14122021 overview My focus is on teaching you concepts you dont get yet Well be skipping rote learning content make sure you cover them though Phenotypic Variability Genetic Testing ID: 920480
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Slide1
By Rayyan Islam
Genetics 2
14/12/2021
Slide2overview
My focus is on teaching you concepts you don’t get yet
We’ll be skipping rote learning content (make sure you cover them though!)
Phenotypic
Variability
Genetic
Testing
Emerging Treatments
Cancer
Genetics
Slide3Phenotypic Variability
Phenotypic Variability
Phenotypic Variability is the variation of gene expression in the same disease in different individuals
Therefore,
individuals with the same genetic disease may not have the same symptoms or presentations
(phenotype)
Environment
Unstable
Mutation
Modifiers
Sex
Slide4Phenotypic Variability
Environment
Causes of Phenotypic Variability
Where the expression of a gene is modified by environmental factors
Unstable
Mutation
Modifiers
Sex
In hereditary haemochromatosis, low iron
intake
improves outcomes
Where
expression of a gene varies by sex
In hereditary haemochromatosis, women lose blood through menstruation and have less iron buildup
Where
expression of a gene is directly affected by the presence of other genes
In cystic fibrosis, a variety of genes can increase the degree of CF and wildly increase chance of infections
Where
different
mutated
subtypes
of the same disease have different presentations
Duchenne vs Becker dystrophy –
slightly different mutations in the same gene
cause slightly different presentations
Trinucleotide Repeat Disorders:
Where an increased number of nucleotide repeats (> 27) cause more severe phenotypes throughout generations
Huntington’s becomes
more severe in future generations
Slide5Phenotypic Variability
PV Question Tips
The disease known as Autosomal recessive deafness-26 (DFNB26) is caused by a homozygous mutation in the GAB1 gene. In an extended family, a large number of people are homozygous for the disease-causing mutation. However, of the family members who are homozygotes for the disease gene, only half are deaf. What is the most likely explanation for this?
NF1 is a type of familial cancer caused by mutations in the Neurofibromin 1 gene. It is inherited in an autosomal dominant fashion. It is known to have a
wide variability
of symptoms both within affected families and between affected families. In a study it was observed
this variability did not apply to monozygotic twins
what is the most likely explanation for this variability
Achondroplasia and Hypochondroplasia are both forms of short limb dwarfism, caused by
specific mutations of the
FGFR3 which result in the receptor always being switched on. One mutation results in either
Achondroplasia, whilst
another results
in Hypochondroplasia. Hypochondroplasia is a milder phenotype of the dwarfism.
Retinitis pigmentosa are a group of degenerative eye disease, which manifests as night blindness. Several members of an extended family have retinitis pigmentosa. However the age of onset and severity of the disease shows
marked variability with no two members being affected in the same way
. What is the most likely explanation for this
Binary = likely presence or lack of presence of a gene
Twins are super common in genetic testing, a lack of variability implies a second gene, and no impact from environment
Anytime they mention a specific mutation and different diseases, it’s literally just ‘different mutation = different disease’
Wide range of variability normally means environmental
Slide6Genetic Testing
Timeline
11-14 week:
Date the pregnancy
Diagnose multiple pregnancy
Diagnose major foetal abnormalities
Diagnose early miscarriage
Assess risk of Down’s syndrome (Nuchal translucency)
20-22 week (mid trimester anomaly scan):
More detailed – look at bones, heart, brain, spinal cord, face, kidneys
Look for 11 rare conditions
Non-invasive:
Maternal blood test
Cell free foetal DNA (
cffDNA
)
Invasive:
Chronic villus sampling (CVS) (11-14 weeks)
Amniocentesis (16+ weeks)
Slide7Genetic Testing
Nuchal Translucency
A collection of fluid at the back of the fetal neck between 10-14 weeks
Increased > 3mm
can indicate:
Chromosome abnormalities (e.g. Downs, Edwards, Patau, Turners)
NT + maternal age detects up to 75% of Down syndrome with 5% false positive rate
-
Birth defects
:
- Cardiac anomalies- Pulmonary defects (diaphragmatic hernia)
- Renal defects
- Abdominal wall defects
-
Skeletal
dysplasias
This is a screening test and NOT DIAGNOSTIC
Slide8Genetic Testing
Prenatal Testing
Arranged following:Abnormal findings at nuchal/mid-trimester scans and in women with high risk of Down’s Syndrome or a previous
history of genetic disease (including previous pregnancies)
To inform / prepare parents for the birth of an affect baby + complications at / after birth
Aims of Prenatal Testing
To allow possible in utero treatment
To aid in managing the remainder of the pregnancy
To allow termination of an affected fetus
Slide9Genetic Testing (Non-Invasive)
Maternal Serum Screening
Tests maternal serum markers in the blood to detect increased risk of fetal trisomy 21 / 18 and neural tube defects
Analyses placental DNA in maternal plasma
Cell-Free Foetal DNA
1
st
Trimester (
11-14 weeks
):
hCG
, PAPP A
2
nd
Trimester (
16-20 weeks
): AFP, UE3,
hCG
Also some private options with combing both screens
Foetal DNA first detectable at 4-5 weeks but
most accurate at 9 weeks
Slide10Genetic Testing (Invasive)
Chorionic Villus Sampling
Sample cells taken from amniotic fluid contain foetal cells
Amniocentesis
Transabdominal/vaginal, sample taken of
chorionic villi as it has same DNA as
foetus
Allows for earlier results than amnio for abortion, but 1-2% risk of miscarriage, so
only done when there is a known risk
Risk of Rh sensitization and infection
1% risk of miscarriage
Slide11Genetic Testing (Further)
CGH Array
Full genetic sequencing, offered where previous pregnancies have had significant anomalies
Trio Exome
Offered when there are
concerns on the 20 week scan
Essentially looks for
chromosomal imbalances
to pick up diseases, and may require
testing of parents
to interpret
Slide12Reproductive Options
Potential Options
Conceive Naturally
Adoption
Egg / Sperm Donors
Pre-Implantation Genetic Diagnosis
Slide13Reproductive Options
Egg / Sperm Donation
No longer anonymous, children conceived have the right to contact donor when 18 Best to go through a UK HFEA licensed fertility centre
– conform to strict medical, ethical and legal standards Can privately find own donor
Some couples may consider going abroad
Adoption
Registration and Checks
- Registering interest with adoption agency
- Medical and criminal background checks; three written references
- Usually takes ~2 months
Assessment and Approval
- Home visits by social worker and compilation of ‘prospective adopters report’, taken to adoption panel
- Panel review information and make a decision whether a couple is suitable to adopt
- Takes ~4 months
Slide14Reproductive Options
Pre-Implantation Genetic Diagnosis
Uses IVF with genetic testing before implantation
1. Stimulation of the ovaries
2. Egg collection
3. Insemination
4. Fertilisation
5. Embryo biopsy6. Embryo testing7. Embryo transfer
8. Pregnancy test
Ovaries are hyper stimulated and eggs are collected, and an intracytoplasmic sperm injection is performed at the centre of each egg
Used for conditions caused by a single faulty gene to reduce the amount of non-embryo DNA
(including sperm DNA) which could make the risk of a wrong diagnosis higher
The embryo is biopsied when it is at the 8 cell stage
Slide15Reproductive Options
PGD Referral Criteria
Female partner is under age 39Female partner has a BMI of 19-30
Both partners are non-smokers
Couple are living together in a stable relationship
No living unaffected children from the relationship
Known risk of having a child affected by a ‘serious’ genetic condition (at least 10%)
Female partner has hormone levels that suggest she will respond to treatmentAn accurate genetic test is availableNo welfare concerns for the unborn child
A licence is required from the HFEA for each genetic condition or indication
Eligible couples are usually funded for three rounds of PGD.
Slide16Cancer Genetics
Cause
Cancer Genetics
These mutations are due to either: -
Tumour
suppressor genes being silence.
- Oncogenes being over-expressed
Due to cells that divide and proliferate
uncontrollably
due to alterations / mutations in DNA
Proliferation
Self synthesis of growth factors
Signal nearby cells to produce growth factors
Increase responsivity to growth factors
Slide17Cancer Genetics
Immune Evasion
Some tumour cells contain a protein PD-L1 which effectively enables it to evade the immune system by down-regulating T cells
A number of immunotherapies
act on this mechanism
by disabling this protein and upregulating the immune system again / enabling it to recognize cancer cells
Slide18Cancer Genetics
Benign / Malignant
BenignMalignant Grows more slowlyGrows faster
Well-differentiated
Poorly differentiated
Capsulated
Not capsulated
Does NOT invade neighbouring tissue
Invades neighbouring tissue
Does NOT metastasizeInvades basement membrane and metastasizes
Slide19Cancer Genetics
Definitions
Cell of originBenignMalignant
Epithelial tissuePapilloma (lining epithelial)Adenoma (gland)Squamous cell carcinomaAdenocarcinoma
Mesenchyme tissue
Osteoma (bone)
Chondroma (chondrocytes)
Angioma (blood vessels)
Osteosarcoma
ChondrosarcomaAngiosarcomaLymph nodesLymphomaBlood cells
Leukaemia
Slide20Cancer Genetics
Mutations
DeletionsDuplication
InversionTranslocation
Single base substitutions (point mutations – silent, nonsense, missense)
Chromosome Instability
Aneuploidy
Deletions
Somatic mutations cannot be passed onto offspring
Germline mutations can be passed onto offspring
Passenger mutations occur during cancer growth
Driver mutations contribute to cancer growth
Slide21Cancer Genetics
Oncogenes
RAS controls a lot of cellular signalling pathways as a switch
Therefore, changes to RAS expression influence cancer development
RAS
A single mutation tends to be sufficient for cancer development
Oncogene issues generally result in an increase in some form of protein (enzyme) activity, or a loss of regulation
Slide22Cancer Genetics
Two Hit Hypothesis
Situations where a form of genetic damage is not sufficient to enable cancer to develop (a second hit initiates cancer)
For example, a high degree of exposure to UV light may be required to initiate melanoma development.
Slide23Genetic Treatments
Inborn Errors of Metabolism
In most disorders such as these, treatment by replacement tends to be most common
Other examples include growth hormone, and a range of enzymes for other disorders like Fabry, Pompe
etc
Disorders where a substrate cannot be converted into a product
In Phenylketonuria, phenylalanine cannot be broken down, treatment is simply to avoid
Phe
In Haemophilia, a lack of factors VII and or IX mean they must be physically replaced
Slide24Genetic Treatments
Protein Targeting Treatments
Pharmacological chaperones:
Some mutations prevent proteins folding properly e.g. Fabry disease caused by
a-galactosidase A deficiency
Migalasat
= small molecule chaperone that
Stabilises enzyme in correct shape
Pharmacological modulators
:
Receptor agonists/antagonist
Ion channel activators/blockers
Combination therapies
:
Cystic fibrosis
Stop codon read through drugs
:
DMD is due to a premature stop, can be converted to BMD by preventing this stop misread
Slide25Genetic Treatments
Gene Therapy
Mitochondrially inherited diseases:
Require IVF and normal mitochondria from a donor egg
Viral Gene Therapy
Where we engineer a virus to carry a therapeutic gene
Anti-sense oligonucleotides and gene silencing
:
Effectively prevent production of targeted proteins, particularly effective in neurological disorders as of now
- CRIPSR and RNAi are additional methods with less practiced consistency
Stop codon read through drugs
:
DMD is due to a premature stop, can be converted to BMD by preventing this stop misread
CAR-T Therapy
Where T-cells are removed from the body, modified to recognise cancer cells and re-infused