7. obsterics genetics Flashcards
Define autosomal dominant
heterozygotes with one copy of abnormal gene are affected
define autosomal recessive
homozygotes with two copies of the abnormal gene are affected
define x linked recessive
males with one copy of the abnormal gene of X chromosome are affected
rarer inheritance patterns
x linked dominant mitochondrial inheritance
x linked recessive
autosomal recessive inheritance carrier risk rate
2/3 sibling carrier risk
what type of inheritance if CF and what is the carrier rate in a general population
AR
1 in 25
What do you do if you don’t know the carrier rate for a recessive condition?
Hardy-Weinburg principle
•The Hardy-Weinberg principle allows the calculation of carrier rates once the incidence of a condition is known as long as the gene frequency is in equilibrium
The Hardy-Weinberg Principle
- In a large, randomly mating population the relative proportion of different genotypes remains constant
- This only holds true if there are no outside influences eg selection or assortative mating
- If you have 2 alleles for an autosomal condition: A and a, with a frequency of p and q, p+q=1
p2 = homozygous unaffected
2pq = carriers
q2 = affecteds
p2+ 2pq+q2= 1
type of inheritance of phenylketonia and carrier rate
AR
1/50
Factors that can disturb the Hardy-Weinberg Principle
- Non-random mating: Assortative mating – tendency to choose a mate with similar characteristics eg height, IQ
* *2. Consanguinity** – relationships between close relatives can lead to an increased carrier risk within a family - The mutation-selection equilibrium: New mutations are arising all the time. Different genes have different new mutation rates according to their size and structure
Usually this is balanced by loss of alleles due to reduced reproductive fitness in affected individuals
An alteration in this balance will affect the equilibrium
-
Selection (heterozygote advantage)
For some AR conditions, carriers seem to have a reproductive advantage. This has lead to certain genes being very common in a particular population -
Small population size (the founder effect)
One allele can be transmitted to a large proportion of children purely by chance leading to an increased incidence of a certain condition in a population
6. Migration (gene flow)
Migration and intermarriage can introduce new alleles into a population
Targeted tests - non-invasive
- Ultrasound scan- Surveillance eg growth, 3D scan, Fetal echocardiogram
- Fetal MRI scan
- Molecular testing on fetal cells/DNA in maternal blood for gender or other conditions
Targeted tests - invasive
- Chorionic villus sampling (CVS)
- Amniocentesis
- Cordocentesis (Fetal blood sampling)
- Fetal tissue biopsy
–liver
–muscle
–skin
Chorionic Villus Sampling
11-13 weeks
transabdominal approach
Chromosomes
- Direct preparation - 1-2 days
- Long-term preparation
–results in 2 weeks
Good yield of fetal DNA for molecular tests
1% miscarriage risk (0.5-1%)
Amniocentesis
15-16 weeks gestation
Amniocytes derived from fetal tissues and amnion
Both amniocytes and supernatant can be used for prenatal tests
Chromosome analysis takes 2-3 weeks
Low yield of fetal DNA, 1% miscarriage risk
Preimplantation Genetic Diagnosis (PGD)
testing embryos produced by IVF for inherited disorders- embryos that are free of the disorder to be replaced.
Suitable for couples at substantial risk of transmitting a serious genetic condition to their children.
- chromosome translocations
- x-linked disorders
- some single gene disorders
Not available for all conditions.
Requires considerable preparation – clinical, counselling, laboratory
Polygenic inheritance
- Polygenic inheritance: inheritance controlled by many genes with small additive effects
- Genes at many different loci contribute to the phenotype
- No one gene is dominant or recessive to another – there is a cumulative effect
- Remember, in locus heterogeneity, more than one gene leads to the same phenotype
Multifactorial inheritance
• is where a condition is cause by the interaction of multiple genes and the environment
liability-threshold model
- The sum of environmental influences and genetic predisposition gives a persons liability to be affected
- If the threshold is exceeded the condition results
Recurrence risks:
•empiric figures from population studies
Golden rules:
- relatives of an affected person have a greater genetic tendency to that condition, so their curve is shifted and more individuals cross the threshold
- The risks are greatest for close relatives
- The risk is greater for relatives when the person is more severely affected – eg severe cleft lip and palate or long segment Hirschsprung disease
- The risk is higher if more than one relative is affected eg 3 relatives with coronary artery disease rather than 1
- The risk is higher if a child of the lower risk gender is affected eg a girl with autism as more boys are affected by this condition or pyloric stenosis - the risk for the brother of an affected girl is 9.2%, but for the brother of an affected boy is 3.8%
- Even someone with a high genetic liability will not be affected if the environment is favourable
- Recurrence risk data collected in one population may not apply to another as the risks are dependent on the incidence of the condition in that population
mendelian inheritance
controlled by a single locus in an inheritance pattern.
(a disease controlled by a single gene)
Neural tube defects
genetic and environment
Celtic origin
Specific variant in MTHFR gene
(methylene-tetrahydrofolate reductase)
Poor socioeconomic status
Multiparity
Valproic acid embryopathy
Periconceptual folic acid reduces recurrence risk
How is trisomy 21 screened for
routine prenatal screening
ultrasound scan
nuchal translucency scan (increased)
-Thickness of NT measured by ultrasound scan in relation to crown-rump length
Biochemical serum screening in second trimester (not for diagnosis)
•Reduced MSAFP levels alpha feto protein
Indications for targeted prenatal tests
- personal and family history
targeted and diagnostic screening tests
- abnormalities identified in pregnancy
abnormal screening test result/ scan
