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PATH2220 > W9 > Flashcards

W9 Flashcards

1
Q

what is genetic pathology

A

investigation of the gene changes that are responsible for disease (inherited or de novo, hemline or somatic, molecular or cytogenetic)

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2
Q

what is cytogenetics

A

primarily concerned with the structure, properties and behaviour of chromosomes. Cytogenetic tests are therefore chromosome- based tests

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3
Q

what is molecular genetics

A

talking about DNA and RNA level and production of polypeptides. the tests are DNA or RNA based

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4
Q

what is a congenital disease

A

present at birth

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5
Q

what is genetic disease

A

cause by chromosome or gene defects

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6
Q

what is inherited disease

A

passed from parent to offspring

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7
Q

what are inherited diseases caused by

A

a genetic abnormality that is transmitted from parent to offspring- can also result from new mutations

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8
Q

are inherited diseases rare or common

A

comparatively rare (e.g. cystic fibrosis)

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9
Q

what are the types of inherited diseases

A

monogenic (mutation/s is one gene sufficient for disease ), polygenic (multiple gene contribute to phenotype, each exerts a small effect), susceptibility (such as heart disease, gene and environment)

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10
Q

what is the difference from germ line and somatic mutations

A

germline is the cell lineage from which gamete are derived, the germ line is an uninterrupted chain of inheritance. somatic cells arise from the germ line but are not apart of it.

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11
Q

what is a sex linked inheritance

A

chromosomes x and y

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12
Q

what is the autosomal inheritance

A

chromosomes 1-22

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13
Q

what is the p arm of the chromosome

A

the short arm

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14
Q

what is the q arm of the chromosome

A

the long arm

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15
Q

what is homologous chromosomes

A

pair of chromosomes that are of the same number but one has come from one parent and the other from the other parent. variation from either parent present in chromosomes

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16
Q

what are the causes of chromosomal abnormalities

A

nondisjunction, translation and deletion and duplication (copy number changes)

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17
Q

what is hemizygous

A

the second allele is absent (deleted or that it one the X chromosome in a male)

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18
Q

what is protein gain of function

A

protein acquires new abnormal function (often dominant after mutation- common in tumour formation)

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19
Q

is the definition of a genetic test

A

analysis of DNA, RNA, chromosomes, proteins or certain metabolites, with the aim of detecting alter national related to a hereditary problem

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20
Q

how can genetic testing be done

A

molecular analysis of DNA or RNA, analysis of protein or other metabolites (e.g. biochemical or immunohistochemical tests)

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21
Q

why do we do genetic testing

A

diagnosis (pre and post natal), identification of at-rick, asymptomatic family members (surveillance and preventive measures, informed reproductive choices), screening (neonatal, carrier testing, early detection and treatment can prevent irreversible consequences, informed reproductive choices), disease prognosis (severity of disease, disease course and survival (genotype- phenotype), disease monitoring (response to treatment, relapse, tumour monitoring and mutations over time of the treatment), treatment choice (drug sensitivity and resistance)

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22
Q

true or false, DNA is only found in nucleated cells,

A

true

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23
Q

what are buccal cells

A

found inside the cheek of your mouth (good for getting blood when patient might not want to get it from the arm, easily collected non-invasively collected). also a second source of DNA (if suspicion of mosaicism)

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24
Q

what is cell free DNA

A

DNA not contained by membranes but floating free in the circulation can be isolated from peripheral blood

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25
Q

what are the source of cfDNA in the peripheral blood

A

– Haematopoietic cells
– Foetal cells: apoptotic placental cells, possibly erythroblasts
– Tumourcells:apoptotictumourcells

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26
Q

what are the applications of testing cfDNA

A

prenatal testing (difficult and can be done week 5 gestation) and tumour detection and monitoring

27
Q

what is more common out of DNA and RNA testing

A

DNA more common but RNA has advantages (mRNA does not have introns (that are large compared to the axons), it also shows splicing mutations (skipping of axons in the mRNA)

28
Q

how do we choose what test to use

A

change to be detected (size, where it occurs, type of change), volume of samples being tested, available resources and purpose of testing (known or unknown mutation)

29
Q

what causes cystic fibrosis

A

change in the CFTR gene

30
Q

why is PCR important

A

first step in a method or the method. Generate lots of copies of a particular piece of DNA.

31
Q

what is sanger sequencing (in pathology)

A

most common thing in routine diagnostic lab. Precursor is PCR. look at base level

32
Q

what is alpha1-antitrypsin

A

a protease inhibitor (prevent enzymes from degrading protein)

33
Q

how is AATD causes

A

by mutations in the SERPINA1 gene (encodes AAT)

34
Q

where is alpha1-antitrypsin produced

A

in the liver cells and then secreted in the blood

35
Q

explain how alpha1-antitrypsin deficiency works

A

gain of function and it clumps in the blood. There is then a deficiency and it doesn’t get to the lung and can’t protect it and loss of lung function (loss of function). can cause gain and loss of function

36
Q

what test would you use to detect for AATD

A

allele specific assay, looks for two different alleles. taxman assay for S and Z alleles. probe bind to DNA in region of amino acid changes that we are interested in. if change is present it will bind vice versa. one looks for S allele and one looks for Z allele. It is PCR based method. probes are made up of complementary DNA that can bind to target, has fluorescent reported and a quencher (stops fluorescence) then DNA is PCR and DNA polyermase removes quencher if bound and gives off light.

37
Q

what is duchenne muscular dystrophy

A

early childhood, slow to walk, sit and stand. children has mower limb weakness and difficulty climbing. majority wheelchair at 12. after 18 is cardiomyography. few survive beyond 3rd decade because of weak muscle. X linked, males are affected and females are carriers (some can show some symptoms).. caused by mutations in DND and encodes dystrophin.

38
Q

what is dystrophin

A

important structural protein. important role in ca homeostasis and intracellular signaling, large gene.

39
Q

what happens if there is mutation in DND

A

dystorphin at cell membrane, and if we stain for it, we can’t see the outline of the cells.

40
Q

what is DND due to

A

deletions of one or more axons of the gene or duplications. small proportion due to sequence level changes. MLPA used for testing for disorder.

41
Q

what is MLPA and how does it work

A

PCR based, detecting changes in copy number. 2 probes per exon that it targets. when DNA is present, the probes bind and are ligated together and 1 probe forms then used for PCR. if exon is missing the probe can’t bind and can’t stick together and PCR cannot occur. run through a capillary PCR. bars represent exons in genes. in affected, axons are missing (bars are missing), for females carrier there will be 0.5 not 0.

42
Q

what is cystic fibrosis how is it occurred

A

multisystem disorder. loss of function mutations in CFTR gene (encodes chloride channel). autsomal recessive disease, have to have two mutations to cause disease. 30 common CFTR mutations account for 88% of mutant alleles. some mutations cause no proteins at all, or reduced protein,

43
Q

what are the genetic testing for CF

A

look for two mutations. use allele specific tests or sequence-level mutations. depends if you found the 2 mutations early with the allele specific tests. \

44
Q

explain sanger sequencing

A

use forward and reverse not sense and antisense. take DNA and use PCR. subject the product to sanger sequencing. use forward primer to look at forward sequence present in the patient. run it through capillaries. put through software and shows as peaks showing nucleotide base and compare it to the normal DNA sequence. two peak sat same proint show heterozygosity.

45
Q

what is huntingtons disease

A

not treatable. affects the brain. early intervention and medical care helps quality of life. autosomal dominant inheritance. complete penetrance (if you have mutation you will develop it). dynamic mutation (triplet repeat expansion in HTT gene)

46
Q

what are dynamic mutations

A

increased or decreased numbers of repeats within a repetitive sequence.

47
Q

how testing would you use for HD testing in a lab

A

sequencing doesn’t work it creates error. use PCR. have primer sitting either side of repeat then see how long it is. if expansion is present, PCR fragment is longer than expected. know how long normal fragment and compare patient fragment lengt to see if longer or shorter. more than 40 repeats are disease causing.

48
Q

what are the causes of trisomy 21 (down syndrome)

A

three copies of chromosome 21. reduced life expectancy. large proportion does make it to birth and terminate. bulk of cases are due to complete additionally copy of chromosome 21. non-disjunction at meiosis.

49
Q

what is the genetic testing for down syndrome

A

karyotyping- white blood cells cultured and harvested, cell membrane bursts and chromosome spread out. staining show bands on the chromosome. dot have to use this, can use other methods but are advantages. such as seeing balanced rearrangements- chromosomes have rearranged itself. not phenotypic effect. such as 21 chromosome joining to chromosome 14. if parent has this, then at a higher risk of down syndrome. 21 comes from mum and dad then another 21 on 14. inherited down syndrome.

50
Q

what are common technical challenges in genetic pathology

A

DNA quality an quantity, availability of positive and negative DNA controls, tricky genomic regions (repetitive and duplicated sequence, pseudogenes, GS risk regions).

51
Q

what are common interpretative challenges in genet pathology

A

limited ability to demonstrate the effect of DNA level changes on protein and cellular function in routine laboratories. limited knowledge of genetic causes/mechanisms of diseases

52
Q

what happens if a abnormality is detected

A

is it real, is it pathogenic, does it fit with the phenotype, does it fit with other test results, down it fit with the inheritance pattern, does this result confirm the diagnosis or predict future disease

53
Q

what happens if a abnormality is not detected

A

did we miss something, could the phenotype observe or results from other investigations be due to another causes (genetic or non-genetic). does this result exclude the diagnosis or risk of future disease

54
Q

what is clinical utility

A

does the results help the patient and the doctor

55
Q

why is a genetic diagnosis important

A

there may be no other way to confirm the diagnosis, access to necessary support services, access to treatment available cessation of further unnecessary tests, psychological/certainty benefit of knowing the cause of disease. they can manage there risk factors i.e. AATD stop smoking etc.

56
Q

explain AATD biochemical tests

A

has no sensitivity, has false negatives

57
Q

how can you treat AATD

A

augmentation the ray (infusion of AAT), slow progression, but very expensive, weekly infusions and not a large amount of evidence supporting therapy, i.e. cost of time and money

58
Q

who has the higher risk of disease ZZ or ZS

A

ZZ

59
Q

what is the rate of carriers of CF

A

1 in 25 people

60
Q

how is CF detected in a baby

A

immunoreactive trypsinogen (pancreatic enzyme precursor). compared to those diagnosed later in childhood.. reductions in vitamin deficiencies, hospitalisations, bacterial colonisation

61
Q

what are the ethical challenges in genetic pathology

A

life decisions made on genetic pathology. Continuation of pregnancy, access to insurance. life choices (marriage, family, occupation). implications for extended family members (are they at risk, should they know, should they be forced to know? guilt that you have passed on a disease, your to affected but someone else is)

62
Q

what is the facts about huntingtons disease

A
  • No treatment/preven4on/cure
  • Risk of developing disease is 100%
  • ~15% of individuals at risk of HD decide to have pre-symptoma4c tes4ng (2009 data)
63
Q

what is the facts about inherited breast cancer

A
  • Surgical prophylaxis and treatment to prolong survival is available
  • Risk of developing cancer is variable
  • ~60% of individuals at risk of inherited breast cancer opt for predic4ve tes4ng (2006 data)

PATH2220 (14 decks)

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