Flashcards in Lecture 21-Multifactorial Conditions Deck (68):
Of single gene disorders, chromosome disorders and multifactorial disorders which is most common genetic condition?
What are 2 different multifactorial conditions that have been found in mummies and therefore have been around for a long time?
frequency of concordance between monozygotic (MZ) and dizygotic (DZ) twins is used to ______
- show the impact of environment and genetics on multifactorial disorders
Give some examples of multifactorial disorders (just be familiar with these). (9)
- atopic disorders
- inflammatory bowel disorders
- mental illness
- coronary artery disease
What is the most common cause of malformations in infants?
- multifactorial/familial disorders (although this is after unknown causes)
multifactorial disorders account for most _____ anomalies.
(T/F) If a condition disproportionately affects families it's genetic. Why?
- False: families have same cultural attitudes, behaviors, diet and environmental exposures
(T/F) inheritance patterns of multifactorial disorders are fairly easy to decipher as such.
False-they're not clear cut
What are the difficulties in understanding multifactorial inheritance? (3)
- separating effects of genetics from the environment
- understanding heterogeneity of the disorder
- ignorance of the basic defects involved
Multifactorial disorders result from _____
- hereditary factors (polygenetic, i.e., they affect multiple genes)
- environmental factors
- when both of these groups of factors push the individual above the "threshold of risk"
What is used for genetic counseling of mutlifactorial disorders?
- empiric risk figures
Aside from disorders, what else is mutlifactorially determined?
- quantitative traits like height, intelligence, bp
How can the population frequency of various multifactorial traits (not disorders necessarily) be represented?
- additive--bell shaped distribution in an Normal/Gaussian curve of variation
How are disorders with a small hereditary influence treated? Give an example.
- changing the environment
- stop smoking for those with predisposition for lung cancer
How are disorders with a large hereditary influence treated? Give an example.
- examination of family members is emphasized
- lifestyle modifications
- breast cancer
What is the concordance rate between MZ and DZ twins for pure genetic conditions?
DZ: <100% and similar to concordance among siblings
What is the concordance rate between MZ and DZ twins for pure environmental conditions?
MZ = DZ
What is the concordance rate between MZ and DZ twins for multifactorial conditions?
MZ>DZ but not 100%
What is the concordance of CL/P among MZ? DZ? What does this tell us?
- CL/P is a multifactorial trait
What are the difficulties in twin studies? (4)
- MZ twins often treated more similarly than DZ
- Somatic mutations can occur during mitotic divisions of the cells in MZ twins
- uterine environment of MZ twins may not be identical
- number of MZ twins reared apart is small
What is the equation for measuring familial aggregation relative risk
lambda r=(incidence in a relative "r" of an affected person)/(population prevalence of the disease)
Which disorder is becoming a good example of a disorder with multifactorial genetics?
- autism: risk ratio for MZ twins 2000 vs. siblings 150
What is the purpose of case control studies?
- assess familial aggregation
What do case control studies do? give an example in which these were used to show higher prevalence of disease in related individuals.
- compare a patient with the disease (the case) to controls
- MS: 3.5% of siblings of patients with MS had MS as well. This was much higher than among the relatives of matched controls who did not have MS
What are the difficulties with case-control studies?
- recall bias
- choice of controls
heritability (include equation)
- % of the population variation that is due to genes
Traits that are largely caused by genes result in a heritability estimate close to ____.
Describe the threshold model for multifactorial disorders
Assuming the polygenic model:
- this assumes a sizable number of different "risk" genes are randomly distributed throughout the population
- the genes themselves are not necessarily defective but accumulation of many risk genes increases risk of having the disorder and can push someone above the threshold which would result in manifestation of the disease
- therefore, all affected individuals possess a high number of risk genes
In multifactorial disorders, the correlation between relatives is proportional to ________.
their genes in common
What is the proportion of alleles in common with the proband of:
- MZ twins
- 1st degree relatives
- 2nd degree (aunts, uncles)
- 3rd degree (cousins)
1st degree: 1/2
2nd degree: 1/4
3rd degree: 1/8
What is the recurrence risk equation for 1st degree relatives?
- R=sqrt(population prevalence)
How does the recurrence risk change with distant relatives?
- decreases sharply because fewer genes are shared
What is the recurrence risk influenced by? (4)
- multiple affected family members
- severe form
- early onset
- affected person of the sex less likely to be affected
- consanguineous marriages
What is an example of a multifactorial disorder which affects the sexes differently? How is this manifested?
- pyloric stenosis
- if a female has it (less likely to be affected) then males in the family will have a higher recurrence rate since they require fewer disease causing genes to be affected.
How are empiric risk factors determined? (2)
- direct observation of data
- specific to a population (can find varying risk in different areas--ex: NTDs in britian-5% and US-2-3%)
Symptoms of NTDs depend on ______
Where the NT doesn't close
NTDs can manifest as ____ (3).
- spina bifida
- failure of the brain to develop normally
spina bifida (3)
- failure of the spine to develop normally and this means that the NS isn't intact so often limbs can't move
- often fatal
- frequent MR and neurological defects
What is the frequency of NTDs in general and how have they changed?
- decreased due to increased use of folic acid and the use of U/S causes many to abort
Where is there a higher rate of NTDs and what is the rate?
- Ireland and Britian: 1/200
- Latino infants whose mothers are born outside of the US
NTDs result from mutations in what gene(s)? How does this cause the phenotype?
- MTHFR 5, 10
- THF cant be recycled and this interferes with methylation of homocysteine to methionine
The mothers of infants with NTDs ______ (genetically).
- have a high incidence of homozygocity for mutant gene
There is no special risk in ______% of patients with NTD births.
- makes it difficult to predict risk
How can NTDs be prevented?
- 0.4-0.8 mg folic acid prevents 70% of NTDs
How are NTDs detected?
With NTDs there is a higher risk of _______.
What is a "small case" of NTD
- cases that have specific causes such as amniotic banding, single gene disorder, chromosome disorder, or a teratogen
NTDs and _____ often go hand in hand.
What are the symptoms of FAS? (2)
- hypoplasia-small nose bridge
- separated eyes
- main symptoms
- not very common but the most common cause of NTDs
- encephalocele, CNS abnormalities, seizures
- poor survival
- MKS2, MKS3, CEP290
Where are the risk genes for schizophrenia located?
- possible risk genes on many chromosomes
Describe the recurrence risk for schizophrenia
- very multifactorial (results from studies can't be replicated)
- increases when more relatives are affected
- decreases with distance from affected relative
What is the recurrence risk for a MZ twin of someone with schizophrenia?
DM is in what gene on what chromosome? What does this gene do?
- Chromosome 20
- represses body's response to insulin so if there is a lot of this protein the body won't respond to insulin
How common is the PTPN1 mutation? The normal version?
- mutation: 35%
- normal: 45%
- other variants neutral
Crohn's mutation/chromosome? What percent of Crohn's cases have the mutation?
- chromosome 16
What is IBDI/Nod2/Card15 responsible for?
- non-specific immune response
If someone carries 1 mutaiton in IBDI what is the chance of developing Crohn's? Severity?
If someone carries 2 mutations in IBDI what is the chance of developing Crohn's? Severity?
Explain the incidence of CL/P
- highest among Japanese (1.7/1000) then whites (1/1000), then African americans (0.4/1000)
How many cases of CL/P are isolated and how many syndromic (from teratogen, single gene or chromosome disorders)
- Isolated: 85%
- syndromic: 15%
Note: also seen with NTDs
What are the teratogens that can cause CL/P? (4)
- valproic acid
What are the genes that contribute to nonsyndromic oral clefts? (4)
severity of CL/Ps depend on ______
the number of genes affected
Van der Woude syndrome
- symptoms/signs (3)
- which chromosome/gene
- lower lip pits (very important for diagnosis of syndromic oral clefts), cleft lip w or w/o cleft palate, heart defects
- Chromosomes 1 and 17: IRF6 can cause this
- AD but variable expressivity