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GiM > Introduction, basics & techniques > Flashcards

Introduction, basics & techniques Flashcards

1
Q

Reasons for genetic referral

A 
For diagnosis/investigation
Family history
Fetal loss
Recurrent miscarriage
Strong family history of cancer
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2
Q

Broad types of testing

A

Prenatal
Carrier
Predictive
Diagnostic

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3
Q

How to make a genetic diagnosis

A

Family tree
Physical examination
Genetic tests: chromosomes (karyotype), genes (DNA testing)

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4
Q

Diagnostic genetic test categories

A

Non-genetic or genetic

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5
Q

Examples of non-genetic tests

A

Bloods - enzyme assay, haematology

X-rays - skeletal dysplasia (achondroplasia)

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6
Q

Examples of genetic tests

A

Genomic architecture - cytogenetics, array based techniques

Gene faults - sequencing, OLA assays, MLPA tests

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7
Q

Pharmacogenomics definition

A

Analysing entire genomes, across groups of individuals, to identify the genetic factors influencing responses to a drug

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8
Q

Pharmacogenetics

A

Studying an individual’s genetic make up in order to predict responses to a drug and guide prescription

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9
Q

Drug treatments targeted at genetic faults

A

Somatic e.g. Gleevec

Germline e.g. RP65

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10
Q

Achondroplasia

A

Affects height - single gene but different heights

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11
Q

Single gene modes of inheritance

A

AD
AR
XL
Mito

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12
Q

AD Inheritance affects:

A

Structural proteins, receptors, transcription factors

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13
Q

AD Inheritance applies to:

A

Myotonic dystrophy
Marfan syndrome
Huntington Syndrome
Chromosome deletion&duplication e.g. 22q11 deletion syndrome

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14
Q

Penetrance definition

A

The frequency with which a specific genotype is expressed by those individuals that posses it, usually given as percentage e.g. 100% Huntington by 80 y.o. but 80% with BRCA1

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15
Q

Expressivity definition

A

Variation in expression - the extent to which a heritable trait is manifested by an individual e.g. Marfans differences or BRCA1 good cause ovarian or breast

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16
Q

Anticipation definition

A

The symptoms of a genetic condition become apparent at an earlier age from one generation to the next - myotonic dystrophy, Huntington’s

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17
Q

New dominant / de novo

A

A new mutation that has occurred during gametogenesis or early embryonic

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18
Q

AR diseases e.g.s

A

CF
Many metabolic
Haemachromatosis
Sickle cell disease

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19
Q

XL

A 
Males affected; maybe female from mild to fully
DMD
Fragile X
Red/green colour-blindness
Haemophilia
No male-male transmission
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20
Q

Influences to XL expression of phenotype

A

X inactivation

XL dominant vs XL recessive

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21
Q

Lyonisation

A

Random X-inactivation in cells with more than one X chromosome which compensates for the presence of the double X gene dose - makes a Barr body

22
Q

X-inactivation

A

Common if two or more X chromosomes
Early in embryogenesis
Random X silenced
Remains inactive forever

23
Q

Types of X-inactivation

A

50% of cells express the normal gene
Skewed X-inactivation
Tissue variability

24
Q

Skewed X-inactivation

A

Random preference for normal X chromosome to be inactivated - significant phenotype

25
Q

Tissue variability

A

Random preference for the X chromosome with the mutation to be active in crucial tissue group e.g. DMD

26
Q

XL Dominant (rare)

A

Rett Syndrome - not compatible with life in males, phenotype only in females
Fragile X syndrome - females range from asymptomatic to fully symptomatic (due to X-inactivation)

27
Q

XL recessive

A

Red-green colour blindness
Haemophilia
DMD
Carrier girls usually unaffected but can be significantly because of X-inactivation

28
Q

Mitochondrial inheritance

A 
Maternally inherited diabetes
Deafness
Rare
Equal in M+F
Passed on through mothers egg
Highly variable expressivity
All children of man unaffected
29
Q

Asymptomatic carrier sign

A

Filled in circle inside

30
Q

Double line

A

Consanguineous relationship

31
Q

Splits in two from one origin on tree

A

Twins

Identical twins have a connecting line making it a triangle

32
Q

Diamond in family tree

A

Unknown sex

33
Q

Consanguinity

A

Couples who are blood relatives
Share recessive gene mutations
Risk of congenital birth defect (5-6%) vs (2-3%)
Seen in all ethnic groups

34
Q

Genetic testing for a mutation we already know of

A

Simple and cheap analytical methods can be used

35
Q

Genetic testing for a mutation we do not know identity of

A 
Discovery methods (e.g. Sanger DNA sequencing)
Clonal sequencing
36
Q

Polymerase chain reaction (PCR)

A

In vitro synthesis of large amounts of DNA by copying small starting quantaties

37
Q

Oligonucleotide definition and use in PCR

A

Small synthetic primers

Define the boundaries of synthesis

38
Q

Process of PCR

A 
Heat denaturation (94 degrees)
Primer annealling (55 degrees - 3'->5')
Primer extension (72 degrees)
Heat denaturation (94 degrees)
Repeats itself
39
Q

How are PCR products seperated

A

Gel electrophoresis

40
Q

Analysis of PCR products

A

Determine presence/absence of product - allele-specific PCR

Determine product size by gel electrophoresis - oloigonucelotide ligation assay or direct sequencing

41
Q

Connexin 26 delta35G assay

A

Most common inherited cause of deafness

42
Q

Allele-specific mutation detection

A

Distinguishes between two alleles that may only differ by a single nucleotide
Designed so 3’ end base pairs with changed nucleotide but will not take place if they are not perfectly base-paired hence distinguishing between them

43
Q

CFTR mutations are identified via

A

Cystic fibrosis genotyping assay.
Genotypes a panel of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in genomic DNA isolated from blood

44
Q

Difficulties in mutation analysis

A

Gene too big for PCR
Hard to deal with repetitive sequencing
GC-rich regions are difficult to PCR

Solution: southern blotting

45
Q

DNA sequencing

A 
Unknown mutations
Ultimate method
Complex and expensive
Determines exact position of mutation
Determines type of mutation
Uses specific PCR product as template
46
Q

Strand synthesis catalyst

A

DNA polymerase

47
Q

Deoxynucleotides required for DNA sequencing

A

dATP, dCTP, dGTP, dTTP

BUT also: dideoxynucleotides: ddATP, ddCTP etc

48
Q

What does it look like on sequencing gel

A

ddTTP, ddGTP lanes
Largest fragments at start (left)
Electric field goes from negative to positive
Exclude the end because of dye blobs - give messy sequence

49
Q

Types of DNA sequencing

A

Traditional - 16 or 96 capillary

Clonal - 3.5-7GB of reads

50
Q

What DNA is sequenced by clonal sequencing

A

PCR products
Long PCR product covering part or whole of a gene
Panels of selected genes known to be mutated for a particular phenotype
Very large ‘exome’ panels based on all coding genes

51
Q

Clonal sequencing of gene panels (difficult)

A

You have bait of cRNA and your genomic DNA
This is target capture
You then use Magbead capture to select the bound oligonucleotides
Wash out the excess stuff
Digest RNA leading to enriched target

GiM (7 decks)

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