6. Multifactorial Genetic Disorders Flashcards
Define and discuss the concepts of multifactorial/complex disorders including: prevalence, discordance and concordance in twin studies, qualitative and quantitative traits, the threshold model of multifactorial/complex disease and heritability (objective)
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Understand genetic counseling principles relating to the recurrence risk of multifactorial/complex diseases (objective)
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Understand why IDDM is felt to be a multifactorial/complex disorder, i.e. the arguments for genetic and non-genetic bases for the disease (objective)
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Discuss the prevalence, and clinical features of the neural tube defects discussed as well as the recurrence risk data generally and prevention data relating to folate (objective)
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Describe some forms of lip and palate clefting (objective)
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Discuss aspects of lip and palate clefting including: prevalence data, genetic basis, and recurrence risk applying genetic counseling principles (objective)
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Intro Remarks
Genetic syndromes and malformations leading cause of mortality/morbidity in infancy
Most common causes:
Cardiovascular disease, cancers, cerebrovascular disease, CV (25% of all deaths in US, $300 million annually)
Common Disorders
Seem to have genetic component (not Mendelian)
Examples: heart disease (myocardial infarction), cancer, mental illness (Alzheimer disease), diabetes, cleft lip and palate
Families share genes: Proportion of Alleles
Monozygotic twin= 100%
First-degree relative (parents, siblings, offspring)= 50%
Second-degree relative= 25%
Third-degree relative (first cousins)= 13%
Examples of Mendelian Subtypes of Complex Disorders
Heart Disease- majority non-Mendelian
CAD, cardiomyopathy, arrhythmias
Familial Hypercholesterolemia= AD
Long QT syndromes: AD
Families Share Many Things
Common disorders also have environmental components
Culture, behavior, SES, diet
Qualitative Traits
Traits indicating a genetic disease is either present or absent: one has disease or not (cleft lip and palate)
Quantitative Traits
Measurable physiological or biochemical quantities such as height, bp, serum cholesterol concentration or blood glucose
Polygenic Inheritance (Simplified Example of Skin Color)
Skin pigmentation, 3 genes: A, B, C
Quantitative
Each gene with 2 alleles
Punnett Square
Also: height, weight, IQ, blood pressure
Environmental role?
Threshold model
One way to relate qualitative traits to quantitative traits
Assumes there is underlying distribution of liability (or risk) and when an individual’s liability exceeds the threshold, they develop the disease
If disease more frequent in one sex (males; male threshold lower than in females)
Therefore, the recurrence risk for another individual in a family to develop the disease is higher in families in which the patient is female, then among families in which the patient is male
Threshold Model (continued)
Liability distribution for a multifactorial disease in a population
To be affected with the disease, a person must exceed the threshold
Pyloric Stenosis (Empirical Risk Data)
Recurrence Risks subdivided by gender of affected probands and relatives
Proband- person we are evaluating
*Increased risk with female proband (brothers and sisters more likely to have higher recurrence risk)
This example involves that males have a lower threshold, so if it’s a female patient then it’s more likely family will get affected (since they have higher threshold)
Genetic Counseling Principles
Recurrence risk for multifactorial disorders increased by:
- Presence of more than one affected family members
- Severe form or an early onset of the disorder
- An affected person of the sex less likely to be affected
How to define genetic component?
Twin Studies
Familial aggregation
Twin Studies
Frequency of disease in multiple family members increases as the degree of relatedness increases
Compare monozygotic twins to first-degree relatives (including dizygotic twins)
Concordance: same for disorder
Disconcordance: different for disorder
MZ Twin Discordance
MZ twin discordance is strong evidence for non-genetic factors being involved
Environmental influences:
Exposure to infection
Diet
Effects of aging (perhaps somatic mutations)
Monozygotic Twins (Genetically Identical)
Does not mean they will be phenotypically the same
Ex. MZ twins with variable expression of Van der Woude Syndrome (VWS)
Bilateral lower lip pits, bilateral cleft lip
Vs.
Bilateral lower lip pits only
Type 1 Diabetes Insulin Dependent Diabetes Mellitus (IDDM)
Type 1: 10%; Type 2: 88%
MZ twin concordance= 40% (something genetic involved plus environment)
DZ twin concordance= 5%
IDDM incidence in white is 1/500 but lower in African and Asian.
Autoimmune destruction of B cells of the pancreas
MHC Association in Type 1 Diabetes
MHC locus is major genetic factor in IDDM: about 95% of all patients heterozygous for certain alleles at the MHC class II locus
Make autoantibodies to own cell
