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MBBCh 2- HAEM2000A > 4. Mendelian Inheritance II (Exceptions and Complications) > Flashcards

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
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2
Q

WHY ARE SOME CONDITIONS MORE PREVALENT IN
CERTAIN POPULATION GROUPS?

A
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3
Q

How does the founder effect produce more genetic conditions?

A
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4
Q

EXAMPLE OF A FOUNDER POPULATION IN SA:

A
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5
Q

How does heterozygotic advantage contribute to some conditions being more prevalent in certain population groups?

A
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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

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7
Q

How does Consanguinity contribute to some conditions being more prevalent in certain population groups?

A
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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

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9
Q

AFRICAN POPULATION: ALBINISM -

A
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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)

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11
Q

CAUCASIANS: CYSTIC FIBROSIS -

A
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12
Q

Caused by variants in the cystic fibrosis transmembrane
conductance regulator (______) gene

A
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13
Q

What is the function of the CFTR gene?

A
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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

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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

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16
Q

COMMON CONDITIONS IN THE ASHKENAZI JEWISH POPULATION:

A
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17
Q

ASHKENAZI JEWISH: TAY-SACHS DISEASE

A
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18
Q

AFRIKANERS
Several diseases with an unusually high frequency in Afrikaners have been suggested to be the result of founder effects:

A
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19
Q

AFRIKANER: SCLEROSTEOSIS

A
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20
Q

INDIAN: THALASSAEMIA

A
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21
Q

How did INDIAN: THALASSAEMIA originate?

A
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22
Q

MANAGEMENT AND GENETIC TESTING: (4)

A
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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

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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

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25
Q

Penetrance
* Definition:

A

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

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26
Q

What is complete penetrance?

A
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27
Q

What is incomplete penetrance?

A
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28
Q

Are pathogenic mutations always completely penetrant?

A
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29
Q

How do we measure penetrance?

A
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30
Q

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)

A

incomplete
penetrant
carriers

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31
Q

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

A

BRCA1
BRCA2
European

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32
Q

What are the genetics of hereditary breast and ovarian cancer syndrome?

A
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33
Q

Possible mechanisms underlying the phenomenon of reduced penetrance: (5)

A
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34
Q
  • 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…
A

as a dimmer on
that light switch (individuals who
have the disease may have it with
varying degrees of severity)

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35
Q

What does variable expressivity refer to?

A
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36
Q

How is Neurofibromatosis an example of variable expressivity?

A
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37
Q

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
→ ______

A

Connective
FBN1

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38
Q
  • 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)
A

range
mildy

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39
Q

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

A

de novo
normal variation

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40
Q

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.

A
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41
Q

Achondroplasia: About ____% of cases are due to a de novo (new) dominant mutation

A

80

42
Q

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

What is the recurrent risk? (2)

A
  • This was a random/chance event
  • Recurrence risk is exceptionally low
43
Q

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

What is the recurrent risk?

A
  • 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
Q

Apert Syndrome –
almost always a ____ mutation

A

new

45
Q

What are the classic laws of Mendelian inheritance? (3)

A
  • 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
Q

An interesting group of disorders was described
* A small group, particularly neuromuscular/neurodegenerative disorders
* Single gene disorders, followed rules of Mendelian inheritance
* Examples:

A
47
Q

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:

A

ATGCCTTATGTATGATTCGCAGCAGCAGCAGCAGTTACTTTTTAGACGACTATAAT

48
Q

TRDs: Molecular basis
* Number of repeats ______
– between individuals
– on different chromosomes
* Part of normal variation

A

varies

49
Q

What happens in Stable Mendelian inheritance?

A

Stable Mendelian inheritance in families (a child
will inherit one allele from each parent).

50
Q
  • 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!
A

triplet
threshold
dogma

51
Q

True or false
Repeats are dynamic.

A

True

52
Q

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

A

non-Mendelian
principles

53
Q

Triplet Repeat Disorders (TRDs)
* Characterised within and between families by: (2)

A
  • Variable disease presentation and progression
  • Anticipation which is defined as
    ‒ Earlier age of onset
    ‒ Increased severity in successive generations
54
Q

What is the threshold concept? (2)

A
  • Repeat number above a threshold results in disease
  • Different for different disorders
55
Q

TRDs:
* The mutation is dynamic
* Tends to increase in repeat number between generations
* Initial change _______ to further change

A

predisposes

56
Q

TRDs
* Instability becomes manifest
* Individuals within a single family have different repeat numbers
* In the same individual, different _______ have different repeat numbers

A

tissues

57
Q

Position of repeats:
* Repeats may be ________ (within the exon or intron) or __________ (5’ or 3’ of the gene)

A

intragenic
extragenic

58
Q

TRDs
* If present within exons: (2)

A
  • Encode a series of identical amino acids, translated to protein
  • Gain-of-function
59
Q

TRDs:
* If present in the UTR: (2)

A
  • Disrupt transcription, translation or protein function
  • Loss-of-function
60
Q

Position of the repeat:

A
61
Q

TRDs
* Coding repeats
– Commonly _____
* Code for the amino acid glutamine (Q)
* Polyglutamine (or polyQ) diseases
– Gain-of-function mutations
* Mutant protein has a ______ effect

A

CAG
toxic

62
Q
  • Non-coding repeats
    – Variable: CGG, GCC, GAA, CTG, or CAG
    – Very large repeat expansions
    – Usually _____-of-function mutations
A

loss

63
Q
  • Diseases with (CAG)n repeats in coding regions: (3)
A

– Huntington disease (HD)
– Spinocerebellar ataxia (SCA) subtypes 1, 2, 3, 6, 7
– Spinobulbar muscular atrophy (Kennedy’s disease

64
Q
  • Diseases with non-coding repeats: (3)
A

– Fragile X syndrome (CGG repeat)
– Myotonic dystrophy (DM) (CTG repeat)
– Friedreich ataxia (GAA repeat)

65
Q

What is Myotonic Dystrophy? (3)

A
  • Most common form of muscular dystrophy in adults (Type I)
  • Autosomal dominant inheritance
  • Marked anticipation
66
Q

Myotonic Dystrophy
* Clinical features: (6)

A

– Onset 20s to 30s
– Myotonia (slow relaxation of muscles)
– Muscle weakness
– Cataracts
– Diabetes
– Intellectual disability

67
Q
A
68
Q

Myotonic Dystrophy genetics
* Increasing repeat number explains anticipation: (5)

A

Normal: 5 - 34 repeats
Premutation: 35 - 49 (Some instability, no disease)
Mild: 50 - 200
Classic disease: 200 - 1500
Congenital: 1000+

69
Q

I-1:
ll-2:
III-1:

A

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
Q

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

A

dominant
onset

71
Q
A
72
Q

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.

A

inversely
decreases

73
Q

What is HDL2?

A
74
Q

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

A

intellectual
FMR1
transcription

75
Q
A
76
Q

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)

A

premutation
none

77
Q

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 ______

A

ovarian
ataxia
FRAX

78
Q

Fragile X Mental Retardation Syndrome
Affected males: (7)

A

– 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
Q

FRAX: Full mutation carrier females
* Mutation present on one X chromosome (>200 repeats)
* Poorly understood
– Either normal or show __________ delay
– Do not develop POF

A

developmental

80
Q

What are FRAX genetics?

A
81
Q

Principles for TRDs: (3)

A
  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
Q
  • _______ 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
A

Normal
Intermediate
Affected

83
Q

Next generation sequencing
Sanger Sequencing vs Next Generation Sequencing

A
84
Q

NGS Applications: (3)

A
85
Q

What is Targeted Gene Panel Testing? (2)

A
86
Q

What is Whole Exome Sequencing (WES)?

A
  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
Q

Whole Exome Sequencing (WES):
Consider if: (2)
Interpretation challenging: (3)

A

◦ Poorly defined phenotype
◦ Suspected new syndrome

◦ Often generate new data
◦ Difficult to prove causation
◦ Negative panel

88
Q

Clinical exome concept: (2)

A

◦ Subset of exome
◦ Genes with known clinical significance

89
Q

Whole Genome sequencing (WGS):

A

Sequence all DNA of an individual
(3000Mb)
Massive data set
◦ Very large number of variant

90
Q

Whole Genome sequencing (WGS):
May detect: (3)

A

◦ Deep intronic mutations
◦ Breakpoints
◦ Structural rearrangements
Increased chance of uncertain
findings
Mainly used in research setting

91
Q

Choosing the Right Genetic Test:

A
92
Q

NGS Challenges:

A
93
Q

NGS Challenges:

A
94
Q

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?

A

complex
Bioinformatic
benign

95
Q

Why do incidental findings prove to be an issue? (2)

A
  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
Q

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

A

heritability
Epigenetic
complexity

97
Q

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)

A

◦ 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
Q
A

Result:

99
Q
A

Result:

100
Q
A

Result:

MBBCh 2- HAEM2000A (30 decks)

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