Multifactorial Genetics

Question 1

What is the most common genetic condition and what is its incidence?

Answer 1

Multifactoral disorders affect 20-40% of people with genetic conditions.

Question 2

What are some examples of multifactorial disorders and their incidence in population?

Answer 2

• Oral clefts (1/500 - 1/1,500)
• Neural tube defects (1/100 - 1/1000)
• Congenital heart defects (1/100)
• Diabetes (1/100)
• Schozophrenia (1/100)
• Hydrocephalus

Question 3

What is the most common multifactorial condition found in newborns?

Answer 3

Congenital heart defects (1%)

Question 4

What are some difficulties in understanding multifactorial genetics?

Answer 4

• Inheritance of multifactorial conditions is more difficult to analyze
• Genetic patterns are not clear cut in individuals families
• Multifactorial conditions are difficult to replicate in animal studies due to environmental conditions
• Separating the effects of genetics and the envrionment to study the conditions is hard

Question 5

Quantitative traits

Answer 5

Traits that can be measured with a number (i.e. weight, height, enzymatic BP, IQ)
- Inheritance of quantitative traits is multifactorially determined: caused by additive effects of genetics and environmental conditions

Question 6

What are some of the characteristics of inheritance patterns of multifactorial conditions?

Answer 6

• Follow a bell shaped curve

- Additive effects of genetic and environmental factors

Question 7

Concordance

Answer 7

Means that both twins in a twin study are affected.

Question 8

Twin Studies

Answer 8

One approach to solve the influence of genetics vs. environment. The frequency of concordance of monozygotic twins is compared with that of dizygotic twins.

Question 9

In twin studies, what is the expected concordance rate in a pure genetic condition?

Answer 9

For monozygotic twins it is 100% and for dizygotic twins it is less than 100% and similar to the concordance rate among siblings

Question 10

In twin studies, what is the expected concordance rate in a pure environmental condition?

Answer 10

Concordance rates for monozygotic and dizygotic twins will be the same/very close

Question 11

In twin studies, what is the expected concordance rate in a multifactorial condition?

Answer 11

In multifactorial conditions, the concordance rate of monozygotic twins is higher than dizygotic twins but not 100%

Question 12

How is the effect of the environment on a genotype studied?

Answer 12

Monozygotic twins reared apart

Question 13

What are the difficulties with twin studies?

Answer 13

• Monozygotic twins are treated differently than dizygotic twins
• Somatic mutations can occur during development leaving monozygotic twins not completely identical
• Uterine environment for monozygotic twins may not be identical
• Number of monozygotic twins reared apart is small

Question 14

Relative risk ratio

Answer 14

Lambda r = (prevalance of the disease in a relative “r” of an affected person)/(population prevalance of the disease)
- Compares the frequency of a disease within a family to the disease’s frequency in the general population

Question 15

Heritability

Answer 15

Percentage of the population variation in a trait that is due to genes

Question 16

Heritability formula

Answer 16

H=2(cmz-cdz)
- cmz: concordance rate for monozygotic twins
- cdz: concordance rate for dizygotic twins
For a pure genetic condition, H is close to 1

Question 17

For different relationships, what is the proportion of alleles family members have in common?

Answer 17

• Monozygotic twins = 1
• First degree (mom & dad) = 1/2
• Second degree (aunts & uncles) = 1/4
• Third degree relatives (cousins) = 1/8

Question 18

What is the recurrence risk for multifactorial conditions for first degree relatives?

Answer 18

The square root of the prevalance of the condition on the general population

Question 19

Which population has a higher empiric risk for NTD?

Answer 19

Britian

Question 20

Anencephaly

Answer 20

Failure of the brain to develop normally. Fatal.

Question 21

Spina bifida

Answer 21

Failure of the spine to develop normally

Question 22

Encephalocele

Answer 22

Sac-like protusion from base of skull. Frequent mental retardation & neurological defects.

Question 23

Genetics of NTD

Answer 23

Mutations in MTHFR 5,10 (methylenetetrahydrofolate reductase) cause instability of the enzyme. This hinders the recycling of tetrahydrofolate and interferes with the methylation of homocysteine to methionine.

Question 24

Mekel-Gruber Syndrome

Answer 24

Autosomal recessive condition that can cause polydactyly, encephalocele, polycystic kidneys, and seizures.

Question 25

Multifactorial genetics of diabetes

Answer 25

Mutation in PTPN1 (protein tyrosine phosphatase N1) (found in 35% of population) on chromosome 20. The gene product represses the insulin response. Excessive amounts of the protein would decrease inability to responde to insulin and thus people tend to develop diabetes.

Question 26

Chron's disease

Answer 26

Multifactoral inheritance. 20% of cases are causes by mutation on IBD1 (Nod2, Card15) located on chromosome 15. THe gene is responsible for non-specific immune response. Carriers of 1 mutation have 2-3% chance of developing mild Chrons. Carriers of 2 mutations have 20-40% risk of developing severe Chrons.

Question 27

MTHFR

Answer 27

Gene involved in development of NTD. Mutations in NTHFR 5,10 (methylenetetrahydrofolate reductase) cause instability of the enzyme. This hinders the recycling of tetrahydrofolate and interferes with the methylation of homocysteine to methionine.

Question 28

PTPN1

Answer 28

Gene involved in increased risk of diabetes. Mutation in PTPN1 (protein tyrosine phosphatase N1) (found in 35% of population) on chromosome 20. The gene product represses the insulin response. Excessive amounts of the protein would decrease inability to responde to insulin and thus people tend to develop diabetes.

Question 29

IBD1

Answer 29

Gene involved in Chron's Disease. 20% of Chron's cases are causes by mutation on IBD1 (Nod2, Card15) located on chromosome 15. THe gene is responsible for non-specific immune response. Carriers of 1 mutation have 2-3% chance of developing mild Chrons. Carriers of 2 mutations have 20-40% risk of developing severe Chrons.

Question 30

Which ethnicity has the highest incidence of CL/P? The lowest?

Answer 30

Highest is Asian populations. Lowest is African Americans.

Question 31

What teratogens can cause CL/P?

Answer 31

Dilantin, alcohol, valproic acid, anticonvulsants.

Question 32

TGFA, TGFB3, IRF6, MSX1

Answer 32

Genes involved in the etiology of non-syndromic oral clefts. The more at risk genes present in the family, the more severe the clefting is.

Question 33

What gense contribute to nonsyndromic oral clefts?

Answer 33

TGFA, TGFB3, IRF6, MSX1

Question 34

Van der Woude Syndrome

Answer 34

LOWER LIP PITS, hypodontia, cleft lip w/ or w/o palate - Autosomal dominant inheritance. - Linkage to chromosomes 1 & 17

Question 35

What inheritance pattern does Van der Woude Syndrome follow?

Answer 35

Autosomal dominant