6. Multifactorial Genetic Disorders

Question 1

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)

Answer 1

Answer later

Question 2

Understand genetic counseling principles relating to the recurrence risk of multifactorial/complex diseases (objective)

Answer 2

Answer later

Question 3

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)

Answer 3

Answer later

Question 4

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)

Answer 4

Answer later

Question 5

Describe some forms of lip and palate clefting (objective)

Answer 5

Answer later

Question 6

Discuss aspects of lip and palate clefting including: prevalence data, genetic basis, and recurrence risk applying genetic counseling principles (objective)

Answer 6

Answer later

Question 7

Intro Remarks

Answer 7

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)

Question 8

Common Disorders

Answer 8

Seem to have genetic component (not Mendelian)

Examples: heart disease (myocardial infarction), cancer, mental illness (Alzheimer disease), diabetes, cleft lip and palate

Question 9

Families share genes: Proportion of Alleles

Answer 9

Monozygotic twin= 100%
First-degree relative (parents, siblings, offspring)= 50%
Second-degree relative= 25%
Third-degree relative (first cousins)= 13%

Question 10

Examples of Mendelian Subtypes of Complex Disorders

Answer 10

Heart Disease- majority non-Mendelian
CAD, cardiomyopathy, arrhythmias
Familial Hypercholesterolemia= AD
Long QT syndromes: AD

Question 11

Families Share Many Things

Answer 11

Common disorders also have environmental components

Culture, behavior, SES, diet

Question 12

Qualitative Traits

Answer 12

Traits indicating a genetic disease is either present or absent: one has disease or not (cleft lip and palate)

Question 13

Quantitative Traits

Answer 13

Measurable physiological or biochemical quantities such as height, bp, serum cholesterol concentration or blood glucose

Question 14

Polygenic Inheritance (Simplified Example of Skin Color)

Answer 14

Skin pigmentation, 3 genes: A, B, C
Quantitative
Each gene with 2 alleles

Punnett Square

Also: height, weight, IQ, blood pressure
Environmental role?

Question 15

Threshold model

Answer 15

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

Question 16

Threshold Model (continued)

Answer 16

Liability distribution for a multifactorial disease in a population

To be affected with the disease, a person must exceed the threshold

Question 17

Pyloric Stenosis (Empirical Risk Data)

Answer 17

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)

Question 18

Genetic Counseling Principles

Answer 18

Recurrence risk for multifactorial disorders increased by:

1. Presence of more than one affected family members
2. Severe form or an early onset of the disorder
3. An affected person of the sex less likely to be affected

Question 19

How to define genetic component?

Answer 19

Twin Studies

Familial aggregation

Question 20

Twin Studies

Answer 20

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

Question 21

MZ Twin Discordance

Answer 21

MZ twin discordance is strong evidence for non-genetic factors being involved

Environmental influences:
Exposure to infection
Diet
Effects of aging (perhaps somatic mutations)

Question 22

Monozygotic Twins (Genetically Identical)

Answer 22

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

Question 23

Type 1 Diabetes Insulin Dependent Diabetes Mellitus (IDDM)

Answer 23

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

Question 24

MHC Association in Type 1 Diabetes

Answer 24

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

Question 25

MHC Haplotype Not the Whole Story

Answer 25

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

Question 26

Common Congenital Malformations with Multifactorial Inheritance

Answer 26

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

Question 27

Neural Tube Defects

Answer 27

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)

Question 28

NTD: Outcomes and Incidence

Answer 28

Leading causes of stillbirth, death in early infancy and handicap in survivors

Incidence at birth variable:
1% in Ireland
0.2% in US

Question 29

NTD (Causes)

Answer 29

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

Question 30

Maternal Folic Acid Deficiency and NTD

Answer 30

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!

Question 31

NTDs (prevention)

Answer 31

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

Question 32

Cleft Lip with/without Cleft Palate (CL/P)

Answer 32

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

Question 33

CL/P Concordance Rates

Answer 33

MZ twins- 30%

DZ twins and siblings- 2%

Question 34

Syndromic vs. Non-syndromic (CL/P)

Answer 34

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)