B2.026 Disorders with Complex Inheritance

Question 1

what is the definition of complex/multifactorial inheritance?

Answer 1

type of non-Mendelian inheritance shown by traits that are determined by a combination of multiple factors (genetic and environmental)

Question 2

what kinds of genetic variants cause complex diseases?

Answer 2

common variants
there are usually variants in multiple genes; no one of which could cause a disease alone but the combination of multiple mutations and environmental factors = complex disorder

Question 3

can a single gene disorder produce a phenotype that is completely independent of other genetic, environmental, or developmental factors?

Answer 3

no

Question 4

what kinds of diseases are minimally affected by other genes or the environment?

Answer 4

Mendelian
autosomal dominant, autosomal recessive, X-linked
clear inheritance pattern

Question 5

how are diseases classified when they show loss of a clear inheritance pattern, but are still familial?

Answer 5

complex

Question 6

how are diseases classified when they begin to show a loss of familial clustering?

Answer 6

sporadic

Question 7

what type of inheritance is associated with cystic fibrosis?

Answer 7

autosomal recessive

Question 8

how frequent are cystic fibrosis carriers in the population?

Answer 8

1/20

Question 9

what is common amongst all forms of CF?

Answer 9

mutations in the CFTR gene

Question 10

what is unique about CF?

Answer 10

displays a lot of clinical heterogeneity

Question 11

what are possible explanations for clinical heterogeneity in CF?

Answer 11

allelic heterogeneity
effects of other modifying loci
nongenetic factors

Question 12

what is the type of inheritance is associated with Huntington’s disease?

Answer 12

autosomal dominant

Question 13

describe incomplete penetrance in the context of huntington’s disease

Answer 13

individuals with 36-41 CAG repeats may or may not express the disease clinically due to presence of different modifier genes/chaperone levels

Question 14

describe the inheritance pattern of myotonic dystrophy

Answer 14

autosomal dominant inheritance with variable expressivity due to anticipation pleiotrophy and incomplete penetrance

Question 15

what is pleiotrophy?

Answer 15

one gene affecting multiple phenotypes

Question 16

what is anticipation?

Answer 16

slippage in transcription that increases # of repeats in a sequence

Question 17

what is reverse anticipation?

Answer 17

slippage in transcription that shorted the repeat sections

Question 18

where does cancer fall on the continuum of inherited diseases?

Answer 18

can be any type

mostly sporadic, followed by familial, with a few genetic

Question 19

what is one big difference between disorders w complex inheritance vs mendelian disorders?

Answer 19

complex much more common in population

Question 20

what are 3 things that complex diseases can exhibit?

Answer 20

familial clustering (inherit blocks of genes, more variants can be present within a fam)
higher recurrence risk among relatives
genetic concordance between monozygotic twins

Question 21

what is the threshold model?

Answer 21

concept that individuals are more or less susceptible to disorders requiring a threshold for the expression of that trait

Question 22

how does increased incidence of a complex disease in a family affect recurrence risk?

Answer 22

increases

Question 23

what causes diseases with 100% concordance in monozygotic twins?

Answer 23

genetic factors

Question 24

what can be said about diseases that are more concordant in MZ than DZ twins?

Answer 24

stronger genetic bs environmental component

Question 25

what genes can be examined that could be implicated as a direct cause of early onset AD?

Answer 25

APP, PSEN1, PSEN2

Question 26

which apoE isoform is “normal”?

Answer 26

e3

Question 27

which apoeE isoform confers increase risk of AD?

Answer 27

e4

Question 28

which apoE isoform has a protective affect against AD?

Answer 28

e2

Question 29

why is apoE phenotype not useful for predicting AD in asymptomatic individuals?

Answer 29

these variants have poor PPV and NPV

they modify the effects of AD mutations, but do not act alone to cause disease

Question 30

what is a modifier gene?

Answer 30

gene that alters the phenotype associated in mutations in a nonallelic gene

Question 31

is there clinical value in an apoE test in asymptomatic individuals? why or why not?

Answer 31

no, no effective treatment and poor PPV and NPV

Question 32

what percentage of AD patients have a monogenic highly penetrant form of AD that is autosomal dominant?

Answer 32

7-10%

Question 33

what is the lifetime risk for AD in the general pop by age 85?

Answer 33

12. 1% in men

20. 3% in women

Question 34

what is the source of familial aggregation in the inheritance of AD?

Answer 34

NOT usually Mendelian
complex genetic contribution involving one or more incompletely penetrant genes that act independently, from multiple interacting genes, or from some combo of genetic and environmental factors

Question 35

what are the values of MZ and DZ concordance in AD?

Answer 35

50% MZ

18% DZ