IMMS - Genetics Flashcards
1
Q
What are the 3 classes of things that can cause disease?
A
2
Q
What are some examples of diseases caused by genetics, multifactorial and environmental?
A
3
Q
What is the genotype?
A
Genetic constitution of an individual
4
Q
What is a phenotype?
A
Appearance of an individual (physical, biochemical, physiological) which results from the interaction of the environment and genotype
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
6
Q
What is polymorphism?
A
Frequent hereditary variations at a locus
7
Q
What is genomics?
A
Study of the entirety of DNA, the genome, together with the technologies which allow sequencing, interpretation and analysis
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
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
10
Q
What is a benign variant?
A
An alteration in genetic sequence which is not disease-causing
11
Q
What is a variant of unknown significance?
A
An alteration in a genetic sequence whose association with disease is unknown
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
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
14
Q
What is penetrance?
A
The proportion of individuals with a particular genotype who express the associated phenotype/ develop the condition
15
Q
What is diagnostic testing?
A
Genomic/ genetic testing in someone affected with features of a condition to aid diagnosis
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
17
Q
What do homozygous and heterozygous mean?
A
-Homozygous - both alleles the same at a locus
-Heterozygous - alleles at a locus are different
18
Q
What does hemizygous mean?
A
Only one allele - refers to a locus on an X chromosome in a male
19
Q
What is ACMG criteria?
A
Formal scoring system to decide if a gene variant is ‘pathogenic’
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
21
Q
What is primary care action for a rare disease?
A
-3 generation family tree
-Use symptoms to search diagnostic tools (phenomizer)
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)
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
24
Q
What are 3 cardiac red flags for rare diseases?
A
-Young age onset
-Sudden unexplained deaths
-Multiple affected relatives
25
What are the 3 classifications of genetic disease?
-Chromosomal
-Mendelian
-autosomal dominant
-autosomal recessive
-X-linked
-Non traditional
-mitochondrial
-imprinting
-mosaicism
26
What are 3 types of mendelian genetic diseases?
-Autosomal dominant
-Autosomal recessive
-X-linked
27
What are 3 types of non-traditional genetic diseases?
-Mitochondrial
-Imprinting
-Mosaicism
28
What does this show?
Metaphase spread
29
How would you describe this?
-47, XY, +21
-Downs syndrome
30
How would you describe this?
-Normal female
-46, XX
31
What is autosomal dominant inheritance?
Disease which manifest in the heterozygous state
32
What does this show?
Autosomal dominant inheritance
33
What are the ratios of offspring for autosomal dominant inheritance?
-50% affected
-50% unaffected
34
What kind of inheritance does this pedigree show?
Autosomal dominant inheritance
35
What is autosomal recessive inheritance?
Disease which manifests in homozygous state
36
What does this show?
Autosomal recessive inheritance
37
What are the offspring ratios for autosomal recessive inheritance?
-25% - not affected/not carrier
-50% - not affected/carrier
-25% - affected
38
What is X-linked recessive inheritance?
Caused by pathogenic variants in genes on the X chromsome
39
What does this show?
X-linked inheritance
40
What are the offspring ratios for X-linked inheritance?
-25% - female/not carrier
-25% - female/carrier
-25% - male/not affected
-25% - male affected
41
What does this show?
Mitochondrial DNA
42
What does this pedigree show and why?
-Mitochondrial inheritance
-Can only be passed on from mother as all mitochondria in foetus are sourced from mother
43
What could this show?
-Non-paternity
-New dominant variant
-Gonadal mosaicism
44
What is a multifactorial disease?
-Due to a combination of genetic and environmental factors
-Most common diseases are multifactorial
45
How do you identify that a condition has a genetic component?
-Clinical observation:
-Family studies
-Twin studies
-Adoption studies
46
What are genetic family studies?
Compare the incidence of a disease amongst the relatives of an affected individual with the general population
47
What 4 things of family studies relates to multifactorial conditions?
-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
48
What are twin studies?
-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
49
What does concordance rate show?
Can give a rough figure for the heritability of a multifactorial disorder
50
What are adoption studies?
-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
51
What is hereditability?
Proportion of aetiology that can be ascribed to genetic factors as opposed to environmental factors
52
How can you calculate and express hereditability?
-One way to calculate is from the concordance rate in monozygotic twins
-Expressed as a proportion of 1 or as a percentage
53
What are 3 characteristics of multifactorial inheritance?
-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
54
What does this show?
-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
55
What does this show?
-The liability/threshold model
-Curve for relatives shifts to the right, increasing risk
56
What is the liability/threshold model?
-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
57
How does liability distribution change for relatives?
-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
58
When is the abnormal phenotype expressed in the liability model?
-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
59
What is GWAS and what are they used for?
-Genome wide association studies
-Used to work out what the genetic component of a condition once one has been established
60
What does GWAS utilise?
-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
61
How does GWAS work?
-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
62
What 4 environmental factors can act on embryogenesis?
-Drugs and chemicals (thalidomide, alcohol, anticonvulsants)
-Maternal infections (rubella, CMV)
-Physical agents (radiation)
-Maternal illnesses (diabetes)
63
What are 4 post-natal environmental factors?
-Obesity - Type 2 diabetes
-Hormonal factors (the pill, HRT, parity, breast feeding, obesity) - Breast cancer
-Smoking - Lung cancer
-Recreational drugs - Schizophrenia
64
What could you do by analysing thousands of variants of genetic diseases for an individual?
Identify the conditions an individual has an increased risk for
64
What could you do by analysing thousands of variants of genetic diseases?
Identify the conditions an individual has an increased risk for
65
What 3 things could genome sequencing tell you about a person?
-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
66
What does this show?
Cell cycle
67
What cell types can you culture for genetic testing?
-Blood - T lymphocytes
-Skin/umbilical cord/placenta
-Bone marrow
-Solid tumour
-Amniotic fluid/chorionic fluid
68
Label this diagram:
What does it show?
Sampling and processing for karyotyping
69
What phases of the cell cycle does the right and left show?
70
What is a karyotype?
An individuals complete set of chromosomes
71
What is an ideogram?
-A graphical representation of chromosomes
-Genetic information location
72
What is the nomenclature of chromosomes?
-ISCN - International System of Chromosome Nomenclature
-46, XX
-46, XY
73
What are 3 numerical chromosomal abnormalities?
-Trisomy - 47,XX,+21
-Monosomy - 45,X
-Polyploidy - 69,XXY
74
What are 4 structural chromosomal abnormalities?
-Translocation - t(1;2)(q24;p12)
-Inversion - inv(7)(q11q21)
-Duplication - dup(11)(p14p15)
-Deletions - del(22)(q11q12)
75
Label the number of copies per cell of successful meiotic disjunction:
76
What does this show?
Non-disjunction at meiosis II
77
What does this show?
Non-disjunction at Meiosis I
78
What does this show? (karyotype)
47, XX, +18
79
What does this show?
47, XX, +13
80
What do each of these show?
Sex chromosome abnormalities
81
What does this show?
Triploid karyotype
82
what does this show?
The iceberg of chromosomal pregnancy loss
83
What does this show?
-Reciprocal translocation
-All the genetic info is there but in a different arrangement
84
What does this show?
Segregation of a 2/18 translocation
85
What does deletion of 15q cause?
Prader Willi/Angelman syndrome
86
What is F.I.S.H?
-Fluorescent in situ hybridisation
-Use DNA probes labelled with fluorophores
-hybridised directly to chromosome preparation or interphase nuclei
87
How is F.I.S.H used in cytogenetics?
-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
What is used here and what does it show?
-F.I.S.H
-Trisomy 21
89
What are microarrays?
-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
Label this diagram:
What does it show?
Microarray basic protocol
91
What does this show?
CGH array profile
92
What does this show?
Chromosome 1 microdeletion
93
Why is microarrays an expanding field?
-As patients are screened by microarrays, contributing to a database of cytogenetic and phenotypic abnormalities
-'New" microdeletion/duplication syndromes are being proposed
94
What are the 3 difference between constitutional and acquired abnormalities?
95
What is the clinical role of cytogenetics (4)?
-Confirmation of malignancy
-Classification of a disease type
-Prognosis
-Monitoring
96
What are 5 features of non-random changes?
-Close association with disease sub-type
-Association with clinical feature
-association with lineage
-No specific association
-Apparent multiple association
97
What are fusion/hybrid genes?
-Breakpoints occur within the two genes involved
-Fusion creates a hybrid gene which gives rise to a chimaeric protein
98
What is deregulation?
-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
What 6 classes can constitutional abnormalities be?
-Prenatal
-Postnatal
-Numerical
-Structural
-Balanced
-Unbalanced
100
What are 3 categories of genetic disorder?
-Chromosome abnormalities
-Single gene disorders
-Multi-factorial and polygenic disorders
101
Label this diagram of common structural anomalies in clinical cytogenetics:
102
How is DNA packaged?
-DNA winds around histones to form nucleosome
-Nucleosomes pack to form chromatin
-Chromatin condenses to form chromosome
103
What are the 3 underlying Mendel principles of genetics?
-Segregation
-Dominance
-Independent assortment
104
What is Mendel's dominance law?
-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
What is Mendel's law of segregation?
-Allele pairs separate randomly from each other during meiosis
-Each cell has a single allele for each trait
106
Describe Mendel's law o independent assortment:
Traits are transmitted to offspring independently of one another
107
What are 2 classes of mendelian inheritance?
-Autosomal and sex-linked
-Dominant and recessive
108
What are 4 classes of non-mendelian inheritance?
-Imprinting
-Mitochondrial inheritance
-Multifactorial
-Mosaicism
109
What does this show and what do the symbols mean?
Pedigree diagram
110
What is an autosome?
Any chromosome (other than sex chromosomes) that occurs in pairs in diploid cells
111
What does recessive mean?
Manifest only in homozygous
112
What is an allele?
One or more alternative forms of a gene at a given location (locus)
113
What is homozygous?
-Presence of identical alleles at a given locus
-Homozygotes affected
114
What is heterozygous?
-Presence of two different alleles at a given locus
-Heterozygotes are unaffected and are usually referred to as carriers
115
What is allelic heterogeneity?
-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
What is a compound heterozygote?
Different variants of the same disease cause the disease
117
What is autosomal recessive inheritance?
Disease manifest in the homozygous state
118
what are 3 typical features of autosomal recessive inheritance?
-Males and females affected in equal proportions
-Affected individuals only in a single generation
-Parents can be related
119
What is it called when there is repoducitve union between two relatives?
Consanguinity
120
What is the commonest autosomal recessive condition affecting northern European population?
Cystic Fibrosis
121
What does cystic fibrosis affect?
-Mainly lung and gut
-Variable presentation
122
What is the genetics behind Cystic Fibrosis?
-CFTR gene on 7q31.2
-Over 1000 mutations
-F508 commonest mutation
-Standard carrier testing detects top 29 mutations
123
What testing is done for CF?
-Sweat testing remains diagnostic test
-Neonatal screening programme for IRT (indirect marker)
124
What is the risk of Mary and John's baby having CF?
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
What is the risk of Mary and John's baby having CF if mary tests +ve and John -ve?
-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
What are the genotype-phenotype correlations in cystic fibrosis?
-Change in F508/F508 del - pancreatic insufficiency and chronic lung disease
-F508 del/ R117H - majority are pancreatic sufficient but have chronic lung disease
127
What is autozygosity?
-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
What does this show?
Consanguineous pedigree
129
Label:
130
131
What is the risk to healthy siblings of an affected sibling being a carrier of a recessive disease allele?
2/3
132
What mode of inheritance is this?
Autosomal dominant
133
What is autosomal dominant inheritance?
-Disease manifests in the heterozygous state
-Only one affected gene needed
134
What are 4 typical features of autosomal dominant inheritance?
-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
What is penetrance?
Percentage of individuals with a specific genotype showing the expected phenotype
136
What is expressivity?
Refers to the range of phenotypes expressed by a specific genotype
137
What is recurrence risk?
-50% for transmission of mutation
-Depends on penetrance and expression
-Can't predict severity of phenotype
138
What is a new mutation?
-Self-explanatory
-De novo mutation - presents for first time in family generation (parents don't have mutated allele)
139
What is anticipation?
-Genetic disorder affects successive generations earlier or more severely
-Usually due to expansion of unstable triplet repeat sequences
140
What is somatic mosaicism?
-Genetic fault present in only some body tissues
-Not present at time of conception
-if present earlier, would probably not be survivable
141
What is gonadal (germline) mosaicism?
-Genetic fault present in gonadal tissue
-Only reproductive tissue
-No effect on health, only offspring
142
What does this show?
Somatic mosaicism
143
What could this show?
Gonadal mosaicism
144
What is late-onset?
Condition not manifest at birth (congenital)
-Classically adult-onset
145
What does it mean if a genetic disease is sex-limited?
-Condition inherited in AD pattern
-Seems to affect one sex more than another
-Equal chance of inheritance
-Different chance of expression
146
What is predictive testing?
Testing for a condition in a pre-symptomatic individual to predict their chance of developing condition
147
What does this shoq?
X-linked inheritance
148
What is a common X-linked inherited disease?
Haemophilia
149
What is X-linked inheritance?
Genes carried only on X chromosome
150
What are 3 typical features of X-linked inheritance?
-Usually only males affected
-Transmitted usually through unaffected females
-No male-to-male transmission
151
What is lyonization?
-X inactivation
-Generally only one of the two X chromosomes are active in each female cell (can be skewed)
152
What is skewed X-inactivation?
-Preferntial inactivation of a X chromosome
-Generally in favour of nora=mal X chromosome
-Lower risk of x-linked disease
153
What is genomic imprinting?
-Epigenetic phenomenon that causes genes to be expressed in a parent-of-origin-specific manner
-Epigenetic = non-genetic influence on gene expression
154
What causes PWS and Angelman syndromes?
-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
Where do you inherit mDNA from?
Mother
156
What is homoplasmy?
Eukaryotic cell whos copies of mitochondrial DNA are all identical (identically normal or identical mutations)
157
What is heteroplasmy?
-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
What are mitochondrial genetic disease (4)?
-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
What is a common example of multifactorial inheritance?
-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
What are the 4 types of testing offered for pathogenic genetic conditions in clinical genetics?
-Diagnostic
-Carrier
-Predictive
-Prenatal tests incl. NIPT
161
What testing is usually done in private sector or forensic lab?
-Testing to clarify familial relationships
-E.g. paternity testing
162
What testing is usually done in a forensic lab?
-Testing to determine identity
-E.g. genetic finger printing
163
What are 7 roles of genetic testing?
-Confirm diagnosis
-Give info about prognosis
-Inform management
-Pre-symptomatic/predictive testing in close relatives
-Carrier testing
-Accurate recurrence risks
-Prenatal diagnosis
164
What are the first 4 questions thought about in the genetic clinic?
-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
What are the last 3 questions to consider during the genetic clinic?
-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
167
What does this show?
Microarray CGH
168
What is Sanger sequencing?
-Uses PCR to amplify regions of interest
-Followed by sequencing of products
-Useful for single gene testing
169
What is next generation sequencing (NGS)?
-High throughput or massively parallel sequencing
-Sequence whole human genome in a day
-Multi-gene panels, whole exome/genome
170
What is the gold standard of gene sequencing?
Sanger sequencing
171
Describe the differences between Sanger and NGS:
172
How is NGS data analysed?
-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
What does 'sifting through the noise' mean in genetic testing?
-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
What 3 categories do you have to interpret a genetic variation into?
-Pathogenic variant
-Variant of unknown significance (VUS)
-Normal variation
175
What 4 things do you consider when interpreting a genetic variation?
-Previously reported?
-In literature?
-Present on variant or reference database?
-Type?
-Nonsense
-Frame shift
-Splice site
-Missense
176
What extra work do unclassified variants require?
177
What is the Databases of disease mutations?
-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
What are additional findings?
-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
What are 3 examples of additional findings?
-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
What do you need to consider with secondary findings?
-Consider when and where to disclose
-Full and informed consent prior to test
-Clinical judgement
181
Describe targeted panels:
-Select specific genes to sequence
-Less 'noise'
-Fewer variants of uncertain significance
-Panels need to be updated
182
183
What are the pick up rates for each of these?
184
What does this show?
-Transcription
-DNA to RNA
185
What does this show?
-Splicing
-RNA to mature RNA
186
How can different proteins be produced from the same genes?
-Alternate splicing (different introns)
-Exon shuffling (e.g. immune system) - can be moved between different genes
187
What are the 3 STOP codons?
-UAA
-UAG
-UGA
188
What is a mis-sense and non-sense mutation?
-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
What are the 7 types of DNA variants/mutations?
-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
How much of the genome codes for protein?
2%
191
Describe deletion variants:
-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
Describe splice-site variant:
-Affects accurate removal of an intron
-Intron is translated into protein
193
Describe non-sense variant:
-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
Describe a mis-sense variant:
-Single base substitution
-Changes type of amino acid in protein
-May or may not be pathogenic
-May be polymorphism or no functional significance
195
How do you distinguish a pathogenic variant from a polymorphism?
-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
What are 3 diseases caused by trinucleotide repeat expansion?
-Huntington's
-Myotonic dystrophy
-Fragile X
197
What is anticipation in terms of trinucleotide repeat?
-Repeat gets bigger when transmitted to next generation
-Worse from generation to generation
-Symptoms develop earlier and more severe
198
What is allelic heterogeneity?
-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
What is locus heterogeneity?
-Variants in different genes
-Give the same phenotypic presentation of clinical disease
200
What are the 3 mechanisms of dominance?
-Loss-of-function variants
-Gain-of-function variants
-Dominant-negative variants
201
Describe loss-of-function variants:
-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
describe gain of function variants:
-Increased gene dosage
-Increased expression and so more gene product
-Increased protein activity
203
What are dominant-negative variants?
-Protein from variant allele interferes with protein from the normal allele
-Varying effect depending on hetero or homozygous
204
What does the type of genetic test depend on?
Clinical context
205
Describe diagnostic test:
-Patient has signs and symptoms suggesting diagnosis
-Molecular genetic test will confirm diagnosis
-Genetic test used to confirm clinical diagnosis
-Issues:
-informed consent
206
Describe predictive testing:
-Health-at-risk family members
-Previously identified familial variant - often dominant
-May be intervention
207
Describe carrier testing:
-Autosomal recessive and X-linked disorder
-Testing individual in isolation not particularly helpful (couple)
-Productive decision making
208
Describe pre-natal testing:
-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
Describe PGD:
-Pre-implantation genetic diagnosis
-IVF
-Before pregancy
-Test embryo (8 cell take single cell for analysis)
210
Describe genetic screening:
-Target population - not high risk families
-E.g. newborn screening for CF
-May be same test but context is different
211
Describe susceptibility testing:
-Increased or decreased risk for multifactorial condition
-Issue is only just emerging
