B2.026 Disorders with Complex Inheritance Flashcards
what is the definition of complex/multifactorial inheritance?
type of non-Mendelian inheritance shown by traits that are determined by a combination of multiple factors (genetic and environmental)
what kinds of genetic variants cause complex diseases?
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
can a single gene disorder produce a phenotype that is completely independent of other genetic, environmental, or developmental factors?
no
what kinds of diseases are minimally affected by other genes or the environment?
Mendelian
autosomal dominant, autosomal recessive, X-linked
clear inheritance pattern
how are diseases classified when they show loss of a clear inheritance pattern, but are still familial?
complex
how are diseases classified when they begin to show a loss of familial clustering?
sporadic
what type of inheritance is associated with cystic fibrosis?
autosomal recessive
how frequent are cystic fibrosis carriers in the population?
1/20
what is common amongst all forms of CF?
mutations in the CFTR gene
what is unique about CF?
displays a lot of clinical heterogeneity
what are possible explanations for clinical heterogeneity in CF?
allelic heterogeneity
effects of other modifying loci
nongenetic factors
what is the type of inheritance is associated with Huntington’s disease?
autosomal dominant
describe incomplete penetrance in the context of huntington’s disease
individuals with 36-41 CAG repeats may or may not express the disease clinically due to presence of different modifier genes/chaperone levels
describe the inheritance pattern of myotonic dystrophy
autosomal dominant inheritance with variable expressivity due to anticipation pleiotrophy and incomplete penetrance
what is pleiotrophy?
one gene affecting multiple phenotypes
what is anticipation?
slippage in transcription that increases # of repeats in a sequence
what is reverse anticipation?
slippage in transcription that shorted the repeat sections
where does cancer fall on the continuum of inherited diseases?
can be any type
mostly sporadic, followed by familial, with a few genetic
what is one big difference between disorders w complex inheritance vs mendelian disorders?
complex much more common in population
what are 3 things that complex diseases can exhibit?
familial clustering (inherit blocks of genes, more variants can be present within a fam)
higher recurrence risk among relatives
genetic concordance between monozygotic twins
what is the threshold model?
concept that individuals are more or less susceptible to disorders requiring a threshold for the expression of that trait
how does increased incidence of a complex disease in a family affect recurrence risk?
increases
what causes diseases with 100% concordance in monozygotic twins?
genetic factors
what can be said about diseases that are more concordant in MZ than DZ twins?
stronger genetic bs environmental component
what genes can be examined that could be implicated as a direct cause of early onset AD?
APP, PSEN1, PSEN2
which apoE isoform is “normal”?
e3
which apoeE isoform confers increase risk of AD?
e4
which apoE isoform has a protective affect against AD?
e2
why is apoE phenotype not useful for predicting AD in asymptomatic individuals?
these variants have poor PPV and NPV
they modify the effects of AD mutations, but do not act alone to cause disease
what is a modifier gene?
gene that alters the phenotype associated in mutations in a nonallelic gene
is there clinical value in an apoE test in asymptomatic individuals? why or why not?
no, no effective treatment and poor PPV and NPV
what percentage of AD patients have a monogenic highly penetrant form of AD that is autosomal dominant?
7-10%
what is the lifetime risk for AD in the general pop by age 85?
- 1% in men
20. 3% in women
what is the source of familial aggregation in the inheritance of AD?
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
what are the values of MZ and DZ concordance in AD?
50% MZ
18% DZ
