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Phase 1 > IMMS - Genetics > Flashcards

IMMS - Genetics Flashcards

1
Q

What are the 3 classes of things that can cause disease?

A
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2
Q

What are some examples of diseases caused by genetics, multifactorial and environmental?

A
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3
Q

What is the genotype?

A

Genetic constitution of an individual

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4
Q

What is a phenotype?

A

Appearance of an individual (physical, biochemical, physiological) which results from the interaction of the environment and genotype

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5
Q

What is an allele?

A

-One of several alternative forms of a gene at a specific locus
-Normal allele (non-mutated) - wild type
-Mutated diseased allele carries a pathogenic variant

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6
Q

What is polymorphism?

A

Frequent hereditary variations at a locus

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7
Q

What is genomics?

A

Study of the entirety of DNA, the genome, together with the technologies which allow sequencing, interpretation and analysis

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8
Q

What is a gene?

A

A segment of DNA that contains the biological instructions for a particular polypeptide, usually a specific protein or component to a protein

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9
Q

What is a pathogenic variant?

A

An alteration in a genetic sequence that increases an individual’s susceptibility or predisposition to a certain disorder

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10
Q

What is a benign variant?

A

An alteration in genetic sequence which is not disease-causing

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11
Q

What is a variant of unknown significance?

A

An alteration in a genetic sequence whose association with disease is unknown

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12
Q

What is a secondary (incidental) finding?

A

Results which provide information about variants which are unrelated to the primary reason or clinical indication for testing

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13
Q

What is an additional looked-for finding?

A

-Results that provide info about variants unrelated to clinical indication for testing
-Patient opts in and consents
-Tend to be conditions with significant health implications, clinical course can be altered by screening and/or risk-reducing measures

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14
Q

What is penetrance?

A

The proportion of individuals with a particular genotype who express the associated phenotype/ develop the condition

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15
Q

What is diagnostic testing?

A

Genomic/ genetic testing in someone affected with features of a condition to aid diagnosis

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16
Q

What is predictive testing?

A

Genomic/ genetic testing in an unaffected individual, specifically for a pathogenic variant known to be present in the family member

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17
Q

What do homozygous and heterozygous mean?

A

-Homozygous - both alleles the same at a locus
-Heterozygous - alleles at a locus are different

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18
Q

What does hemizygous mean?

A

Only one allele - refers to a locus on an X chromosome in a male

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19
Q

What is ACMG criteria?

A

Formal scoring system to decide if a gene variant is ‘pathogenic’

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20
Q

What are the statistics around recognising rare disease in primary care?

A

-Affects fewer than 1:2000 people
-Collectively 1:17 people in the UK have a rare disease
-Around 10,000 rare diseases
-100 diseases account for 80% of rare disease patients

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21
Q

What is primary care action for a rare disease?

A

-3 generation family tree
-Use symptoms to search diagnostic tools (phenomizer)

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22
Q

How can you recognise rare diseases in primary care? (GENES)

A

-G - group of congenital anomolies
-E - extreme presentation of common conditions (very early onset IHD, recurrent miscarriage)
-N - neurodevelopmental delay or early onset neurodegeneration
-E - extreme pathology
-S - surprising laboratory values (very high cholesterol)

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23
Q

What are some general red flags for rare diseases?

A

-Young age of onset
-Multiple generations
-Unusual symptoms
-Unusually severe
-Developmental delay
-Epilepsy
-No environmental risk factors
-Bilateral disease in paired organs

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24
Q

What are 3 cardiac red flags for rare diseases?

A

-Young age onset
-Sudden unexplained deaths
-Multiple affected relatives

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25
Q

What are the 3 classifications of genetic disease?

A

-Chromosomal
-Mendelian
-autosomal dominant
-autosomal recessive
-X-linked
-Non traditional
-mitochondrial
-imprinting
-mosaicism

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26
Q

What are 3 types of mendelian genetic diseases?

A

-Autosomal dominant
-Autosomal recessive
-X-linked

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27
Q

What are 3 types of non-traditional genetic diseases?

A

-Mitochondrial
-Imprinting
-Mosaicism

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28
Q

What does this show?

A

Metaphase spread

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29
Q

How would you describe this?

A

-47, XY, +21
-Downs syndrome

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30
Q

How would you describe this?

A

-Normal female
-46, XX

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31
Q

What is autosomal dominant inheritance?

A

Disease which manifest in the heterozygous state

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32
Q

What does this show?

A

Autosomal dominant inheritance

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33
Q

What are the ratios of offspring for autosomal dominant inheritance?

A

-50% affected
-50% unaffected

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34
Q

What kind of inheritance does this pedigree show?

A

Autosomal dominant inheritance

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35
Q

What is autosomal recessive inheritance?

A

Disease which manifests in homozygous state

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36
Q

What does this show?

A

Autosomal recessive inheritance

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37
Q

What are the offspring ratios for autosomal recessive inheritance?

A

-25% - not affected/not carrier
-50% - not affected/carrier
-25% - affected

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38
Q

What is X-linked recessive inheritance?

A

Caused by pathogenic variants in genes on the X chromsome

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39
Q

What does this show?

A

X-linked inheritance

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40
Q

What are the offspring ratios for X-linked inheritance?

A

-25% - female/not carrier
-25% - female/carrier
-25% - male/not affected
-25% - male affected

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41
Q

What does this show?

A

Mitochondrial DNA

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42
Q

What does this pedigree show and why?

A

-Mitochondrial inheritance
-Can only be passed on from mother as all mitochondria in foetus are sourced from mother

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43
Q

What could this show?

A

-Non-paternity
-New dominant variant
-Gonadal mosaicism

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44
Q

What is a multifactorial disease?

A

-Due to a combination of genetic and environmental factors
-Most common diseases are multifactorial

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45
Q

How do you identify that a condition has a genetic component?

A

-Clinical observation:
-Family studies
-Twin studies
-Adoption studies

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46
Q

What are genetic family studies?

A

Compare the incidence of a disease amongst the relatives of an affected individual with the general population

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47
Q

What 4 things of family studies relates to multifactorial conditions?

A

-Risk of a condition in relatives of affected individual is dramatically higher than gen pop
-Risk varies directly with degree of genetic relationship
-Risk varies with severity of proband’s illness
-Risk varies with number of relatives affected

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48
Q

What are twin studies?

A

-Compare genetically identical (MZ) with genetically non-identical (DZ) twins
-Concordance rate is the % of twin pairs studied that both have the condition
-If a condition has a genetic component you would expect higher concordance rate in monozygotic twins than dizygotic twins
-High risk for MZ twins is found even when they are reared apart

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49
Q

What does concordance rate show?

A

Can give a rough figure for the heritability of a multifactorial disorder

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50
Q

What are adoption studies?

A

-Adopted children of parent with multifactorial disease have high risk of developing disease
-Compare above group with group of adoptees of normal biological parents and an adoptive parent with condition - low risk
-Look at adoptive individuals with condition and rates of that condition is biological and adoptive families - high only in biological families

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51
Q

What is hereditability?

A

Proportion of aetiology that can be ascribed to genetic factors as opposed to environmental factors

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52
Q

How can you calculate and express hereditability?

A

-One way to calculate is from the concordance rate in monozygotic twins
-Expressed as a proportion of 1 or as a percentage

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53
Q

What are 3 characteristics of multifactorial inheritance?

A

-Incidence of condition is greatest amongst relatives of most severely affected patients
-Risk is greatest for first degree relatives and decreases rapidly in more distant relatives
-If there is more than one affected close relative then risk for other relatives is increased

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54
Q

What does this show?

A

-Characteristic of multifactorial disease
-If a condition is more common in one particular sex, relatives of an affected individual of less frequently affected sex will be at higher risk than relatives of an affected individual of the more frequently affected sex

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55
Q

What does this show?

A

-The liability/threshold model
-Curve for relatives shifts to the right, increasing risk

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56
Q

What is the liability/threshold model?

A

-Factors that influence development of a multifactorial disorder (genetic + environmental) can be considered as a single entity = LIABILITY
-Liabilities of all individuals form continuous variable which has a normal distribution

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57
Q

How does liability distribution change for relatives?

A

-Curve for relatives is shifted to the right compared to the general population
-Closer the relationship, greater the shift to the right
-Familial incidence is the proportion of people beyond the threshold

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58
Q

When is the abnormal phenotype expressed in the liability model?

A

-Threshold exists above which the abnormal phenotype is expressed
-In the general population, proportion beyond the threshold is the population incidence
-In relatives, proportion beyond the threshold is the familial incidence

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59
Q

What is GWAS and what are they used for?

A

-Genome wide association studies
-Used to work out what the genetic component of a condition once one has been established

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60
Q

What does GWAS utilise?

A

-Utilises fact that gene can have several alleles
-Some alleles in a gene can be inactivated or behave abnormally - pathogenic
-Most genetic variation still results in functioning gene - polymorphisms
-Different types of polymorphisms exist:
-SNP
-Differing lengths of CA repeat

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61
Q

How does GWAS work?

A

-Compare frequency of markers in a sample of patients and in healthy controls
-Can use candidate genes nowadays to try and aim for complete genome coverage
-Look for markers (e.g. SNP seen more frequently in disease population)
-Sequence that area to try and identify gene and particular allele that is associated with the increased likelihood of developing condition

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62
Q

What 4 environmental factors can act on embryogenesis?

A

-Drugs and chemicals (thalidomide, alcohol, anticonvulsants)
-Maternal infections (rubella, CMV)
-Physical agents (radiation)
-Maternal illnesses (diabetes)

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63
Q

What are 4 post-natal environmental factors?

A

-Obesity - Type 2 diabetes
-Hormonal factors (the pill, HRT, parity, breast feeding, obesity) - Breast cancer
-Smoking - Lung cancer
-Recreational drugs - Schizophrenia

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64
Q

What could you do by analysing thousands of variants of genetic diseases for an individual?

A

Identify the conditions an individual has an increased risk for

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64
Q

What could you do by analysing thousands of variants of genetic diseases?

A

Identify the conditions an individual has an increased risk for

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65
Q

What 3 things could genome sequencing tell you about a person?

A

-Carrier status - find out if children are at risk for inherited conditions, plan health of family
-Health risks - understand genetic health risks, change and manage what you can
-Drug response - arms doctor with information about how you might respond to certain medication

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66
Q

What does this show?

A

Cell cycle

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67
Q

What cell types can you culture for genetic testing?

A

-Blood - T lymphocytes
-Skin/umbilical cord/placenta
-Bone marrow
-Solid tumour
-Amniotic fluid/chorionic fluid

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68
Q

Label this diagram:
What does it show?

A

Sampling and processing for karyotyping

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69
Q

What phases of the cell cycle does the right and left show?

A
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70
Q

What is a karyotype?

A

An individuals complete set of chromosomes

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71
Q

What is an ideogram?

A

-A graphical representation of chromosomes
-Genetic information location

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72
Q

What is the nomenclature of chromosomes?

A

-ISCN - International System of Chromosome Nomenclature
-46, XX
-46, XY

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73
Q

What are 3 numerical chromosomal abnormalities?

A

-Trisomy - 47,XX,+21
-Monosomy - 45,X
-Polyploidy - 69,XXY

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74
Q

What are 4 structural chromosomal abnormalities?

A

-Translocation - t(1;2)(q24;p12)
-Inversion - inv(7)(q11q21)
-Duplication - dup(11)(p14p15)
-Deletions - del(22)(q11q12)

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75
Q

Label the number of copies per cell of successful meiotic disjunction:

A
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76
Q

What does this show?

A

Non-disjunction at meiosis II

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77
Q

What does this show?

A

Non-disjunction at Meiosis I

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78
Q

What does this show? (karyotype)

A

47, XX, +18

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79
Q

What does this show?

A

47, XX, +13

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80
Q

What do each of these show?

A

Sex chromosome abnormalities

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81
Q

What does this show?

A

Triploid karyotype

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82
Q

what does this show?

A

The iceberg of chromosomal pregnancy loss

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83
Q

What does this show?

A

-Reciprocal translocation
-All the genetic info is there but in a different arrangement

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84
Q

What does this show?

A

Segregation of a 2/18 translocation

85
Q

What does deletion of 15q cause?

A

Prader Willi/Angelman syndrome

86
Q

What is F.I.S.H?

A

-Fluorescent in situ hybridisation
-Use DNA probes labelled with fluorophores
-hybridised directly to chromosome preparation or interphase nuclei

87
Q

How is F.I.S.H used in cytogenetics?

A

-Can ‘count’ chromosomes in interphase nuclei
-Look for submicroscopic deletions using locus-specific probes
-Interpret abnormalities more clearly
-Look for specific rearrangements such as gene fusions

88
Q

What is used here and what does it show?

A

-F.I.S.H
-Trisomy 21

89
Q

What are microarrays?

A

-New technology
-Improves resolution for detecting cytogenetic abnormalities
-G-band resolution 5-10Mb
-Microdeletions can be 3Mb
-Arrays can have resolution <1Mb (200kb) = BETTER

90
Q

Label this diagram:
What does it show?

A

Microarray basic protocol

91
Q

What does this show?

A

CGH array profile

92
Q

What does this show?

A

Chromosome 1 microdeletion

93
Q

Why is microarrays an expanding field?

A

-As patients are screened by microarrays, contributing to a database of cytogenetic and phenotypic abnormalities
-‘New” microdeletion/duplication syndromes are being proposed

94
Q

What are the 3 difference between constitutional and acquired abnormalities?

A
95
Q

What is the clinical role of cytogenetics (4)?

A

-Confirmation of malignancy
-Classification of a disease type
-Prognosis
-Monitoring

96
Q

What are 5 features of non-random changes?

A

-Close association with disease sub-type
-Association with clinical feature
-association with lineage
-No specific association
-Apparent multiple association

97
Q

What are fusion/hybrid genes?

A

-Breakpoints occur within the two genes involved
-Fusion creates a hybrid gene which gives rise to a chimaeric protein

98
Q

What is deregulation?

A

-Relocation of genetic material can bring gene under influence of a new regulation gene
-Juxtaposition of gene to a regulating gene
-Altered regulation can result in increased transcription and neoplastic growth

99
Q

What 6 classes can constitutional abnormalities be?

A

-Prenatal
-Postnatal
-Numerical
-Structural
-Balanced
-Unbalanced

100
Q

What are 3 categories of genetic disorder?

A

-Chromosome abnormalities
-Single gene disorders
-Multi-factorial and polygenic disorders

101
Q

Label this diagram of common structural anomalies in clinical cytogenetics:

A
102
Q

How is DNA packaged?

A

-DNA winds around histones to form nucleosome
-Nucleosomes pack to form chromatin
-Chromatin condenses to form chromosome

103
Q

What are the 3 underlying Mendel principles of genetics?

A

-Segregation
-Dominance
-Independent assortment

104
Q

What is Mendel’s dominance law?

A

-Every gene has 2 alleles that code for a trait
-In heterozygotes, one allele is dominant meaning it will always show
-One is recessive and is masked by the dominant allele

105
Q

What is Mendel’s law of segregation?

A

-Allele pairs separate randomly from each other during meiosis
-Each cell has a single allele for each trait

106
Q

Describe Mendel’s law o independent assortment:

A

Traits are transmitted to offspring independently of one another

107
Q

What are 2 classes of mendelian inheritance?

A

-Autosomal and sex-linked
-Dominant and recessive

108
Q

What are 4 classes of non-mendelian inheritance?

A

-Imprinting
-Mitochondrial inheritance
-Multifactorial
-Mosaicism

109
Q

What does this show and what do the symbols mean?

A

Pedigree diagram

110
Q

What is an autosome?

A

Any chromosome (other than sex chromosomes) that occurs in pairs in diploid cells

111
Q

What does recessive mean?

A

Manifest only in homozygous

112
Q

What is an allele?

A

One or more alternative forms of a gene at a given location (locus)

113
Q

What is homozygous?

A

-Presence of identical alleles at a given locus
-Homozygotes affected

114
Q

What is heterozygous?

A

-Presence of two different alleles at a given locus
-Heterozygotes are unaffected and are usually referred to as carriers

115
Q

What is allelic heterogeneity?

A

-Different mutations within the same gene result in the same clinical conditions
-CF an example
-Individual with autosomal recessive condition may be a compound heterozygote for two different mutations

116
Q

What is a compound heterozygote?

A

Different variants of the same disease cause the disease

117
Q

What is autosomal recessive inheritance?

A

Disease manifest in the homozygous state

118
Q

what are 3 typical features of autosomal recessive inheritance?

A

-Males and females affected in equal proportions
-Affected individuals only in a single generation
-Parents can be related

119
Q

What is it called when there is repoducitve union between two relatives?

A

Consanguinity

120
Q

What is the commonest autosomal recessive condition affecting northern European population?

A

Cystic Fibrosis

121
Q

What does cystic fibrosis affect?

A

-Mainly lung and gut
-Variable presentation

122
Q

What is the genetics behind Cystic Fibrosis?

A

-CFTR gene on 7q31.2
-Over 1000 mutations
-F508 commonest mutation
-Standard carrier testing detects top 29 mutations

123
Q

What testing is done for CF?

A

-Sweat testing remains diagnostic test
-Neonatal screening programme for IRT (indirect marker)

124
Q

What is the risk of Mary and John’s baby having CF?

A

Chance Mary is carrier x chance John is carrier x risk of affected child if both carriers
-1/2 x 1/25 (population carrier frequency) x 1/4 = 1/200

125
Q

What is the risk of Mary and John’s baby having CF if mary tests +ve and John -ve?

A

-Chance Mary is carrier x chance John is a carrier x risk of affected child if both carrier
-1 x 1/250 x 1/4 = 1/1000
-john does not have 0% as test only detects 90% of mutations

126
Q

What are the genotype-phenotype correlations in cystic fibrosis?

A

-Change in F508/F508 del - pancreatic insufficiency and chronic lung disease
-F508 del/ R117H - majority are pancreatic sufficient but have chronic lung disease

127
Q

What is autozygosity?

A

-Homozygosity by descent
-i.e. inheritance of the same altered allele through two branches of the same family
-Relatives who have same allele for disease
-Increased risk of recessive condition

128
Q

What does this show?

A

Consanguineous pedigree

129
Q

Label:

A
130
Q
A
131
Q

What is the risk to healthy siblings of an affected sibling being a carrier of a recessive disease allele?

A

2/3

132
Q

What mode of inheritance is this?

A

Autosomal dominant

133
Q

What is autosomal dominant inheritance?

A

-Disease manifests in the heterozygous state
-Only one affected gene needed

134
Q

What are 4 typical features of autosomal dominant inheritance?

A

-Male and females affected in equal proportions
-Affected individuals in multiple generations
-Transmission by individuals of both sexes, to both sexes
-Penetrance and variability

135
Q

What is penetrance?

A

Percentage of individuals with a specific genotype showing the expected phenotype

136
Q

What is expressivity?

A

Refers to the range of phenotypes expressed by a specific genotype

137
Q

What is recurrence risk?

A

-50% for transmission of mutation
-Depends on penetrance and expression
-Can’t predict severity of phenotype

138
Q

What is a new mutation?

A

-Self-explanatory
-De novo mutation - presents for first time in family generation (parents don’t have mutated allele)

139
Q

What is anticipation?

A

-Genetic disorder affects successive generations earlier or more severely
-Usually due to expansion of unstable triplet repeat sequences

140
Q

What is somatic mosaicism?

A

-Genetic fault present in only some body tissues
-Not present at time of conception
-if present earlier, would probably not be survivable

141
Q

What is gonadal (germline) mosaicism?

A

-Genetic fault present in gonadal tissue
-Only reproductive tissue
-No effect on health, only offspring

142
Q

What does this show?

A

Somatic mosaicism

143
Q

What could this show?

A

Gonadal mosaicism

144
Q

What is late-onset?

A

Condition not manifest at birth (congenital)
-Classically adult-onset

145
Q

What does it mean if a genetic disease is sex-limited?

A

-Condition inherited in AD pattern
-Seems to affect one sex more than another
-Equal chance of inheritance
-Different chance of expression

146
Q

What is predictive testing?

A

Testing for a condition in a pre-symptomatic individual to predict their chance of developing condition

147
Q

What does this shoq?

A

X-linked inheritance

148
Q

What is a common X-linked inherited disease?

A

Haemophilia

149
Q

What is X-linked inheritance?

A

Genes carried only on X chromosome

150
Q

What are 3 typical features of X-linked inheritance?

A

-Usually only males affected
-Transmitted usually through unaffected females
-No male-to-male transmission

151
Q

What is lyonization?

A

-X inactivation
-Generally only one of the two X chromosomes are active in each female cell (can be skewed)

152
Q

What is skewed X-inactivation?

A

-Preferntial inactivation of a X chromosome
-Generally in favour of nora=mal X chromosome
-Lower risk of x-linked disease

153
Q

What is genomic imprinting?

A

-Epigenetic phenomenon that causes genes to be expressed in a parent-of-origin-specific manner
-Epigenetic = non-genetic influence on gene expression

154
Q

What causes PWS and Angelman syndromes?

A

-Two distinct disorders
-Occur due to loss of function of specific genes

PWS - Deletion of paternal genes, absence of active paternal genes

Angelman - loss of function of maternal UBE3A due to point mutation or deletion

155
Q

Where do you inherit mDNA from?

A

Mother

156
Q

What is homoplasmy?

A

Eukaryotic cell whos copies of mitochondrial DNA are all identical (identically normal or identical mutations)

157
Q

What is heteroplasmy?

A

-Multiple copies of mtDNA in each cell
-Denote mutations which affect only a proportion of the molecules of a cell
-Level can vary between cells in the same tissue or organ, from organ to organ within a person or between individuals of the same family

158
Q

What are mitochondrial genetic disease (4)?

A

-Group o disorders caused by dysfunctional mitochondria
-Mutations in mitochondrial DNA (15%)
-Mutations in nuclear genes, whose gene products are imported into the mitochondria
-Acquired conditions caused by e.g. drugs

159
Q

What is a common example of multifactorial inheritance?

A

-Cleft lip and palate
-In many families thought to be combination of both genetic and environmental factors
-increased risk of recurrence above general population risk in future child

160
Q

What are the 4 types of testing offered for pathogenic genetic conditions in clinical genetics?

A

-Diagnostic
-Carrier
-Predictive
-Prenatal tests incl. NIPT

161
Q

What testing is usually done in private sector or forensic lab?

A

-Testing to clarify familial relationships
-E.g. paternity testing

162
Q

What testing is usually done in a forensic lab?

A

-Testing to determine identity
-E.g. genetic finger printing

163
Q

What are 7 roles of genetic testing?

A

-Confirm diagnosis
-Give info about prognosis
-Inform management
-Pre-symptomatic/predictive testing in close relatives
-Carrier testing
-Accurate recurrence risks
-Prenatal diagnosis

164
Q

What are the first 4 questions thought about in the genetic clinic?

A

-What is condition (phenotype)?
-Can a diagnosis be made clinically?
-Is genetic cause known?
-Is genetic test available?
-Service versus research test
-Not all genes known

165
Q

What are the last 3 questions to consider during the genetic clinic?

A

-What type of test?
-Diagnostic
-Carrier
-Predictive
-Is consent full and informed?
-Who else affected
-Children and adults with learning difficulties
-Any other implications?
-Employment
-Insurance

166
Q
A
167
Q

What does this show?

A

Microarray CGH

168
Q

What is Sanger sequencing?

A

-Uses PCR to amplify regions of interest
-Followed by sequencing of products
-Useful for single gene testing

169
Q

What is next generation sequencing (NGS)?

A

-High throughput or massively parallel sequencing
-Sequence whole human genome in a day
-Multi-gene panels, whole exome/genome

170
Q

What is the gold standard of gene sequencing?

A

Sanger sequencing

171
Q

Describe the differences between Sanger and NGS:

A
172
Q

How is NGS data analysed?

A

-Generates millions of short DNA fragments (reads)
-Need to be filtered for quality and aligned to reference sequence
-Reference genome
-identify variants
-Interpret variants
-Insilico tools (bioinformatics)

173
Q

What does ‘sifting through the noise’ mean in genetic testing?

A

-Every genome contains many rare, potentially functional variants
-Around 500 rare missense variants
-Around 100 loss of function variants
-Around 100 rare variants in known disease genes
-5-10 recessive disease causing mutations
-1-2 de novo coding mutations
-Sequencing errors
-In mendelian disease patients, need to find 1-2 true causal mutations

174
Q

What 3 categories do you have to interpret a genetic variation into?

A

-Pathogenic variant
-Variant of unknown significance (VUS)
-Normal variation

175
Q

What 4 things do you consider when interpreting a genetic variation?

A

-Previously reported?
-In literature?
-Present on variant or reference database?
-Type?
-Nonsense
-Frame shift
-Splice site
-Missense

176
Q

What extra work do unclassified variants require?

A
177
Q

What is the Databases of disease mutations?

A

-Drawn from literature collected over decades with variable standards
-Up until recently, no large reference database
-Many variants misinterpreted as pathogenic/causative
-New database more careful of evidence

178
Q

What are additional findings?

A

-Concern patient or research participant that may or may not have potential health implications
-Discovered during the course of a clinical or research investigation
-Beyond aims of original test or investigation

179
Q

What are 3 examples of additional findings?

A

-Non-paternity on examination of family trio
-Variant known to confer high risk of adult-onset
-Variants of uncertain clinical significance, possibly requiring further investigation

180
Q

What do you need to consider with secondary findings?

A

-Consider when and where to disclose
-Full and informed consent prior to test
-Clinical judgement

181
Q

Describe targeted panels:

A

-Select specific genes to sequence
-Less ‘noise’
-Fewer variants of uncertain significance
-Panels need to be updated

182
Q
A
183
Q

What are the pick up rates for each of these?

A
184
Q

What does this show?

A

-Transcription
-DNA to RNA

185
Q

What does this show?

A

-Splicing
-RNA to mature RNA

186
Q

How can different proteins be produced from the same genes?

A

-Alternate splicing (different introns)
-Exon shuffling (e.g. immune system) - can be moved between different genes

187
Q

What are the 3 STOP codons?

A

-UAA
-UAG
-UGA

188
Q

What is a mis-sense and non-sense mutation?

A

-Mis-sense = substitution of a base leads to one different amino acid being coded for
-Non-sense = premature STOP codon produced, different length of polypeptide produced

189
Q

What are the 7 types of DNA variants/mutations?

A

-Mis-sense variant (change of one amino acid)
-Non-sense variant (premature STOP codon)
-Expansion of trinucleotide repeats
-Duplications of genes or part of gene
-Deletions (whole gene or some exons)
-Variants within regulatory sequence (expression)
-Splice site variants (introns not spliced properly)

190
Q

How much of the genome codes for protein?

A

2%

191
Q

Describe deletion variants:

A

-1 or more base deleted not in a multiple of 3
-Whole frame-shift
-Downstream change
-Usually significant effect
-Out of frame deletion disrupts protein

192
Q

Describe splice-site variant:

A

-Affects accurate removal of an intron
-Intron is translated into protein

193
Q

Describe non-sense variant:

A

-Change codon to STOP
-Out of frame deletion produces STOP codon either at deletion site or further along
-RNA detaches from ribosome and eliminated
-Non-sense mediated delay

194
Q

Describe a mis-sense variant:

A

-Single base substitution
-Changes type of amino acid in protein
-May or may not be pathogenic
-May be polymorphism or no functional significance

195
Q

How do you distinguish a pathogenic variant from a polymorphism?

A

-Amino acid change conserved through evolution
-Disrupts active site or splice site
-Not seen in large number of normal individuals
-Previosuly seen in individuals of same condition and segregates with disease
-Functional studies show effect on protein function

196
Q

What are 3 diseases caused by trinucleotide repeat expansion?

A

-Huntington’s
-Myotonic dystrophy
-Fragile X

197
Q

What is anticipation in terms of trinucleotide repeat?

A

-Repeat gets bigger when transmitted to next generation
-Worse from generation to generation
-Symptoms develop earlier and more severe

198
Q

What is allelic heterogeneity?

A

-Lots of different variants of the same gene
-Cause the same phenotypic presentation of disease

HOWEVER - different variants in the same gene can give rise to different clinical conditions - genotype/phenotype correlations

199
Q

What is locus heterogeneity?

A

-Variants in different genes
-Give the same phenotypic presentation of clinical disease

200
Q

What are the 3 mechanisms of dominance?

A

-Loss-of-function variants
-Gain-of-function variants
-Dominant-negative variants

201
Q

Describe loss-of-function variants:

A

-Only 1 allele functioning
-If pathway very sensitive to amount of gene product so if only half produced it cannot function will cause problem
-Haplo-insufficiency
-Not enough gene product made

202
Q

describe gain of function variants:

A

-Increased gene dosage
-Increased expression and so more gene product
-Increased protein activity

203
Q

What are dominant-negative variants?

A

-Protein from variant allele interferes with protein from the normal allele
-Varying effect depending on hetero or homozygous

204
Q

What does the type of genetic test depend on?

A

Clinical context

205
Q

Describe diagnostic test:

A

-Patient has signs and symptoms suggesting diagnosis
-Molecular genetic test will confirm diagnosis
-Genetic test used to confirm clinical diagnosis
-Issues:
-informed consent

206
Q

Describe predictive testing:

A

-Health-at-risk family members
-Previously identified familial variant - often dominant
-May be intervention

207
Q

Describe carrier testing:

A

-Autosomal recessive and X-linked disorder
-Testing individual in isolation not particularly helpful (couple)
-Productive decision making

208
Q

Describe pre-natal testing:

A

-Performed in pregnancy where there is increased risk of specific condition affecting foetus
-Chorionic villous sample or amniocentesis
-Often chromosomal or DNA if specific variation in family identified
-Issues:
-Counselling

209
Q

Describe PGD:

A

-Pre-implantation genetic diagnosis
-IVF
-Before pregancy
-Test embryo (8 cell take single cell for analysis)

210
Q

Describe genetic screening:

A

-Target population - not high risk families
-E.g. newborn screening for CF
-May be same test but context is different

211
Q

Describe susceptibility testing:

A

-Increased or decreased risk for multifactorial condition
-Issue is only just emerging

Phase 1 (23 decks)

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