Download Single gene disorders

Autosomal Dominant Disorders
More than half of Mendelian phenotypes
are autosomal dominant
 Examples:
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Familial hypercholesterolemia
Myotonic dystrophy
Huntington disease
Neurofibromatosis
Polycystic kidney disease
Achondroplasia
In typical AD inheritance, every affected
person in a pedigree has an affected
parent
 This is also true for X-linked dominant
traits
 Male-to-male transmission can readily
distinguish AD phenotypes

Autosomal Dominant Disorders
Familial
hypercholesterolemia
Familial hypercholesterolemia
Punnett Square
“a” = normal allele
“A” = mutant allele
Maternal
P
A 1/2
What is the
probability that this
pregnancy will be
affected?
a Aa
Paternal
1/2
a Aa
1/2
a 1/2
aa
1/4
1/4
+
aa +
1/4
1/4
affected unaffected
1/2
1/2
New Mutation in AD Disorders
New alleles arise by mutation and are
maintained or removed by selection
 Survival of new mutation in the population
depends on the fitness of persons carrying
it as compared to persons with other
alleles at the locus concerned
 Many autosomal dominant disorders are
associated with reduced fitness

• Fitness-probability of transmitting one’s genes to
the next generation
• 0 if having the disorder eliminates the ability to
reproduce--ex. Death by age of reproduction
• 1 if the same ability to reproduce as gen. pop.
If the fitness is 0, all affected individuals must be due
to new mutations
If the fitness is 1, i.e., the onset of the disorder is
after reproduction and therefore does not affect it, a
patient is more likely to have inherited the disorder
FITNESS - the relative reproductive
success of a particular phenotype,
between 0 and 100%. It may be
reduced by decreased survival to the
age of reproduction or diminished
fertility.
Hutchinson-Gilford Progeria
• Autosomal Dominant, Zero Fitness
• Always the Result of a New Mutation
Autosomal Dominant disorders frequently have
differences in expression of mutant genes
1. Penetrance: probability of any phenotype
all or none concept
2. Expressivity: severity of the phenotype
in individuals with the same
genotype
3. Pleiotropy: a genetic defect results in diverse
phenotypic effects
Example: Neurofibromatosis
Neurofibromatosis (NF1)-common disorder of the nervous system
1. Multiple benign fleshy tumors (neurofibromas) in the skin
Neurofibromatosis (NF1)-common disorder of the nervous system
2. Multiple flat, irregular pigmented skin lesions known as
café au lait spots
Neurofibromatosis (NF1)-common disorder of the nervous system
3. Small benign tumors (hamartomas) on the iris of the eye
Neurofibromatosis (NF1)-common disorder of the nervous system
4. Less frequently, mental retardation, CNS tumors,
diffuse plexiform neurofibormas and the development
of cancer of the NS or muscle
Adult heterozygotes almost always demonstrate some sign
of the disease  Penetrance is 100% but age-dependent
Phenotype ranges from café au lait spots to tumors of the
spinal cord  Variable expressivity
Pleiotropic  affects skin, iris, brain, muscle
Pedigree of a family with NF-1, apparently originating as
a new mutation in the proband
Reduced Penetrance
Example: Split-hand deformity (lobster-claw
malformation) a type of ectrodactyly
This female is
non-penetrant
Sex-dependent Penetrance
Example: BRCA2 Familial Breast Cancer
Although men can get
breast cancer,
penetrance is much
lower than in woman
who inherit BRCA2
mutations
Age of Onset
(age-dependent penetrance)
Example: Huntington Disease
% affected
100
25
0
30
80
age in years
?
What is the probability that she has inherited a
huntingtin mutation
given that she's unaffected at 30?
Possible Causes of incomplete
penetrance
 Genotypes
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do not act in isolation
Interaction with the wild-type allele
Interaction with other loci
Interaction with the environment
Not known!
Homozygotes for AD Traits

Matings that could produce homozygous
offspring are rare (A/a x A/a, A/A x A/a or A/A x
A/A)
 Disorders are usually more severe in
homozygotes
 Example 1:
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Achondroplasia: a skeletal disorder of short-limb
dwarfism and large head size
Marriage b/w achondroplastic (heterozygotes) is
common
Homozygous achondroplastic patients are much more
severely affected & commonly do not survive early
infancy
Achondroplasia
 Short
limbs, a normal-sized head and
body, normal intelligence
Caused by mutation in the FGFR3 gene
 Fibroblast

growth factor receptor 3
Inhibits bone growth by inhibiting chondrocyte
proliferation and differentiation
 Mutation
causes the receptor to signal
even in absence of ligand
Normal FGFR3 signaling
FGF ligand
extracellular
intracellular
FGFR3
Normal FGFR3 signaling
extracellular
intracellular
Inhibition of bone growth
Achondroplasia
Gly380Arg mutation in
transmembrane domain
extracellular
intracellular
*
• Receptor signals in absence of ligand
• Bone growth attenuated
Example 2:
 familial hypercholesterolemia, an AD
disorder leading to premature coronary
heart disease
 Homozygotes have a very severe disease
with much shorter life expectancy as
compared to heterozygotes
Cutaneous xanthomas
in a familial
hypercholesterolemia
homozygote.
Huntington Disease

HD is a neurodegenerative disease
characterized by progressive dementia and
abnormal movements
 HD is an exception in that severity of the
disorder (clinical expression) is the same in
heterozygotes and homozygotes (onset age?)
 HD homozygotes can be distinguished from
heterozygotes by molecular analysis of mutant
gene
Sex-Limited Phenotype in Autosomal Disease

Defect is autosomally transmitted but expressed
in only one sex
Example:
 male-limited precocious puberty (familial
testotoxicosis), an AD disorder, affected boys
develop 2º sexual characteristics and adolescent
growth spurt at ~ 4 yrs
 In some families, mutation is in leutinizing
hormone receptor gene (mutant receptor signals
without hormone).
 The defect is non-penetrant in heterozygous
females (another example of sex-dependent
penetrance)
Pedigree pattern of male-limited precocious puberty. This AD
disorder can be transmitted by affected males or by unaffected
carrier females. Male-to-male transmission shows that inheritance is
not X-linked. Because the trait is transmitted through unaffected
carrier females, it can not be Y-linked.
Characteristics of Autosomal Dominant
Disorders
• phenotype appears in every generation
• each affected person has an affected parent (exceptions!)
• each child of an affected parent has 50% risk to inherit
trait.
• unaffected family members do not transmit phenotype to
children (exceptions again).
• males and females equally likely to transmit the trait, to
children of either sex. In particular, male-to-male
transmission does occur (in contrast to sex-linked
dominant inheritance).
• new mutations relatively common