WK3 - Multifactorial Inheritance

Question 1

What is multifactorial inheritance responsible for?

Answer 1

• most normal phenotypic differences among individuals ex. height
• many congenital anomalies
• common complex diseases of adulthood

Question 2

Define multifactorial.

Answer 2

• traits resulting from the interplay of multiple environmental factors with multiple genes
• implies both a familial nature and an environmental dependence

Question 3

Define polygenic.

Answer 3

• traits or diseases caused by the impact of many different genes, each having only a limited impact on phenotype
• multifactorial is a better term because it includes environmental factors

Question 4

What constitutes multifactorial inheritance?

Answer 4

• diseases familial, but follows no Mendelian pattern
• the genetic predisposition is usually inherited from BOTH parents
  ex. height of children follows mid parental height
• the genes and environmental factors affecting a given multifactorial trait vary among different individuals, but are some common factors within each family

Question 5

What are quantitative traits?

Answer 5

• those that can be measured (eg. height, weight, blood pressure, cholesterol levels)
• exhibit continuous variability
• in a quantitative trait, choose a cut-off to define a disease state (eg. a diastolic BP of >100)
• essential hypertension is the extreme manifestation of a multifactorial continuous trait

Question 6

Why are there normal variation?

Answer 6

• most due to multifactorial traits
• a child’s value tends to resemble the average of the parent’s value (eg. mid-parental height)
• may be altered by single gene or environmental interaction (eg. achondroplasia or starvation)

Question 7

What are qualitative traits?

Answer 7

• all-or-nothing phenotypes (eg. spina bifid a)
• also called discrete traits
• qualitatively different from the normal state
  ie. the condition/disease does or does not occur

Question 8

What is the liability/threshold model? What does liability mean in this model?

Answer 8

• models based on the assumption that the disorder represents the “visible” tail end or extreme of a characteristic believed to show a normal distribution
• abnormal morphogenesis beyond a threshold
  Liability: all of the factors (genetic and environmental which influence presence or absence of a genetic disorder or disease)
  eg. all factors leading to timing of lip closure

Question 9

What are some clinical characteristics with recurrence risk?

Answer 9

• recurrence risk falls rapidly with more distant relationship
  ex. prim - 2-4%; 2nd - 1/100; tert - 2/200
• may occur more frequently in one sex than the other
  ex. lupus affects female more
• higher risk if affected relative is of the LESS frequently affected sex
• higher risk with a more severe lesion
• recurrence risk is higher if more than one close relative is affected
  ex. 1 affected sib = 2-4%; 2 affected sib = 10%; sib and affected parent = 10%
• more common among children of consanguinous unions
• recurrence risk lower in population with lower incidence
  eg. neural tube defects
• recurrence risk do not pertain to the situation where the condition is not multifactorial

Question 10

What is calculated recurrence risk?

Answer 10

• where the population incidence is known and then calculated
  = square root of population incidence

Question 11

What is empiric recurrence risk?

Answer 11

• the observed recurrence risk

Question 12

How would you calculate recurrence risk in first degree (sibs and children) if the disease frequency is known?

Answer 12

approximately equal to square root of the disease frequency

Ex. for anomalies with population incidence of 1/1000, recurrence risk to first degree relatives about 3%; for 1/100 about 10%