches and multiple neurofibroma but some can appear to be skin tags
What is reduced penetrance?
When someone who is heterozygous shows no clinical signs of a condition (“skipped generation”)
Give an example of reduced penetrance
Huntington’s disease gene containing between 36-39 CAG repeats has reduced penetrance, HD is a progressive neurological disorder resulting in involuntary movements, dementia and psychiatric disturbance
What is age-related penetrance?
When there is a delayed onset of genetic disease (BRCA mutation)
What is new mutation?
When there is a new mutation in egg/sperm of the parent of affected offspring
Give an example of new mutation
Achondroplasia causing short stature due to new mutation in sperm, the chance of which increases with paternal age
What is anticipation?
Unstable, expanding trinucleotide repeat mutation resulting in reduced age of onset and/or increased phenotype severity in successive generations
Give an example of anticipation
Muscular dystrophy (CTG repeats) causing muscle weakness and impaired muscle contraction after relaxation (myotonia)/Huntington’s disease (CAG repeats)
What is mosaicism?
Formation of two populations of cells with different genetic constitutions usually due to mitotic error
Give an example of mosaicism
Severe osteogenesis imperfecta (brittle bone disease)
What are autosomal recessive conditions?
Conditions that manifest only in a homozygous state
Give four characteristics of autosomal recessive conditions
1) Can’t follow the disease through pedigree diagrams
2) “Horizontal transmission”-see siblings affected
3) M+F affected equally
4) May be evidence of consanguinity due to increased chance of two carriers
What is consanguinity?
When parents have a biological ancestor in common (eg. siblings)
LOOK AT PEDIGREE DIAGRAM FOR:
AUTOSOMAL RECESSIVE CONDITION
What are X-linked recessive conditions?
Disorders which are sex-linked and normally manifest only in males
Give an example of an X-linked recessive condition
Duchenne Muscular Dystrophy (DMD)
What is the permutation of males with an affected X chromosome?
They have the disorder due to hemizygosity
What is hemizygosity?
Diploid individual with only one gene at a specific locus (due to XY)
What are the permutations of females with an affected X chromosome?
1) They have the disorder due to homozygosity
2) They are a carrier of the disorder due to heterozygosity
Give three characteristics of X-linked recessive conditions
1) All daughters of males with the condition are obligate heterozygotes (but may be homozygotes)
2) When a mother is a carrier and the father is unaffected, each son has a 1/2 chance of having the condition; each daughter has a 1/2 chance of being a carrier (“Knight’s move” pattern of transmission-mother to son)
3) Affected males cannot transmit disorder to their sons
What are the reasons that may cause a female to show signs of an X-linked recessive disease?
1) Homozygous for allele
2) Has single X chromosome (Turner’s syndrome)
3) Has structural rearrangement of X chromosome
4) Is heterozygous but has skewed or non-random X-inactivation (carrier with mild symptoms)
How does an X-linked dominant disease’s pedigree diagram differ slightly from that of an autosomal dominant condition?
1) Excess affected females
2) No male-to-male transmission
What is the result of lyonisation?
Females being less severely affected than males by X-linked dominant conditions
What is lyonisation?
Inactivation of an X chromosome
Give an example of an X-linked dominant condition
Vitamin D resistant rickets
What is a characteristic in X-linked dominant disease?
M-F transmission always results in the disorder being passed on
How does mitochondrial inheritance occur?
Exclusively via the mother as sperm mitochondria is actively expelled from the fertilised egg
What is multifactorial inheritance?
The type of hereditary pattern seen when there is more than one genetic factor involved and, sometimes, also environmental factors
What is the continuum of effect of DNA variants?
Responsible for normal variation—>Modulate disease susceptibility or resistance to environmental triggers—>Directly cause disease
What are DNA sequence variants?
DNA sequences with varying effects on health depending on where they occur and whether they alter essential gene function and/or their controlling elements
Give the characteristics for Non-Mendelian Inheritance
Polygenic
Multifactorial
Maternal inheritance (mitochondrial)
What does multifactorial inheritance cause?
Common complex disorders
What two factors go into multifactorial inheritance?
Inherited predisposition/genetic susceptibility (genetic factors) and environmental factors`
What is the characteristic of inheritance patterns for common conditions due to multifactorial inheritance that is different to mendelian inheritance?
No obvious pattern
Give examples of common complex conditions
CHD DM Hypertension Cerebrovascular disease Schizophrenia Breast and bowel cancers
How do you measure how much of disease aetiology is due to genetic or environmental factors in multifactorial conditions?
Observational studies of disease incidence in different groups of people (eg. family clustering, twin/adoption studies, population/migration studies)
What is family clustering?
Analysing risk to family members of someone with a common complex disease
How do you determine whether environmental factors influence common complex conditions by twin studies?
Assess monozygotic (all genes shared) and dizygotic (50% genes shared) twins
What is meant by polygenic?
Multiple genes which each make a small additive contribution to the final phenotype
What is polygenic inheritance the basis for?
Continuous traits following normal distribution in the population
Give examples of polygenic/continuous traits
Blood pressure, height, IQ
How do single genes contribute to a continuous characteristic?
Additive effects (they blend)
Give an example of single genes contributing to a continuous characteristic
Eye colour
What is the result of genetic and environmental factors varying from person to person?
They produce differing liabilities to a multifactorial condition for each individual
What is liability threshold?
The threshold for liability above which a person will develop a multifactorial condition
What is the shift in liability curve for relatives of a family member with a multifactorial condition?
Leftward due to increased likelihood of similar genetic and environmental factors
What is the trend in recurrence risk when moving away from the origin relative?
It decreases
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
What may SNPs identify in common conditions?
They may increase or decrease risk or have indirect association/act as a marker for nearby major genetic influence
What is the 100,000 Genome Project?
Government plan to sequence full genomes of up to 100,000 NHS patients with cancer, rare inherited diseases or infectious diseases
What is hypothesised with genetic testing?
Showing individualised risk could provide motivation to change behaviour to cause decrease in risk
