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YEAR 2 SEMESTER 2 > GENETICS - wk 1 > Flashcards

GENETICS - wk 1 Flashcards

1
Q

describe the autosomal dominant inheritance pattern

A
  • More than one generation involved
  • Transmission of disease from father to son (male to male transmission)
  • Males and females affected in equal frequency
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2
Q

define penetrance and expressivity

A

Penetrance
- Affected person may or may not develop symptoms or show signs of the disorder “skipping a generation”

Expressivity
- Variation in the clinical presentation/ phenotype between patients

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3
Q

describe x-linked pattern of inheritance

A
  • Usually only males affected
  • More than one generation involved with the disease appearing to be passed on through normal females
  • No male-to-male transmission
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4
Q

explain x-inactivation

A
  • Female carriers can be affected by x-linked disorders
  • Consequence of the process called x-inactivation or lyonization
  • It is a random process
  • If in an excess of cells – the normal X chromosome has been switched off then a female carrier of an x-linked disorder can be affected
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5
Q

describe the autosomal recessive pattern of inheritance

A
  • One or more affected children with unaffected parents
  • Usually only one generation involved
  • Males and females affected with equal frequency and severity
  • A higher incidence of consanguinity
    (Meaning the fact of being descended from the same ancestor)
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6
Q

state the hardy weinberg equation and explain it’s use

A

p^2 + 2pq + q^2 = 1

p^2 is the proportion of the population who are unaffected

2pq is the proportion of the population who are carriers

q^2 is the proportion of the population who are affected (THE DISEASE INSTANCE)

therefore if you know the disease frequency (q^2) you can work out the risk of a child getting the disease (2pq)

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7
Q

define consanguinity and explain what this means in regard to shared genes through generations

A

a consanguineous marriage is defined as a union between two individuals who are related as second cousins or closer,

first degree relatives = 50% same genetic info

second degree relatives = 25% same genetic info

third degree relatives = 12.5% same genetic info

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8
Q

define genome

A

Complete complement of DNA sequence that constitutes the genetic blueprint for inherited characteristics of that organism

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9
Q

describe a mammalian chromosome

A
  • Single linear molecule of DNA that interacts with many multimeric proteins and molecules to produce complex high order structures required for cellular function or replication
  • Total length 1862 mm
  • Must be condensed to fit inside nuclei
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10
Q

define packing ratio and state the packing ratio at different stages of DNA condensation

A

packing ratio (length of native DNA/ length after condensation)

Winding DNA around a protein core = ‘bead-like’ structure called a nucleosome
o Packing ratio ~6
Coiling of beads in a helical structure called the 30nm fibre is found in both interphase chromatin and mitotic chromosomes
o Inc. packing ratio ~40
Then fibre organised into topologically associated domains (loops and scaffold)
o Final packing ratio ~1000 in interphase chromosomes
Most condensed state of chromosome achieved in the mitotic phase of cell division (after chromosomes are replicated and the copies held together as sister chromatids)
o Here there’s a packing ratio of ~7000-10,000
o They can be observed by standard light microscopy using fluorescent or cytochemical stains

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11
Q

explain centromeres - what is the location for microtubule attachment within these?

A
  • Centromeres condensed regions visible on mitotic chromosome that are responsible for accurate segregation of replicated chromosome during cell division
  • During mitosis, the centromere of each chromosome must divide so that sister chromatids can migrate to opposite poles of the cell
  • Within the centromere region the location of microtubule attachment is called the kinetochore and is composed of both DNA and protein
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12
Q

describe telomeres and their purpose

A
  • Telomeres provide terminal stability to the chromosome and ensure its survival
  • The ends of broken chromosomes are sticky, whereas the normal end is not sticky
    o Suggests the ends of chromosomes have unique features
  • Telomeres contains tandemly repeated sequences – TTAGGGTTAGGGTTAGGG etc
  • This repeat is added to chromosomes by a complex enzyme called telomerase
  • The lengths of telomeres appear to be under genetic control and may represent a genetic clock
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13
Q

define and explain ploidy in the context of humans, elaborate on egg and sperm cells in this context

A
  • Ploidy refers to the number of the copies of the genome are present in each cell
  • In almost all humans the nucleus of each cell = 46 chromosomes
    o in females = 23 identical pairs
    o in males x is unpaired, and y is present
  • the chromosome pairs represent 2 copies of the human genome, we are thus diploid organisms
  • the only true haploid cells in humans are sperm cells
  • egg cells are functionally haploid but actually contain a total of 92 chromosomes if the polar bodies are included
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14
Q

give a brief overview of what genes we inherit and how cells divide normally

A
  • in each indiv. One copy of the genome is maternally inherited via egg, one paternally via sperm
  • gametes have 23 chromosomes each, ie one copy of the genome they are haploid
  • most human cells divide via mitosis resulting in 2 genetically identical diploid daughter cells
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15
Q

describe meiosis

A
  • in order to make sperm of egg cells in the gonad use a diff. process called meiosis resulting in haploid nuclei
  • meisosis involves 2 sequential meiotic cell divisions – MI and MII that both differ significantly from mitotic cell division
  • prior to the first meiotic cell division extensive recombination of DNA occurs between homologous chromosomes (ie the identical paternally and maternally inherited chromosomes)
    o thus recombined chromosome present in the gamete is a combination of material from the maternally and paternally derived chromosome pair
    o this recombination is an essential component of evolution and is the origin of almost all human genomic disorders
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16
Q

define aneuploidy and what it results in in humans

A
  • the term euploidy is used to describe the normal balanced state of ploidy in an organism
    o aneuploidy describes the deviation of the euploid state
  • some regions of genome can tolerate copy number variation but significant deviation from the standard diploid (2n) genome of a cell is almost always deleterious to an organism
  • aneuploidy in humans usually results of errors in meiosis resulting in either numerical or structural chromosomal abnormality
  • relatively common in humans occurring in
    o ~20% of preimplantation human embryos
    o 50% of spontaneously aborted pregnancies
    o ~6% of stillborn infants
    o 0.9% in livebirths
    o In ~6% of children
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17
Q

how do we detect aneuploidy

A
  • Modern clinical analysis of chromosome structures uses DNA-based techniques, particularly array-based methods
    o which provide a vv high resolution method for detecting genomic copy number variation (aneuploidy) using DNA probes that are immobilised onto a glass surface
    o whole genome sequencing is being increasingly used to identify aneuploidy
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18
Q

at what stages do numerical chromosomal abnormalities happen, what different versions of this mutation can occur

A
  • are the most frequently observed forms of aneuploidy
  • they can result of non-disjunction events in
    o MI > failure of homologous chromosome pair separation
    o MII > failure of sister chromatid separation
    o Mitotic divisions that follow fertilization > post zygotic non-disjunction
  • Most commonly involved in gain or loss of a single chromosome
    o Results in trisomy or monosomy
  • Is abnormality seen in every cell it is called constitutional
  • If it’s only a proportion of cells it is known as mosaic
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19
Q

what are the most common cause of aneuploidy via chromosomal abnormalities - what are the 2 genetic mechanisms behind these mutations

A
  • Aneuploidy that is caused by chromosome abnormalities is most commonly loss or gain of contiguous segments of genomic DNA – deletions and duplications
  • There are 2 important genetic mechanisms that can result in deletions and duplications
    o Both are related to meiotic recombination…
     Non-homologous end joining (NHEJ)
     Non-allelic homologous recombination (NAHR)
    • The boundaries of NHEJ structural chromosome anomalies are essentially random whereas NAHR targets specific regions of the genome
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20
Q

describe haploininsufficiency

A
  • Used to describe the situation where one copy of normally diploid genes is insufficient to allow development to proceed normally or health or homeostasis to be maintained
    o Only have the total level of a gene product is produced by a cell leading to abnormal cell function
  • It is most commonly used to describe diseases where the phenotype associated with deletion of the entire gene is identical, or vv similar, to that associated with an intragenic loss of function mutation affecting one copy of the gene
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21
Q

what is a balanced structural chromosome abnomalies

A
  • Structural chromosome anomalies that change the order of sequence in the genome without altering the copy no. are known as balanced structural chromosome anomalies
  • These anomalies are almost always a result of NHEJ during meisosis
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22
Q

what are the different types of balanced structural chromosome anomalies and are they harmful in general

A
  • If change in order occurs within a chromosome it is known as an inversion
  • If they occur between non homologous chromosomes they are known as balanced reciprocal translocations
  • Robertsonian translocations arise from NAHR fusing 2 of the 5 chromosomes with vv similar, highly repetitive sequences on their short arms
    o Robertsonian translocations affect chromosomes 13, 14, 15, 21 or 22
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23
Q

are balanced structural chromosome anomalies dangerous?

A
  • Balanced inversions and translocations are mostly not associated with disease unless one of the breakpoints has interrupted a haploinsufficeint disease gene

However
- When the carrier of a balanced translocation makes gametes there is a high risk on an unbalanced results due to the requirement to pair structurally unusual and normal chromosomes

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24
Q

WAGR syndrome - features and what genes affected

A
  • Wilms tumour, anirida, genitourinary anomalies, mental retardation
  • Gene PAX6 and WT1 is affected in a deletion mutation of both genes causing striking combination of abnormalities
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25
Q

describe an interstitial deletion

A
  • Occur within one arm of the chromosome

- If you lose a section in the middle of the chromosome the 2 free ends will join > non-homologous end joining

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26
Q

describe a terminal deletion

A
  • End of the strand is lost during cell division as this fragment does not have a centromere
  • This end doesn’t join with anything else but the telomerase will repair it.
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27
Q

NON-HOMOLOGOUS END-JOINING gene syndromes commonality between them. give examples

A
  • Recognised via phenotypes as a result of haploinsufficiency for one or more high-penetrant genes
  • Breakpoints in these deletions are essentially random so people have different mutations
  • some specific individual genes in a region can have strong effects on the phenotype if there are lost making it possible to diagnose patients clinically

cri du chat syndrome > 5p15
WAGR syndrome > 11p13

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28
Q

explain non-homologous end-joining between chromosomes and what are their effects

A
  • With double stranded breaks you can also get an abnormality caused by non-homologous end joining between different chromosomes
  • Eg if chromosome A and B are near each other and both have double stranded breaks and there’s errors in the normal homologous recombination repair = section of chromosome B joined onto chromosome A, and part of A joined onto chromosome B
    o Doesn’t cause issues by itself because you still have all the genetic material
    o But can cause issues with meiosis
    o Known as RECIPROCAL TRANSLOCATION
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29
Q

balanced reciprocal translocation problems

A
  • Major problem isn’t in individuals carrying these mutations but more in their reproductive health as they can pass it on
  • Problems arise if normal chromosome is combined with mutated chromosome
  • So that you have ½ a copy of one chromosome and 1 ½ copies of another chromosome
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30
Q

describe how a balanced reciprocal translocation would affect a family

A
  • 1st generation has balanced translocation and grandfather doesn’t
  • 2nd generation have inherited the balanced translocation

3rd generation have inherited unbalanced translocation…EG
- one child is missing a fragment of A chromosome (monosomic for the fragment of the chromosome)
 And trisomic for the fragment of the reciprocal B chromosome
 Leads to issues eg learning difficulties, epilepsy etc

another child has inherited the whole A chromosome but missing fragment of B chromosome
 Trisomic for the A chromosome
 Monosmic for region of B chromosome
 Leads to brain abnormality, learning difficulties etc

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31
Q

what is a denovo reciprocal translocation

A
  • A random translocation that the parents don’t have
  • Gene can be specifically interrupted by a reciprocal translocation
  • Most often the first time the translocation occurs during meiosis in the parents when making the gametes
32
Q

explain non-allelic homologous recombination

A

non-allelic genes are genes that don’t show any major characteristics

they are are segments called low copy tandem repeats

  • they tend to be quite long and they’re identical between homologs
  • these have high sequence similarity but they’re not alleles

if these low tandem repeat areas pair with the wrong part of the corresponding homolog this can lead to recombination between 2 non-allelic homologs which can lead to micro deletions and duplications

33
Q

what chromosomes can non-allelic homologous recombination occur between and why

A
  • Only occurs between specific chromosomes called acrocentric chromosomes
    o Chromosomes 13, 14, 15, 21, 22
    o This is because their centromeres are at the end of their chromosomes
    o Other chromosomes (metrocentric) in boundary functions have their centromeres roughly in the middle
  • Acrocentric chromosomes have very distinct short arms giving them a specific appearance down the microscope
    o this is because the short arms of acrocentric chromosomes are factories for producing ribosomes
34
Q

what is a robertsonian translocation and what are its effects on the person at hand

A
  • Short arm of one acrocentric chromosome has fused with a different acrocentric chromosome so 2 acrocentric chromosomes becomes stuck together
    o So instead of 46 you have 45 chromosomes
  • still have all the genetic information but in a different combination
  • occurs as a non-allelic homologous recombination in meiosis with DNA breakage and mis repair
  • if mutation is balanced = no problems but maybe infertility
  • suggests that losing a reasonable amount of ribosomal genes itself isn’t an issue as long as it’s on acrocentric chromosomes
35
Q

what are the problems you can face with a robertsonian translocation

A

problems can occur in Robertsonian translocations during meiosis leading to unbalanced translocations in offspring
- homologous pairing happens in an unusual way = 3 non-identical chromosomes pairing

In MI during segregations can create a balanced translocation where there’s a full set of genetic info in each daughter cell
OR
unbalanced forms where the Robertsonian translocation and another chromosome gets dragged into one daughter cell = too much info (trisomy) and only one chromosome into another cell = too little info (can be in diff variations)

36
Q

what is the general anatomy of a gene

A
  • Gene is transcribed
  • Transcribed RNA goes through post-transcriptional modifications to produce a mature mRNA
  • Which is transported to the Golgi apparatus and translated to a protein
    o Each 3 nucleotides of mRNA makes up a codon sequence
37
Q

what is the pathogenic mutation criteria

A
  • Does it affect the function of the protein
  • It is in a conserved region of the protein
  • Does it co-segregate with the disorder in the family
  • Is the change seen in the normal population
38
Q

types of mutations in DNA sequences

A

Deletions
- Ranges from 1bp (basepair) or megabases

Insertions

  • Ranges vary can be as small as 1bp up to megabases
  • Duplication and

inversions
Single base pair substitutions (point mutations)

Frameshifts
- Caused by deletions, insertions or splice site errors

Dynamic Mutations
- Tandem repeats

39
Q

what are the 2 types of point mutations

A

Synonymous mutation

  • Changes a codon into another that specifies the same amino acid as the original codon
  • Due to redundancies within genetic code

Nonsynonymous
- Changes codon into another that specifies a different amino acid to that of the original codon

40
Q

what are the types of point mutations

A 
Missense mutations
-	Replace one amino acid with another
Nonsense mutations
-	Replace an amino acid codon with a stop codon
Splice site mutations
-	Create or destroy splicing signals
41
Q

explain the effects of missense mutations with examples of effects on aminoacids

A

conserved or non-conservative change in amino acid
Meaning…
- Has there been a change in polarity and/ or hydrophobicity of the amino acid present

Eg
- If valine is changed to leucine, both are similar sized and hydrophobic = prob no destruction = conservative change
However
- If valine changed to arginine, they are different sizes and hydrophobicity = destruction = non-conservative change

42
Q

what is the Grantham matrix

A
  • Method in calculating the significance of the amino acid substitution
  • The bigger the score the more likely that the missense mutation has caused a change in the resultant protein structure
43
Q

splice-site mutations - where do they occur and what are the 2 variations

A
  • 4 nucleotides at the start and end of intron is highly conserved across species
  • Therefore, mutation occurring in these 4 nucleotides = abnormal splicing
  • Nucleotides on either side of these 4 nucleotides are also conserved to a certain manner so disruption of these nucleotides can also cause an alteration in splicing

Introns are normally spliced out and exons retained when mRNA are made

Introns may be retained via…

  • If there’s mutations in splice donor site, the post transcriptional mechanism fails to recognise the start of the intron leading to failure to splice that intron
  • Gives rise to mRNA with inclusion of said intron
  • Introns can be extremely large so in this situation protein translation can be affected = abnormality

Exons may be excluded via…

  • If there’s a mutation in the splice receptor site, the post transcriptional mechanism fails to recognise the ending of the intron and splices material that’s actually exons
  • Leads to exons between to splice donor sites be excised
44
Q

what are the 4 ways in which mutation can cause disease

A 
MUTATION CAN CAUSE DISEASE BY…
1-	Loss of function (abolition) of gene product
2 - haploininsiffuicienyc
3 - dominant negative
4 -	Modification of gene product
45
Q

loss of function, haploinsufficiency and dominant negative explain and examples

A

Due to non-functioning or truncated protein
- Usually due to intragenic mutations
o Marfan syndrome, Duchennes muscular dystrophy

Haploinsufficiency
- Usually refer to submicroscopic chromosomal deletions
o William syndrome

Dominant Negative
o Collagen disorders, deafness syndromes

46
Q

explain disease manifestation in terms of dominant vs recessive conditions

A

Threshold for dominant conditions - >50%
- So with loss of one gene dominant conditions will manifest

Threshold for recessive conditions - <50%
- So they only manifest if both copies of the gene are lost

47
Q

explain dominant negative mutations

A

Special class of loss of functions

  • Mutation produces a non-functioning protein
  • The non-functioning protein interferes with the protein of the normal functioning homologous gene
  • Resulting in no effective gene product
48
Q

what are the variations of modification of gene product and give clinical examples for each

A

Creating a poorly functioning protein
- Beckers muscular dystrophy
Abnormal activation of protein (overexpression)
- Cancer genes
Gain of function of protein (novel function)
- Huntington disease, cancer genes (Philadelphia chromosome-fusion protein)

49
Q

general 2 types of testing

A

Direct testing
- The DNA from a consultand is tested to see whether or not it contains a given pathogenic mutation
Indirect testing (gene tracking)
- Linked markers are used in family studies to discover if the consultand inherited the disease carrying chromosome/ allele from a parent

50
Q

polymerase chain reaction (PCR)

A
  • Very efficient at amplification of template DNA to yield products for analysis
  • DNA can be extracted from various sources – blood, mouthwash, tissue specimen
  • Only requires small amounts of patient genomic DNA
  • Best at amplifying small specific segments of DNA
51
Q

explain DNA amplification by PCR

A
  • Requires knowledge of targeted sequence
    o To be able to design primers for amplification of target DNA
  • Specificity is dictated by 2 short (~25 bases) synthetic single stranded DNA molecules or oligonucleotides (primers)
  • Mis-priming
    o Amplification of none target DNA
  • Preferential amplification of normal allele (PCR drop-out)
52
Q

what are the 3 mutation detection techniques and describe each one

A

Sanger sequencing
o Gold standard
o Well established and robust
o Labour intensive because one reaction is equivalent to 1 sequencing reaction
o To sequence whole gene it takes along time

Next generation sequencing (massive parallel sequencing)
o Very expensive – getting cheaper
o Produces a High volume of data
o High no. of genetic variants of unknown significance so requires sophisticated bioinformatics to actually find the mutation
o Good for multi-gene analysis

Gel electrophoresis
o Rate of DNA migration is determined by size of DNA molecule (due to DNA being negative)
o Not used a lot but vv effective
o Used in Huntington Disease

53
Q

give a brief summary of huntingtons disease

A
  • Autosomal dominant
  • 1 in 10,000
  • Neurodegenerative
  • Triplet repeat expansion
  • Onset in 3rd decade
  • Progressive deterioration of cognitive functions > dementia
  • Associated with abnormal movement
  • CAG triplet repeat
54
Q

explain the nature of the CAG triplet repeat in the normal population vs Huntingtons

A
  • CAG triplet repeat is amplified in PCR
    o gives us variable repeat sizes in the individual
    o distinct size ranges in affected HD population and normal population
    o first spike is 5CAG, other spikes are singular CAG repeats
    o normal indiv. Has 8-35 CAG repeats
     a repeat size >36 is diagnosed with HD
     alleles between 36-39 = milder/ later onset
     27-35 = pot. Unstable, can expand to more in next generation
55
Q

explain exclusion testing in relation to high risk alleles

A

Identifying high risk haplotype by link marker analysis
- Done if the indiv. Wants to know if their children will be free of the disease not just if they have it
- Use the polymorphisms around the HD gene to identify the 2 alleles that are inherited
o These are called high risk alleles event though they might not be carrying disease/ mutation
o Then you can look in the embryo to see what embryos have the high-risk allele
 However, children are only ½ risk of being carriers because not sure if the high risk allele is actually carrying the mutation

56
Q

what are the syndromes associated with a mutation in fibroblast growth factor receptor 2 FGFR2

A

craniosynostosis
- premature closure of sagittal or coronal fissures between bones of skull

apert syndrome

  • polysyndactyly (mitten hands and sock feet)
  • characteristic facial features
  • craniosynostosis

crouzon syndrome

  • craniosynostosis
  • shallow orbits
  • proposis
  • risk of blindness

pfeiffer syndrome

  • severe skull deformities
  • limb abnormalities
57
Q

what conditions is associated with mutations in the TSC1 and TSC2 genes

A

TUBEROUS SCLEROSIS

  • Autosomal dominant
  • Harmatomatous lesions
  • Multisystem involvement
  • Prevelance is 1 in 6000
  • 2/3 sporadic (new mutation)
  • 1/3 familial

also issues with…

  • skin
  • face
  • renal
  • cardiac
  • eyes
  • CNS
58
Q

what is the general structure of antenatal care provided

A
  • GP appointment following positive pregnancy test
  • Booking appointment with midwife 7 – 10 wks including dating US scan and haemoglobinopathy screening
  • First trimester screening offered for T21, T13, T18 at 11-14 wks
  • If late booker second trimester screening offered for T21 at 14-18 wks
  • Detailed second trimester US scan
59
Q

what are the odds of a mum being a carrier when their son has DMD

A

2/3rds of mothers of boys with DMD are carriers. This is reduced to ½ if they have an unaffected son

60
Q

chronic villus sampling

A

o Outpatient procedure
o 10-12 weeks gestation
o Miscarriage risk 0.5%
o Transabdominal under US guidance

61
Q

foetal sexing with maternal blood -

A

o Used in x-linked conditions
o 5-10% of total cell free foetal DNA is in maternal plasma
o Originates from trophoblasts
o Detectable 4-5wks then levels increase
o Vv small fragments – cleared rapidly after delivery (means prev. pregnancies don’t affect results)
o If foetal DNA sample contains SRY (a marker in the y chromosome) then baby is male

62
Q

cell free foetal DNA

A

o Challenges of non-invasive foetal sexing
 Technically difficult
• Vv low DNA concentrations
• High levels of maternal DNA background
 Reliable detection of cffDNA only poss. From ~9 wks gestation – confirm by scan
 Not applicable in twin
 Samples need to be extracted and transported quickly into lab

63
Q

preimplantation genetic diagnosis

A

o Uses IVF and analyses each embryo that is conceived in IVF
 Embryo is biopsied via cells being removed and genetically tested
o Allows us to test what embryo is affected and then can use an unaffected embryo to implant in the woman’s womb

PGD - Genetic testing by haplotyping is used too

64
Q

criteria to receive NHS funded PGD

A
  • Known genetic condition which conveys ‘significant risk”
  • No living unaffected child as a couple
  • Female age <39 yrs at referral
  • Anti-Mullerian hormone (AMH) > 7.5 or antral follicle count > 8
  • Female BMI < 30
  • Both partners non-smokers for > 3 months
  • Couple living at same address for > 2 yrs
  • Both partners must be eligible for NHS treatment
65
Q

neural tube defects - spina bifida

A
  • Neural tube closure occurs early in pregnancy – from cervical spine distally day 18-28
  • Outcome varies from spina bifida to anencephaly
  • Incidence 1/300 N. Ireland – 1/1000 USA
  • Polymorphisms in MTHFR
  • Mostly multifactorial but can be syndromic, chromosomal or tetratogen-induced
66
Q

whats the reoccurrence rates of neural tube defects and how to reduce risk

A
  • If couple has one affected child > inc. chance in future (5%)
  • Recurrence risk can be dec. by high dose folic acid
  • Pre-conceptual folic acid important for all women – 400mg 2 months prior to conception and up to 12 wks of pregnancy
67
Q

screening for downs syndrome, edward’s syndrome, and patau’s syndrome

A
  • first trimester screening offered 11-14 wks (nuchal translucency, hCG, PAPP-A)
    o pos. predictive values 13.3% negative predictive values 99.95%
  • second trimester screening offered to late bookers for T21 between 14-20 wks (hCG, AFP, inhibin A, unconjugated Estriol)
    o positive predictive values 2.3% neg pred. value 99.8%
68
Q

Down Syndrome clinical findings and calculating likelihood from these

A
  • low AFP/ PAPP-A MoM
  • Raised mCG MoM
  • Increased nuchal translucency

These factors are used to calculate a likelikood of if this pregnancy is affected by downs syndrome

  • If the chance is higher than 1/150 considered to be high risk
  • Choices at this point is an NIPT, amniocentesis or chronic villus sampling or no further testing and instead opt for a second trimester US scanned
69
Q

NIPT

A

non-invasie prenatal testing

  • Uses cffDNA
  • Non-invasive = no risk of miscarriage
  • Not diagnostic
  • In higher chance (> 1 : 150) population has positive predictive values
    o 91.3% for trisomy 21
    o 84% for trisomy 18
    o 87% for trisomy 13

Potential problems…

  • Confined placental mosaicism
  • Maternal malignancy
  • Maternal chromosome anomalies
  • Vanished or demised twin
  • Blood transfusion or transplant in last 4 months
70
Q

amniocentesis

A
  • Performed 15 wks gestation
  • 15-20mls amniotic fluid
  • Small risk of membrane rupture
  • Associated miscarriage rate 0.5%
  • Rapid aneuploidy screen for trisomy 21. 13 and 18
71
Q

QF-PCR

A

Quantitative fluorescence polymerase chain reaction

  • Amplification of chromosome-specific short tandem repeats (STRs)
  • Sample DNA is amplified by PCR using fluorescent primers
  • Products can be visualised and quantified as peak areas of the respective repeat lengths
72
Q

TRISOMY 21 - occurence, recurrence and causes

A
  • 1 in 650 births
  • Maternal age effect
  • Risk > population risk by mid 30s
  • Recurrence risk is 1 in 100 or twice the risk for age if due to non-disjunction (~95%)
    o Can also occur through
     Mosaicism
     Robertsonian translocation (between chromosome 21 and usually 14 in this case there’s a higher recurrence risk – 12% if mother carries translocation, 3% if father does)
    o Therefore, full karyotype is needed to measure recurrence risk
73
Q

what is allelic heterogeneity

A
  • The same disease phenotype is often caused by different mutations in the same gene, this is an example of Allelic Heterogeneity.
74
Q

what is locus heterogeneity

A
  • The same disease phenotype can be caused by mutations in different genes, this is locus heterogeneity.
75
Q

what factors make a mutation more likely to cause a genetic disease

A
  • It can be demonstrated to have an effect on protein production or function
  • It is present in all the affected individuals in a family.
  • It is in a conserved region of the protein.
  • It does not occur as a population polymorphism.
  • Unknown mutations can be detected by different screening techniques, including SSCP, Heteroduplex detection and Sequencing.
  • Known mutations can be detected using different techniques, including RGPCR and ARMS.
76
Q

explain linkage and its limitation

A
  • When two loci are close together on the same chromosome, so that the chance of crossing over between the two loci at meiosis is less than 50%, they are said to be linked.
  • Polymorphisms whose location in the genome are known, can be used as markers for linkage.
  • Linkage analysis allows location of unknown disease genes. It also allows tracking of a disease of known location through a family. It is not necessary to know the mutation in the gene for this, just the location of the gene involved. Locus heterogeneity, however, limits the application of this technique.

· Linkage is only useful for tracking disease in a family where markers are informative and phase can be determined.

YEAR 2 SEMESTER 2 (14 decks)

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