4. Mendelian Inheritance II (Exceptions and Complications) Flashcards
1
Q
Many genetic conditions have population-specific distributions.
Why is it important to study the diversity of genetic diseases in different population groups?
A
2
Q
WHY ARE SOME CONDITIONS MORE PREVALENT IN
CERTAIN POPULATION GROUPS?
A
3
Q
How does the founder effect produce more genetic conditions?
A
4
Q
EXAMPLE OF A FOUNDER POPULATION IN SA:
A
5
Q
How does heterozygotic advantage contribute to some conditions being more prevalent in certain population groups?
A
6
Q
- Expected that the allele frequency will ______ overtime if it only has a negative result.
- However, areas with _____ outbreaks carriers have a distinct advantage.
A
decrease
malaria
7
Q
How does Consanguinity contribute to some conditions being more prevalent in certain population groups?
A
8
Q
- Most genetic disorders are caused by ______ mutations,
- Recessive disease mutations are much more common than dominant diseases mutations
- “Dominant” mutations are more easily eliminated by _____ ______.
Humans carry an average of ____ to two disease causing mutations
A
recessive
natural selection
one
9
Q
AFRICAN POPULATION: ALBINISM -
A
10
Q
Trinucleotide repeat disorders
* Neither ______ dystrophy nor Friedreich’s ataxia has ever been reported in an black patient in South Africa
* Absence of a predisposing chromosomal background (haplotype)
* ________ disease shows some unique features in black individuals.
- Previously thought to be rare in this ethnic group.
- HD in people of African ancestry has been shown to be genetically heterogeneous.
- HD due to mutations in the _____ gene occurs, but on African-specific haplotypes that differ from
those in white patients.
- In addition, a second HD gene (____) has been implicated in African patients with an HD-like
phenotype (HDL2)
- Individuals with HDL2 share many clinical features with individuals with HD - clinically
indistinguishable
A
myotonic
Huntington
HTT
(JPH3)
11
Q
CAUCASIANS: CYSTIC FIBROSIS -
A
12
Q
Caused by variants in the cystic fibrosis transmembrane
conductance regulator (______) gene
A
13
Q
What is the function of the CFTR gene?
A
14
Q
In South Africa, approximately
* 1 in ___ individuals in the Caucasian population,
* 1 in ____ in the population of mixed ancestry
* and up to 1 in 90 black Africans carry a CF mutation.
* It is estimated that 1 in 2 000 Caucasian babies, 1 in 12 000 babies of mixed ancestry and up to 1 in 32 000 black African are born with CF in South Africa.
A
27
55
15
Q
ASHKENAZI JEWISH POPULATION:
* Several autosomal recessive genetic disorders that are more common in Jewish populations
* Due to population bottlenecks as well as practice of _________ marriages
* Lead to a decrease in _______ diversity
* Higher likelihood that two parents carrying the same mutation will have a child who will then have both mutations
A
consanguineous
genetic
16
Q
COMMON CONDITIONS IN THE ASHKENAZI JEWISH POPULATION:
A
17
Q
ASHKENAZI JEWISH: TAY-SACHS DISEASE
A
18
Q
AFRIKANERS
Several diseases with an unusually high frequency in Afrikaners have been suggested to be the result of founder effects:
A
19
Q
AFRIKANER: SCLEROSTEOSIS
A
20
Q
INDIAN: THALASSAEMIA
A
21
Q
How did INDIAN: THALASSAEMIA originate?
A
22
Q
MANAGEMENT AND GENETIC TESTING: (4)
A
23
Q
Although in theory _____
dominant inheritance appears to
be the simplest mode of
inheritance, in clinical practice AD
inheritance can be confusing and
unclear
We know a particular disorder is
autosomal dominant
* single gene
* on an autosome
* _______ in one allele is sufficient to cause the
phenotype
But sometimes _______ in the
pedigree is observed
A
autosomal
mutation
Inconsistency
24
Q
- It is useful to consider the
possibility of _______
penetrance when considering
apparent inconsistencies in a
family history, such as “skipped
generations“ - If it is possible for some people
to carry a mutation but not
develop the disorder, the
condition is said to have
reduced or _______
penetrance
A
reduced
incomplete
25
Penetrance
* Definition:
– measurement of the proportion of
individuals in a population who carry a
disease-causing allele and express the
disease phenotype
26
What is complete penetrance?
27
What is incomplete penetrance?
28
Are pathogenic mutations always completely penetrant?
29
How do we measure penetrance?
30
Example: Dominant Retinoblastoma
* A cancer of the retina that primarily affects
children
* Retinoblastoma exhibits ______ penetrance
* RB is 90% ______
* -90% of mutation carriers WILL develop the
disease
– 10% of gene ______ WILL NOT develop
the tumour
* but they may pass on the gene
(Mendelian laws apply)
incomplete
penetrant
carriers
31
Example: Familial Cancers
* Many people with a mutation in the _____ or _____
breast cancer genes will develop cancer during their
lifetime
– But some people will not
– Penetrance of BRCA1 mutations in females of _______ descent: approx. 85% by age 70 years
* Clinicians cannot predict which people with these
mutations will develop cancer
BRCA1
BRCA2
European
32
What are the genetics of hereditary breast and ovarian cancer syndrome?
33
Possible mechanisms underlying the phenomenon of reduced penetrance: (5)
34
* Penetrance is different to
expressivity
* Think of penetrance as a light
switch that can only be on or off
(an individual either has the
disease or not)
* and expressivity as...
as a dimmer on
that light switch (individuals who
have the disease may have it with
varying degrees of severity)
35
What does variable expressivity refer to?
36
How is Neurofibromatosis an example of variable expressivity?
37
Example of variable expressivity:
Marfan Syndrome
* ________ 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
→ ______
Connective
FBN1
38
* For disorders which exhibit variable
expressivity: the same genotype can lead
to a ______ of phenotypes
* This can make diagnosis difficult, which in
turn, can complicate a pedigree/family
history (as ______ affected individuals may be missed)
range
mildy
39
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:
__ _______ (or ‘new’) mutations
– 44 to 82 de novo single-nucleotide mutations
when compared to the two parental genomes
– 1 - 2 usually affect the coding sequence
* These occurred either during the formation of the gametes or post-zygotically in the early embryo
* This is a natural occurrence, leading to
____ ______ and allows for evolution
de novo
normal variation
40
Scenario:
A couple presents at Genetic Counselling Clinic. They have just had a child affected with achondroplasia (autosomal dominant inheritance). Both parents are normal and there is no family history.
41
Achondroplasia: About ____% of cases are due to a de novo (new) dominant mutation
80
42
For parents who have a child with a disorder resulting from a new mutation event.
What is the recurrent risk? (2)
* This was a random/chance event
* Recurrence risk is exceptionally low
43
For the individual who now has an autosomal dominant disorder resulting from a new mutation event.
What is the recurrent risk?
* 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
44
Apert Syndrome –
almost always a ____ mutation
new
45
What are the classic laws of Mendelian inheritance? (3)
* Biparental inheritance - one allele from each parent
* The phenotype is controlled by the action of one, and only one, gene (sequence variation at only one locus is necessary and sufficient to bring about phenotype change)
* Stable inheritance of mutations i.e. parent and child have the identical DNA change
46
An interesting group of disorders was described
* A small group, particularly neuromuscular/neurodegenerative disorders
* Single gene disorders, followed rules of Mendelian inheritance
* Examples:
47
Repeat sequences are a part of normal
variation – we all have them
* As discussed in Module 1: repeats occur throughout the genome; repeat units come in different sizes; repeat length is polymorphic; most repeats do not occur in functional regions
of the genome and they have no phenotypic effect
* An example of a repeat sequence:
ATGCCTTATGTATGATTCGCAGCAGCAGCAGCAGTTACTTTTTAGACGACTATAAT
48
TRDs: Molecular basis
* Number of repeats ______
– between individuals
– on different chromosomes
* Part of normal variation
varies
49
What happens in Stable Mendelian inheritance?
Stable Mendelian inheritance in families (a child
will inherit one allele from each parent).
50
* 1990’s: It was discovered that in all these disorders, the gene involved had an associated repeat sequence. The repeat was usually always a 3 nucleotide / _______ repeat (hence – ‘triplet repeat disorders’).
* In all affected individuals, the number of repeat units was above a certain _______ (expansion of the repeat resulted in disease).
* This instability in genetic transmission was outside the central ______ of molecular biology and presented a new type of mutation mechanism!
triplet
threshold
dogma
51
True or false
Repeats are dynamic.
True
52
Triplet repeat disorders both obey and deviate from Mendel’s rules
* However, because certain patterns of inheritance cannot be explained only on the basis of Mendel's laws
– Fall into a category referred to as _____-______ inheritance
* Do NOT disobey Mendelian ________ but cannot be
explained by these principles alone
non-Mendelian
principles
53
Triplet Repeat Disorders (TRDs)
* Characterised within and between families by: (2)
* Variable disease presentation and progression
* Anticipation which is defined as
‒ Earlier age of onset
‒ Increased severity in successive generations
54
What is the threshold concept? (2)
* Repeat number above a threshold results in disease
* Different for different disorders
55
TRDs:
* The mutation is dynamic
* Tends to increase in repeat number between generations
* Initial change _______ to further change
predisposes
56
TRDs
* Instability becomes manifest
* Individuals within a single family have different repeat numbers
* In the same individual, different _______ have different repeat numbers
tissues
57
Position of repeats:
* Repeats may be ________ (within the exon or intron) or __________ (5’ or 3’ of the gene)
intragenic
extragenic
58
TRDs
* If present within exons: (2)
* Encode a series of identical amino acids, translated to protein
* Gain-of-function
59
TRDs:
* If present in the UTR: (2)
* Disrupt transcription, translation or protein function
* Loss-of-function
60
Position of the repeat:
61
TRDs
* Coding repeats
– Commonly _____
* Code for the amino acid glutamine (Q)
* Polyglutamine (or polyQ) diseases
– Gain-of-function mutations
* Mutant protein has a ______ effect
CAG
toxic
62
* Non-coding repeats
– Variable: CGG, GCC, GAA, CTG, or CAG
– Very large repeat expansions
– Usually _____-of-function mutations
loss
63
* Diseases with (CAG)n repeats in coding regions: (3)
– Huntington disease (HD)
– Spinocerebellar ataxia (SCA) subtypes 1, 2, 3, 6, 7
– Spinobulbar muscular atrophy (Kennedy's disease
64
* Diseases with non-coding repeats: (3)
– Fragile X syndrome (CGG repeat)
– Myotonic dystrophy (DM) (CTG repeat)
– Friedreich ataxia (GAA repeat)
65
What is Myotonic Dystrophy? (3)
* Most common form of muscular dystrophy in adults (Type I)
* Autosomal dominant inheritance
* Marked anticipation
66
Myotonic Dystrophy
* Clinical features: (6)
– Onset 20s to 30s
– Myotonia (slow relaxation of muscles)
– Muscle weakness
– Cataracts
– Diabetes
– Intellectual disability
67
68
Myotonic Dystrophy genetics
* Increasing repeat number explains anticipation: (5)
Normal: 5 - 34 repeats
Premutation: 35 - 49 (Some instability, no disease)
Mild: 50 - 200
Classic disease: 200 - 1500
Congenital: 1000+
69
I-1:
ll-2:
III-1:
I-1: Grandfather, symptoms of myotonia since age 50, no significant disability
II-2 Mother, myotonia since late teens
III-1 Daughter, congenital myotonic dystrophy
Note: Age at onset is inversely correlated with repeat number (the more repeats, the earlier disease onset)
70
Huntington disease
* Autosomal __________ inheritance
* Clinical features:
– Typically adult onset, 35 to 44 years
– Median survival, 15 to 18 years after ______
– Movement disorder (chorea)
– Psychiatric disturbances
– Individuals lose ability to walk, talk and reason
dominant
onset
71
72
Huntington disease genetics:
* Age of onset is _________ correlated with repeat number.
* Increasing CAG repeats in the HD disease gene ________ the age of onset of symptoms of
the disease.
* Early onset/juvenile HD symptoms can be seen at
repeat numbers above 60.
inversely
decreases
73
What is HDL2?
74
Fragile X Mental Retardation Syndrome
* Most common inherited form of _______ disability
* 1/2000 – 1/5000 males
* X-linked dominant, _____ gene
* CCG repeat expansion in the 5’ UTR
* Leads to silenced ________, loss-of-function mutation
intellectual
FMR1
transcription
75
76
Premutation Carriers: males
(55-200 repeats)
* Males: only one X chromosome
* Normal intellect and appearance
* Some have subtle intellectual or behavioural symptoms
including learning difficulties or social anxiety
* A male who is a ________ carrier is called a “normal
transmitting male”
– All his daughters inherit the premutation
– Small increases in the premutation may occur when transmitted by a father but the premutation does not expand into the full mutation range. Usually passed on as is.
– _____ of his sons inherit this allele (as they inherit only his Y chromosome)
premutation
none
77
Premutation Carriers: females
* Mutation present on one X chromosome (55-200 repeats),
her other X has a repeat in the normal range
* Normal intellect and appearance- possibly learning
difficulties or social anxiety
– May develop premature _______ failure (POF)
– May develop Parkinsonian-like disorder in later life called Fragile X associated tremor _______ syndrome (FXTAS)
* Unstable; risk of passing on an expanded allele: risk of
having children with ______
ovarian
ataxia
FRAX
78
Fragile X Mental Retardation Syndrome
Affected males: (7)
– Mutation present (>200 repeats)
– Intellectual disability
– Developmental delay
– Poor speech
– Hyperactivity/Autistic behaviour
– Long face, large ears, prominent jaw (post-puberty)
– Large testes (post-puberty)
79
FRAX: Full mutation carrier females
* Mutation present on one X chromosome (>200 repeats)
* Poorly understood
– Either normal or show __________ delay
– Do not develop POF
developmental
80
What are FRAX genetics?
81
Principles for TRDs: (3)
1. Generally follow Mendelian laws
* Autosomal dominant (SCA, HD)
* Autosomal recessive (Friedreich ataxia)
* X-linked (FRAX)
2. BUT:
* Variable severity correlated with number of repeats
* Exhibit anticipation
3. Often missed clinically because of variability
* Family history is very important
82
* _______ range: stable, not expected to expand on
transmission
*________ range:
* No disease
* However, may expand upon transmission to the next generation
* Possible grey zone, individual may show some mild features of
the disorder (reduced penetrance)
* ________ range: disease-associated
Normal
Intermediate
Affected
83
Next generation sequencing
Sanger Sequencing vs Next Generation Sequencing
84
NGS Applications: (3)
85
What is Targeted Gene Panel Testing? (2)
86
What is Whole Exome Sequencing (WES)?
1. Sequence entire coding sequence of human genome (exons)
◦ Analyse 1-2% of the genome BUT 85% of pathogenic mutations in exons
◦ Less targeted approach
◦ Useful to identify new genes involved in pathogenesis
◦ Increased chance of uncertain findings
87
Whole Exome Sequencing (WES):
Consider if: (2)
Interpretation challenging: (3)
◦ Poorly defined phenotype
◦ Suspected new syndrome
◦ Often generate new data
◦ Difficult to prove causation
◦ Negative panel
88
Clinical exome concept: (2)
◦ Subset of exome
◦ Genes with known clinical significance
89
Whole Genome sequencing (WGS):
Sequence all DNA of an individual
(3000Mb)
Massive data set
◦ Very large number of variant
90
Whole Genome sequencing (WGS):
May detect: (3)
◦ Deep intronic mutations
◦ Breakpoints
◦ Structural rearrangements
Increased chance of uncertain
findings
Mainly used in research setting
91
Choosing the Right Genetic Test:
92
NGS Challenges:
93
NGS Challenges:
94
Variants of Uncertain Significance:
An alteration in the normal sequence of a gene, the
significance of which is unclear
*Knowledge limitations
*Classification of variants ______
◦ ________ analysis
◦ Database knowledge
◦ Lack of African data
*Additional studies may prove it to be ______ or disease-
causing
◦ Family segregation studies
◦ Functional studies
*Translation for patient?
complex
Bioinformatic
benign
95
Why do incidental findings prove to be an issue? (2)
1. Incidental or secondary findings
◦ Unrelated to the indication for testing
◦ May be of medical value for patient care
◦ Not part of reason for test
◦ Counselling issues
◦ When to inform
2. Reportable/actionable variant
◦ 1% of tests have a reportable incidental variant
◦ ACMG list of 59 genes
◦ Pathogenic and likely pathogenic variants must be reported to patients e.g. inherited
cancer, cardiomyopathy, familial hypercholesterolaemia, Marfan syndrom
96
Other Challenges
Missing _________
◦ Missed mutations – challenges of a negative test
◦ Larger rearrangements
◦ Technical issues
◦ ________ changes
◦ Other ?
Genetic _______ (heterogeneity)
◦ Gene mutations in different genes cause same disease
◦ Mutations in same gene cause different diseases
◦ Pathways – modifiers
heritability
Epigenetic
complexity
97
Adapting Genetic Counselling for the Genomic Era
The scale of information provided by genomic sequencing is vast
◦ How do we determine which results to return and when to return them?
A more critical evaluation of genetic variants and their association with disease risk is require: (5)
◦ Primary literature
◦ Online and other electronic tools
Strong focus on informed consent particularly with respect to:
◦ Uncertainty
◦ Ownership of genetic data
◦ Duty to re-contact and/or re-annotate
98
Result:
99
Result:
100
Result:
