GiM Lecture 1,2,3 Flashcards by Pip Banks

Reasons for clinical genetics referrals

Child
Birth anomalies, dysmorphic features, learning difficulties

Adult
Diagnosis, predictive testing, carrier testing, family history, foetal loss/recurrent miscarriage

Pregnancy
genetic disorder, screening abnormality

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What is genetic counselling

Education process to assist affected or at risk individuals understand the nature of genetic disorder, transmissions and available options

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How are genetic diagnosis made

Family tree - pattern of inheritance
Physical examination
Genetic Tests - Chromosome, Genes

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Testing For genetic disorders

Non genetic tests
Genetic tests

Blood tests

Enzyme assays
Inborn errors of metabolism

Haematology
-thalassaemia
X Rays
-Skeletal dysplasia

Genetic
Genomic architecture
-Cytogenetics
-Array based techniques
Gene faults
-Sequencing
-OLA assays
-MLPA tests

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Advantages and disadvantages of genetic testings for disorders

Advantages

Early diagnosis
Early interventions
Carrier testing
Reproductive choices
Prenatal testing

Disadvantages

no treatment
does knowing help

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What is Pharmacogenomics

Analysis of entire genomes of a group

aim to identify genetic factors influencing response to a drug

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What is pharmacogenetics

Study an individuals genetic make up to predict drug response and guide prescription

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What is Glevec

Treatment for CML (chronic myeloid leukemia)

Targeted at novel fusion protein which is the product of translocation in CML

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What are contributions to human diseases

genetic

environmental

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Define

- Multifactorial genetic disorder

the interaction of multiple genes (genetic predisposition) in combination with environmental factors eg type II diabetes, ischemic heart disease.

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define

- single gene genetic disorder

a mutation in a single gene = Mendelian inheritance – AD, AR, XL eg cystic fibrosis

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Define -

Chromosomal genetic disorder

an imbalance or rearrangement in chromosome structure eg aneuploidy, deletion, translocation

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Define

- Mitochondrial genetic disorder

a mutation in mitochondrial DNA

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Define

- somatic mutations

mutation(s) within a gene(s) in a defined population of cells that results in disease eg breast cancer

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What are the single gene modes of inheritance

Autosomal Dominant
Autosomal Recessive
X-linked
Mitochondrial

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What is Autosomal dominant inheritance

What does it mainly affect
give 3 examples of autosomal dominant conditions

A trait or disease runs from one generation to the next

Males and females equally affected

Offspring of affected person has a 50% (1 in 2) chance of inheriting the mutation

Structural proteins, receptors, transcription factors

Myotonic dystropy
Marfan Syndrome
Huntingdon Disease

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Autosomal Dominant Inheritance

What genotype are those affected
What is the change off spring is
a) affected
b) unaffected

Affected = 50% 
Affected = heterozygous

Unaffected - 50%
Homozygous

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What is Penetrance?

- give example of a disease with 100% penetrance

The frequency with which a specific genotype is expressed by those individuals that possess it,
e.g huntingdons has 100% penetrance

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What is expressivity

variation in expression - the extent to which a heritable trait is manifested by an individual

e.g. marfan - aortic dilation –> stretch marks

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What is anticipation?

- two disease examples

the symptoms of a genetic disorder become apparent at an earlier age as it is passed from one generation to the next. In most cases there is an increase in the severity of symptoms too

myotonic dystrophy
huntington’s disease

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Define

De Novo Mutation

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new mutation that has occurred during gametogenesis or in early embryonic development.

Explain Autosomal Recessive inheritance

give examples of autosomal recessive inheritance diseases

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Disease seen in one generation
consanguineous relationship increases risk of disease offspring
relatives maybe carriers
affects M and F equally
Gene mutations not chromosomes
cystic fibrosis
metabolic disorders
haemachromatosis
sickle cell

Autosomal Recessive inheritance

What genotype are affected
What risk of being affected
risk of being an unaffected carrier

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Affected = homozygous or compound heterozgous
Affected = 25%
unaffected Carrier = 2/3
unaffected = 25%

X linked inheritance

Explain
Example diseases

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Males affected
Females - spectrum - unaffected –> fully
M usually more affected
Female transmission ONLY
Possible in
- Gene mutations, chromosome deletions and duplications

Duchenne Muscular Dystrophy
Fragile X syndrome
Red/green colour blindness
Haemophilia

X linked inheritance - Carrier Mother - Affected Boy - Carrier Girl - Normal Boy - Normal Girl

25%

X linked inheritance - affected father - daughters? - Sons?

``` D = All carriers S = unaffected - no male transmission ```

X linked inheritance | Why can females have varying phenotypes

X inactivation XL dominant vs XL recessive inheritance CANNOT predict female phenotype in prenatal testing

What is Lyonisation?

- X- inactivation - One X chromosome in cells with XX is turned off. - Occurs in early embryogenesis - Most but not all inactivated X genes turned off.

X inactivation and disease expression What is skewed X inactivation? What is tissue variability

Skewed = random preference for normal X chromosome to be inactivated over abnormal X Tissue - Random prefernece for mutated X chromosome to be active in crucial tissue group

X linked Dominant inheritance - Affects? - Who does Rett syndrome effect - Who does Fragile X syndrome effect

Males and females Rett - lethal in M, phenotype only in F Fragile X - M affected, F - spectrum

X linked Recessive - affects? - are carrier girls affected?

Affects - males, carrier females can be affected F is homozygous carrier girls - affected if x inactivation skews

Mitochondrial Inheritance - explain - example

- Maternally inherited diabetes and deafness - Rare , M = F affected - only 27 genes in mitchondrial DNA - always maternally inherited - affected mother = ALL offspring affected - affected father - no affect

``` Family trees What does .... mean? - Circle - square - diamond - diamond crossed out - triangle - triangle crossed out - filled circle/square - square/circle with dot ```

- female unaffected - male unaffected - unknown sex - still born unknown sex - miscarriage - abortion - affected F/M - asymptomatic carrier

What is the symbol for - Consanguinity How does it affect genetics

Double line between couple - blood relative - congenital birth defect 5-6% risk (pop normal = 2-3%)

What is Polymerase chain reaction

In Vitro synthesis of large amounts of DNA Oligonucleotides define boundaries of synthesis DNA synthesized by DNA polymerase enzyme 1) Heat denaturation 94 degree 2) primer annealing 55 degree 3) primer extension 72 degree Products separated by GEL electrophoresis and visualized with UV

What can be determined by PCR

Presence/absence of something - allele specific PCR product size by gel electrophoresis - Oligonucleotide ligation assay - direct sequencing

How does gel electrophoresis work

Electrical current small products move towards +ve end large products remain at -ve end DNA is -ve charged therefore moves towards +ve

What is the mutation for the most common inherited cause of deafness

Connexin 26 | GJB2

What can a delta35g assay show

accurate size analysis - can show single base deletions - able to distinguish hetero zygotes, homo zygotes, and normal

What is Allele specific mutation detection - method - use

- distinguish between 2 alleles that differ by one nucleotide aka - Oligonucleotide Ligation Assay - allele specific primer- 3' nucleotide base pair with changed nucleotide - reaction will not occur if base pair not perfect - able to tell abnormal from normal alleles

How can Cystic fibrosis gene mutations be identified

Cystic Fibrosis genotyping assay

What is Multiplex Ligation- dependent probe amplication analysis (MLPA)

- detects chromosomal DNA copy number changes in multiple targets

What is the amount of product from PCR proportional to?

the amount of target DNA present

What are the problems with mutation anaylsis

gene might be too big for PCR gene may be repetitive GC rich regions are hard to PCR

Souther Blotting is used for what?

Fragile X syndrome | DNA

what is DNA sequencing

Detection of unknown mutations = exact position of mutation - type of mutation uses specific PCR product as template

What nucleotides are used in sequencing?

dNTP deoxyribose nucleotides | dideoxyNTP dideoxyribosenucleotides

how do ddTTPs help with sequencing

stop chains continuing to grow lots of chains different lengths can read sequence by gel electrophoresis

What is MEGF10 mutation screening

distinguish between different muscular dystrophies

What is clonal sequencing

next generation Illumina Method Long PCR product covering gene produces flow cell images

GiM Lecture 1,2,3 Flashcards

(50 cards)