Risk Assessment Flashcards
How do you calculate frequency of an allele?
Count. 2x homozygous and 1x heterozygous. Add up and divide by total number of alleles in population
What must be known to use counting methods?
Phenotypes need to be identifiable
Frequently, the possible genotypes are NOT all
phenotypically distinguishable without specialized testing
Hardy-Weinberg principle is?
A mathematical statement of the
relationship between genotype frequencies
and allele frequencies at a Mendelian locus.
Frequency of A? Frequency of a?
A=p (dominant)
a=q (recessive)
What is true about p and q?
p+q=1
Frequency of the alleles
Freq of AA? Freq of Aa? Freq of aa?
AA = p^2 Aa = 2pq aa = q^2
For autosomal genes what can be said about sum of frequencies?
(p+q)^2=1=p^2+2pq+q^2
This can be expanded for any number of alleles e.g. (p+q+r)^2=p^2+q^2+r^2+2pq+2pr+2qr
CF is inherited as?
Autosomal recessive
Disease prevalence of CF in northern european white? Carrier prevalence?
1/2500 (i.e. q^2=1/2500)
Carrier is thus 2pq=1/25
Why calculate carrier risk if carrier testing is available?
An accurate understanding of the carrier risk is
important for genetic counseling prior to carrier
testing:
- Understanding of the inheritance pattern
- Perception of risk
- Decision-making about carrier testing
- Waiting period for results of carrier testing
- Carrier testing may not be 100% sensitive
For autosomal recessive disease, if you know parent/patient is not affected, what is risk of carrier or absent (if known that the parents are obligate carriers)
2/3 carrier
1/3 none
Remove the option of being affected in probability
Assumptions of Hardy-Weinberg
•No mutation at the locus.
•No selection for any of the genotypes at the locus
•No migration into the population.
•Mating is completely random with respect to
genotype
What is heterozygote advantage?
Certain mutant alleles may be deleterious in homozygotes but confer increased fitness in heterozygotes.
Sickle cell disease
What is founder effect?
A high frequency of a mutant gene in a population
founded by a small ancestral group
Hardy Weinberg and Consanguinity?
DO NOT USE HARDY WEINBERG
Use mendelian counting instead
What is genetic testing?
The use of specific genetic tests or
assays to determine the genetic status of an
individual already suspected to be at high risk for
developing (or transmitting) a particular inherited
condition because of family history or clinical
symptoms.
What is genetic screening?
The use of specific genetic tests
or assays on a population basis, to identify individuals at risk of developing or transmitting a specific disorder, independent of clinical symptoms or a family history of the disorder.
Settings for genetic screening?
- Newborn
- Prenatal
- Carrier (heterozygote)
- Gamete donors
- Epidemiological
- Occupational
Major principles of screening?
Absence of compulsion
-testing must be voluntary
- program must not stigmatize or impose constraints on
childbearing or mate selection
Protection of participants
- informed consent essential
Privacy and access to information about results
- results available only to screenee
Community involvement in :
- planning
- education about program and impact of results
Equal access
to information about screening, testing, and test facilities
General criteria for genetic screening?
-Severe, relatively common, well-understood disease
-Identifiable high-risk population
-An acceptable screening test
-Easy to perform
-Inexpensive
-Good validity and reliability
-More specific additional tests are available to confirm
or rule out the diagnosis.
- Useful and realistic interventions are available
-Effective therapy
-Reproductive options
-Risk reducting strategies
What is clinical validity?
The extent to which a test result is predictive
for disease
What is clinical utility?
The degree to which test results will change
what medical care an individual receives, and
improves the outcome of care.
What does clinical validity depend on?
- Sensitivity
- Specificity
- Positive predictive value
How do you design a screening program?
Selection of a “cut-off” criterion as a balance between the desired
sensitivity and specificity.
• In some cases, the screening test may be designed to give a test with high sensitivity, understanding that the trade-off will be a higher
proportion of ‘false – positives’ (corresponding to a lower specificity).
• In other cases, the screening program may accept a percentage of ‘false negatives’ (corresponding to a lower sensitivity), in order to
minimize the occurrence of false-positives.
SNOUT and SPIN
Sensitivity to rule out
Specificity to rule in
Does prenatal screening detect all conditions e.g. Trisomy 21, 18 etc?
Nope
What does amniocentesis test?
- Fetal chromosomes
- Fetal dna
- Biochemical & viral testing
What does Chorionic villi sampling test?
- Fetal chromosomes
* Fetal DNA
What is a physical map?
Defines the location of a gene or marker on a chromosome relative
to landmarks on that chromosome.
What is a genetic map?
Defines the location of one locus (gene or marker) relative to another locus by observing the co‐inheritance of the two loci.
What is Mendel’s first law?
Mendel’s first law: Segregation
When an individual produces gametes, the alleles at a gene locus ‘segregate’, so that each gamete receives just one copy of the gene.
What is Mendel’s second law?
Mendel’s second law: Independent Assortment
The alleles at different genes assort independently of each other when gametes are formed.
When is Mendel’s second law true?
The second law is true, UNLESS the two different
genes lie close to each other on the same
chromosome.
Strategies for genetic mapping
What is recombination? Likeliness of DNA exchange in recombination?
In gamete formation, the homologous chromosomes pair and recombine before assorting into haploid gametes.
- Exchange can occur between homologous chromatids.
- This exchange can be detected if loci within the segments differ in sequence or in another measurable trait.
- The farther apart two loci are, the more likely that exchange will occur between them.
What is frequency of recombination?
Genetic distance between two loci can be
measured by the frequency of recombination
(theta), estimated from a large series of meioses.
• If the two loci are very close so that crossover
never occurs between them, then theta = 0%.
• The farther apart two loci are on the same
chromosome, the more likely a cross-over will
occur.
What is linkage analysis?
Ascertain a set of families who are ‘segregating’ a disease gene. Could be:
Extended families
Sibling pairs
Other pairs of affected relatives
Genotype the family members for a set of polymorphic markers.
Analyze the data to find markers which are inherited together with the disease gene (“co‐segregation”).
Describe the connection between genetic and physical distance?
1% recombination = 1cM (‘centimorgan’)
1 cM corresponds to ~1 million base pairs, 1Mb
Linkage analysis limitations?
Linkage analysis does not identify the exact gene causing the condition, but rather the location of the gene.
HOWEVER, it has been and remains an important tool for identifying the genomic location of disease genes.
NOTE: The tools for identifying genetic variation at marker loci have evolved, allowing multiple loci across the genome to be genotyped concurrently.
Linkage analysis is good for what type of conditions?
Linkage Analysis has been used most frequently to identify the location of genes for ‘simple’ Mendelian conditions.
What is complex inheritance?
Heredity contributes to most common disorders.
– Birth defects, mental illness, diabetes, Alzheimer disease, cardiovascular disease, etc.
• However, most are not single gene disorders, nor does the inheritance follow a simple Mendelian pattern.
• Most common disorders involve an interaction
between the genotype at one or more loci, and
environmental factors.
What are some common congenital complex disorders?
– Neural tube defects – Cleft lip with or without cleft palate – Congenital heart malformations – Congenital hip dislocation – Pyloric stenosis
What is the background risk for congenital malformation?
2-3% per pregnancy
Congenital inheritance is described by?
Empiric data
• Most of the time, we are left with observations
from large numbers of families (empiric data):
– Familial aggregation
– Increased empiric recurrence risk among relatives of an
affected individual.
– Increased concordance among MZ twins compared to DZ
twins.
• This suggests complex inheritance.
What is recurrence risk?
The probability that a genetic disorder present in one or more members of a family will recur in another relative of a specified degree of relationship.
Recurrence risk for mendelian disease?
For conditions which follow a Mendelian inheritance pattern, we calculate recurrence risk based on Mendelian principles.
Recurrence risk for complex inheritance?
For conditions with complex inheritance, recurrence risk is based on observations (empirical) not on theoretical calculations.
For example, after the birth of a child with and isolated NTD, the empiric recurrence risk to future full siblings is 3‐4%.
What is the multi-factorial threshold model?
Normal distribution of susceptible alleles
Past a threshold value of a number of susceptibility alleles means develop birth defect
Empiric recurrence risk and relation? 4 trends.
Decreases with increasing degree of relationship to the affected individual
Increases with the presence of more than one affected relative
May increase with increasing severity of the condition
Is greater for the sibling of an affected individual of the less frequently affected sex (e.g. less common for females and sister has it, then brother and sister are more likely to have it too than if the more common sex had the first demonstration)
Can threshold vales for the susceptibility alleles differ for genders
Yes
What are qualitative traits?
– “Discrete”
– “Discontinuous”
– Either present or absent
What are quantitative traits?
– “Measurable”
– Height; Blood pressure; Finger ridge count
– Often normally distributed in the population
Describe genetic mapping in families. Limitations?
The mapping method we discussed earlier in this lecture is linkage mapping, which relies on observing whether or not there is recombination between a marker locus and a disease locus within families.
• This method is less powerful for identifying
susceptibility alleles, since the presence (or absence) of the condition does not give as clear an indication of which predisposing alleles are present.
What is co-occurance?
We can also look at the co‐occurrence of alleles at one genetic locus with the alleles at another locus, in unrelated individuals in the population.
• If alleles at two linked loci occur together in the
population more often than would be expected by
chance, we infer:
– Recombination between the loci has been infrequent
– The distance between the loci must be small.
What type of study looks at co-occurance?
- “Linkage Disequilibrium” mapping
* Also known as Association Analysis
What does a linkage disequilibrium study entail?
• Collect a sample of affected and unaffected
individuals (“cases” and “controls”)
• Compare the allele and genotype frequencies
between the two groups
– For a specific candidate gene or genes
– For genome‐wide genetic markers
• Find genetic variants with significantly different
frequency between the two groups
What specifically is linkage disequilibrium?
For two very closely linked loci, in some
cases it is true that an allele at one locus is
preferentially associated with an allele at
the other locus – Linkage Disequilibrium.
How does one interpret a linkage disequilibrium finding?
• A genetic variant which is found significantly
more frequently in a group of affected
individuals compared to controls may be:
– Involved in the etiology of the disease
– Very close to another sequence variant that is
involved in the etiology of disease
– (Need to also consider whether the association may be a false positive, or due to problems with
experimental design).
Linkage Mapping is used for?
Within families Find single genes with large effects Large distances >5 Mb Fewer markers needed Mode of inheritance is specified Retains power even with allelic heterogeneity Most powerful for highly penetrant genes
Association mapping is used for?
Unrelated individuals
Find susceptibility alleles
Small distances ~1kb
More markers needed
Does not require specified mode of inheritance
Loses power rapidly with increasing allelic heterogeneity
Able to detect gene variants with smaller effects
Describe the risk for down syndrome if Robertsonian translocation occurs
Affected parent has 21, 14, t(14;21) w/ 45 total chormosomes
For a Father/Mother with translocation options of zygotes are:
Normal, balanced translocation, trisomy 21
Non-viable: Trisomy 14, monosomy 14, monosomy 21
1/3 chance of getting trisomy 21 from dad/mom
