Autosomal Dominant Disorders

Classification of Genetic Disorders

 Multifactorial
 Single gene (Autosomal/X-linked; dominant/recessive)
 Chromosomal (Number/structure/Mosaicism)
 Mitochondrial
 Somatic mutations (cancer)

Single Gene Disorder: Mutations in single genes (often causing loss

of function)

Multifactorial Diseases: Variants in genes causing alteration of

function (also called common complex disorder)

Chromosome Disorders: Chromosomal imbalance causes alteration

in gene dosage

Mitochondrial Disorders: Generally affect organ system with high

energy requirement
Genes controlling function and structure of the mitochondria are
found both in mitochondrial and nuclear DNA

Somatic Mutations: Causes cancer. Inactivation of both alleles (two

“hits”) of a gene involved in growth requires

Single Gene Disorders

Dominant
 Heterozygotes with one copy of the altered gene have the
conditions

Recessive
 Homozygotes with two copies of the altered gene have the
condition

X-linked recessive
 Males with one copy of the altered gene on the X-chromosome
have the conditions

Serious single gene disorders (autosomal/X-linked;

dominant/recessive) – Why are they important?
  20 account for 70-80% incidence (although several thousand
known)
 confer upon 2-3% population a chance of greater than 1 in 10
of being affected or being a carrier
 Majority are individually relatively rare bu collectively
contribute substantially to morbidity and mortality

How is the diagnosis of a genetic condition made?

 Pedigree analysis to detect a pattern of inheritance
 Precise clinical diagnosis (history and examination)
 Genetic testing (karyotype, nucleic acid analyssi(

Autosomal Dominant Conditions

 Dominant: Describe a trait expressed in a heterozygote
 Distinctive pattern of segregation within families

Of clinical importance:
 Variation in expression
 Penetrance
 New mutations
 Anticipation
 Mosaicism

Most Frequent Autosomal Dominant Disorders:

 Dominant Otosclerosis (Deafness)
 Familial hypercholesterolaemia (heart attack, increased
cholesterol)
 Von WIllebrand disease (prolonged bleeding)
 Adult polycystic kidney disease (renal failure)
 Huntington’s Disease
 Neurofibromatosis (non-malignant tumours on nerves)
 Myotonic Dystrophy (Muscle weakness)
 Familial adenomatous polyposis (Colon cancer)
 Dominant blindness

Everyone who inherits an autosomal dominant altered gene shows

clinical signs (the condition is fully penetrant)
How does a dominant gene cause its effects?

How is knowing the DNA sequence of a gene helpful in clinical

practice?
 It can be used to undertake direct mutation analysis (usually
by DNA sequencing)
 Or for tracking the inheritance of that gene through a family
Understanding how each particular mutation causes the features of
the disease (genotype-phenotype analysis) could be helpful in
clinical management

Diagnosis using DNA

The aim is to determine a sequence/copy number variant

Is this a normal variant or pathogenic?

 Synonymous/silent SNP
 Missense mutation?
 Nonsense mutation?
 Frameshift mutation?

Can also:
 Demonstrated mutation in more than one affected person (in
familial dominant disorders)
 Shows not present in unaffected family members

Before assuming that a sequence change is the cause of a genetic

condition (and not just a polymorphism) one needs to determine the
likely effect on gene expression or function

Using currently available technology, it may not be possible to

detect all pathogenic changes affecting expression or structure of a
gene

It may still be possible to undertake DNA diagnosis by undertaking.

 Gene tracking: using linked DNA markers – must have DNA
from affected person

Following inheritance of regions of DNA (and disease genes) through

a family by using microsatellite markers (CA repeats)
There are exceptions to Mendel’s rules in autosomal dominant
inheritance which are very important clinically

 Variation in expression
 Reduced/incomplete penetrance
 New mutation
 Anticipation
 Mosaicism (somatic or gonadal) for an allele for a dominant
trait

e.x. Neurofibromatosis Type 1

Variation in Expression
Family members have different symptoms and signs of same
disorders
Severity of the symptoms and signs can vary from person to person
Very important clinically in autosomal dominant disorders
? Caused by other genes modifying the phenotypes

Neurofibromatosis type 1 9NF1) is an example of a dominant

conditions which is said to show complete penetrance
Everyone with a pathogenic geen alteration (mutation) always
shows at least one clinical sign of the condition

However, NF1 shows variation in expression:

Everyone with a pathogenic gene alteration (mutation) shows some
signs or symptoms, but the number and severity can vary from
person to person both within and between families

 Other autosomal dominant conditions demonstrate

reduced/incomplete penetrance
  When referring to a person who has the disease-causing
genotype but who shows no clinical signs of the conditions,
we say the condition is “non-penetrant” in that person
 He/she may develop signs later in life – then the condition is
said to be “penetrant” in that person
 For instance, if someone has inherited the altered allele for
Huntington’s disease – what is the probability that person will
develop signs of the condition?

Reduced/incomplete penetrance
Huntington disease: an example of age-dependent penetrance

Age dependent penetrance of breast cancer in women who have

mutation in one allele of BRCA1 compared with general population

Age-dependent Penetrance
 A delay in the onset of a genetic disease
o Huntington’s disease
 50% of people with one cop of the altered allele
have developed signs by age 50, 95% by age 70
 o Breast cancer
 80% of women who have inherited a BRCA1 allele
with a mutation have developed breast cancer by
age 70
 As well as age-dependent penetrance, these two medical
conditions show incomplete penetrance – not 100% of the
people with the disease genotype will shows signs of the
condition

Clinical implications of incomplete penetrance and variation in

expression
 Each one of these genetic phenomena
o Incomplete penetrance
o Age-dependent penetrance
o Variation in expression
Can make a person appear not to have an autosomal dominant
conditions when in fact they have the genotype, with potential
implications for the person and other family members

New Mutations for Dominant Disorders

New mutations cause the condition in 80% patients with

achondroplasia (dwarfism) (inherited from a parent in the other
20%) => shows complete penetrance

New mutations increase with paternal age

Higher mutation rates in males are likely to be related to the greater

number of germ cell divisions (the DNA in a particular sperm is the
result of hundred rounds of replication)
Anticipation: Another cause of variation within families
The disease features of myotonic dystrophy are occurring at an
earlier age (cataracts) or increasing severity (muscle weakness)
from generation to generation iin this family

What is anticipation and what is the mechanism that causes it?

 A phenomenon in which the age of onset of a disorder is
reduced and/or the severity of the phenotype is increased in
successive generations
 Molecular basis is an unstable, expanding trinucleotide repeat
mutation
 Severity/age of onset correlate with repeat length which tends
to increase as the gene is transmitted down the generations

Two examples of intragenic triplet repeats causes diseases

inherited in a dominant manner
 Numbers of repeats above the upper normal limit cause the
disease

Huntington Disease – A disease caused by intragenic triplet repeats

CAG CAG CAG CAG CAG CAG CAG CAG CAG … CAG

11 – 34 CAG triplet repeats are normal in the gene for HD

As CAG codes for glutamine, they cause a run of 11-34 glutamine
amino acid residues to be placed in the protein
A run of more than 34 glutamine residues causes the protein to
aggregate in the brain cell and cause progressive cell death

Symptoms will occur when the number of cells remaining reaches a

critical number, and will progress as more cells die – this is likely to
be the basis for the age-dependent penetrance seen in HD

In addition, runs of >34 CAG repeats in the HD gene are unstable in

meiosis and can expand further during replication (particularly
during male meiosis). This also results in anticipation 0 there can be
an earlier age of onset in the children of men who have HD

Gonadal Mosaicism for an Autosomal Dominant Disorder

E.x. Osteogenesis Imperfecta (OI)

Two children affected in one generation with normal parents can
suggest autosomal recessive inheritance. However, in this family
the father had gonadal mosicism for a new mutation causing the
autosomal dominant conditions
Probability that a child of the following will inherit an autosomal
dominant condition

A person with an autosomal 50%; 1 in 2

dominant condition – inherited
or as the result of a new
mutation in gamete
A person with somatic Virtually nil
mosaicism for a dominant
conditions (but not in gonads)
A person with gonadal Up to 50%
mosaicism for a dominant
condition
Unaffected parents with a child Recurrence generally very low
with an autosomal dominant (but not zero because of the
conditions (the couple’s own possibility of parental gonadal
parents are also unaffected) mosaicism)

Other possible explanations:

 New mutation in gamete
 Mistaken paternity

Summary: single gene disorders inherited in an autosomal dominant

manner
 High probability of relatives inheriting condition
 Vertical transmission pedigree pattern:
o Affected people in each generation
o Males and females affected (in equal numbers)
o All forms of transmission seen (including male to male
transmission)
 Some isolated cases due to new mutations
 Structural proteins, receptors, transcription factors