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
MHC Haplotype Not the Whole Story
Even when siblings share same MHC class II haplotypes, the risk of disease is approximately 20% (well below MZ twin concordance rate of 40%)
Probably other genes involved
Maybe infectious exposures too
Common Congenital Malformations with Multifactorial Inheritance
Population incidence:
Cleft lip with or without cleft palate 1/1000
Cleft palate .5/1000
Neural tube defects (NTD) 2/1000
Neural tube defect more common, then cleft lip then cleft palate
Neural Tube Defects
Familial aggregation, increased recurrence risk in siblings of affected family members
Anencephaly: forebrain, overlying meninges, skull vault, skin are all absent (these infants are stillborn, and those born alive survive a few hours, 2/3 of affected infants female)
Spina bifida: failure of fusion of vertebrae arches (lumbar)
NTD: Outcomes and Incidence
Leading causes of stillbirth, death in early infancy and handicap in survivors
Incidence at birth variable:
1% in Ireland
0.2% in US
NTD (Causes)
Amniotic bands (fibrous connections between amnion and fetus caused by early rupture of the amnion, which may disrupt structures during embryological development)
Single gene defects
Some chromosome disorders
Some teratogens
Maternal Folic Acid Deficiency and NTD
NTD: seem to have genetic basic but also environmental
Studies showed mothers of affected children had:
Reduced blood folate levels
Elevated homocysteine levels
This is why folate added to food products!
NTDs (prevention)
Dietary supplementation of 0.8mg of folic acid per day for women who plan their pregnancies (reduce incidence of NTDs by more than 75%)
If family has one case of NTD, 4mg/day to prevent recurrence
All women of reproductive age, take 0.4
Cleft Lip with/without Cleft Palate (CL/P)
Incidence worldwide (1/1000) Ethnic variation: Japanese most then European-American, then African-Americans
Familial aggregation, increased recurrence risk in siblings of affected family members
Failure of fusion of the frontal process with the maxillary process around 35th day of gestation
60-80% of CL(P) are males
High rates in Native Americans of SW
CL/P Concordance Rates
MZ twins- 30%
DZ twins and siblings- 2%
Syndromic vs. Non-syndromic (CL/P)
CL/P heterogeneous
- Syndromic: clefting is one of many features
- Non-syndromic: isolated
Syndromic CL/P can involve:
- Mendelian single-gene disorder (VWS)
- Chromosome disorders (trisomy 13 and 4p deletion)
- Teratogenic exposure (virus or drug)
