MODULE 4- UNUSUAL GENETIC PHENOMENA

Question 1

Although in theory autosomal
dominant inheritance appears to
be the simplest mode of
inheritance, in clinical practice AD
inheritance can be confusing and
unclear

Answer 1

true

Question 2

We know a particular disorder is

autosomal dominant because?

Answer 2

• single gene
• on an autosome
• mutation in one allele is
sufficient to cause the
phenotype
But sometimes inconsistency in the
pedigree is observed

Question 3

Penetrance

Answer 3

measurement of the proportion of
individuals in a population who carry a
disease-causing allele and express the
disease phenotype

Question 4

It is useful to consider the
possibility of reduced
penetrance when considering

Answer 4

apparent inconsistencies in a
family history, such as “skipped
generations“

Question 5

If it is possible for some people
to carry a mutation but not
develop the disorder, the
condition is said to have

Answer 5

reduced or incomplete

penetrance

Question 6

“Complete” penetrance: means

Answer 6

a mutation, when present, is expressed in

all members of the population who have that mutation

Question 7

“Incomplete” or ‘reduced’ penetrance: means

Answer 7

s that a mutation, when present,

is expressed in only part of the population

Question 8

Pathogenic mutations are completely penetrant most of the time. However,
for certain traits, it is now described that a pathogenic mutation might only
lead to a phenotype in a subset of individuals from a population.

Answer 8

true

Question 9

Measuring Penetrance- Complete penetrance

Answer 9

• Complete penetrance = 1.0 (or 100%)
– All individuals with a given genotype have
the same phenotype

Question 10

Measuring Penetrance- Incomplete penetrance

Answer 10

– E.g. If 10 individuals have a certain
genotype, but only 8 of them express the
phenotype, the disease is said to have a
penetrance of 0.8 (or 80%)

Question 11

Example of penetrance: Dominant Retinoblastoma

Answer 11

• A cancer of the retina that primarily affects
children
• Retinoblastoma exhibits incomplete penetrance
• RB is 90% penetrant
• -90% of mutation carriers WILL develop the
disease
– 10% of gene carriers WILL NOT develop
the tumor
• but they may pass on the gene
(Mendelian laws apply)

Question 12

Example of penetrance: Familial Cancers

Answer 12

• Many people with a mutation in the BRCA1 or BRCA2
breast cancer genes will develop cancer during their
lifetime
– But some people will not
– Penetrance of BRCA1 mutations in females of European
descent: approx. 85% by age 70 years
• Clinicians cannot predict which people with these
mutations will develop cancer

Question 13

Possible mechanisms underlying the

the phenomenon of reduced penetrance

Answer 13

• Mutation type – severe vs mild mutations
• Environment – breast ca – age at first pregnancy, breast
feeding, BMI
• Age – you might still get the disease later in life
• Gender – breast ca if female
• Modifier genes – genes at other loci influence trait

Question 14

2. Variable Expressivity

Answer 14

1. Think of penetrance as a light switch that can only be on or off(an individual either has the disease or
   not)
2. and expressivity as a dimmer on
   that light switch (individuals who
   have the disease may have it with
   varying degrees of severity)

Question 15

Variable Expressivity definition

Answer 15

Variable expressivity refers to the range of
symptoms that can occur in different
people with the same genetic condition

Question 16

example of neurofibromatosis- variable expressivity

Answer 16

Café-au-lait spots; Neurofibromas (benign tumors which grow along nerves)
Family members who carry the same mutation may have varying degrees of
the phenotype!

Question 17

Example of variable expressivity:

Marfan Syndrome

Answer 17

• Connective tissue disorder
• Some people have only mild symptoms
– such as being tall and thin with long, slender
fingers
• Others also experience life-threatening
complications involving the heart /
blood vessels
• All have mutations in the same gene
→ FBN1

Question 18

For disorders that exhibit variable
expressivity: the same genotype can lead
to

Answer 18

a range of phenotypes

Question 19

This can make diagnosis difficult, which in
turn can complicate a pedigree/family
history (as mildly

Answer 19

affected individuals may

be missed)

Question 20

In addition to the genetic information
passed on from generation to generation
(egg and sperm), each of us is born with
a small number of novel genetic changes:
de novo (or ‘new’) mutations

Answer 20

– 44 to 82 de novo single-nucleotide mutations
when compared to the two parental genomes
– 1 - 2 usually affect the coding sequence

Question 21

3. new mutations

Answer 21

• These occurred either during the
formation of the gametes or postzygotically in the early embryo
• This is a natural occurrence, leading to
normal variation and allows for evolution

Question 22

No family history →

Answer 22

sporadic

Question 23

Laboratory testing reveals:

Answer 23

– De novo (new) mutation present
in the affected individual
– Neither parent carries the mutant allele

Question 24

example of new mutation- Achondroplasia –

often a new mutation

Answer 24

About 80% of cases are
due to a de novo (new)
dominant mutation

Question 25

Recurrence risk For parents who have a child with
a disorder resulting from a new
mutation event

Answer 25

• This was a
random/chance event
• Recurrence risk is
exceptionally low

Question 26

Recurrence risk For the individual who now has
an autosomal dominant disorder
resulting from a new mutation
event

Answer 26

Recurrence risk is as
per the Mendelian mode
of inheritance: so for AD
disorders, they have a
50% chance of having
an affected child, with
each pregnancy

Question 27

Apert Syndrome –

almost always a new mutation

Answer 27

okay

Question 28

One of these can usually explain inconsistencies seen

in an autosomal dominant pedigree:

Answer 28

– Incomplete Penetrance
– Variable Expressivity
– New Mutations