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Y2 Essential Medical Science > Genetics in Medicine > Flashcards

Genetics in Medicine Flashcards

1
Q

What is Human genetics

A

The science of heredity and variation in humans

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2
Q

What is medical genetics

A

The subset of human genetics that is important In medicine and medical research

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3
Q

What is the genotype

A

The written genetic make up

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4
Q

What is the phenotype

A

How the gene variations manifest within the body

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5
Q

What was the 100kg

A

100,000 patients were going to have there entire geneome processed which was funded by £300m from the government

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6
Q

Why are people referred to clinical genetics

A

Child: Birth abnormalities, Dysmorphic features, Learning difficulaties

Adult:
Diagnosis
Predictive testing 
Carrier testing 
Family history

Pregnancy:
Known genetic disorders
Abnormality detected on screening
Fetal loss or recurrent miscarriages

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7
Q

What is the purpose of different genetic tests

A

Diagnostic:
Answer specific or broad questions

Predictive testing:
Tells patient whether they will have a problem in the future

Carrier testing:
For autosomal and X-linked recessive genes

Prenatal testing:
For diagnosing and preventing genetic disease

Screening:
For testing of whole populations

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8
Q

Why are rare diseases a priority

A

Individually rare but they add up to a lot of chronic diseases
Disproportionally effect children (1/4 to 1/3 of children in hospital)
Tell us a huge amount about Biology and therefore inform us of other clinical diseases

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9
Q

What drugs act on BCR-ABL translocation gene

A

Imatinib

Nilotinib

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10
Q

What is the molecular anatomy of the body

A

Almost all inheritable information is written in DNA sequences
Some information is in other chromatin features

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11
Q

How long is a heritable information DNA sequence

A

3 x 10^9 nucleotides

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12
Q

What are epigenetics

A

Information stored outwit the genome

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13
Q

What is the stability difference between DNA and RNA

A

DNA is incredibly stable but RNA is very transient and breaks down quickly

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14
Q

How is a DNA sequence written

A

In a 5’ to 3’ direction
Written as a single strand but infers that it is a double strands as that is how DNA is written
The sense strand is the one which is written (the one which ends up in the mRNA when transcribed)

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15
Q

How many human chromosomes are there

A

46 chromosomes in 23 pairs

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16
Q

What happens in telomeres over time

A

Due to lack of telomerase as the body ages, telomeres shorten with somatic cell division and so there are a finite number of cell divisions

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17
Q

What is a chromosome ideogram

A

An idealised graphical representation of the chromosome

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18
Q

What is haploinsufficiency

A

Loss of one copy of the gene, resulting in pathological clinical presentation

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19
Q

What is a gene family

A

Most genes belong to a family of structurally related genes which may be clustered together or widely dispersed

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20
Q

What is a pseudogene

A

A gene which would have been functional a long time ago but, due to evolution, no longer is

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21
Q

What is a processed gene

A

Intronless copies of other genes which are usually remote from parent gene
The result of reverse transcription and reintegration
Occasionally remain functional but most non-functional

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22
Q

What are the types of repetitive DNA

A

Satellite DNA:
Large blocks of repetitive DNA sequence

Interspersed repeats:
Scattered around the genome

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23
Q

What are molecular genetics

A

The study of the structure and function of individual genes

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24
Q

What are clinical genetics

A

The application of genetics for diagnosis and patient care (in individuals and families

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25
Q

What is the purpose of modern genetics

A

To understand the fundamental role of the gene in basic life processes

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26
Q

What are the types of inherited disorders

A

Single gene
Chromosomal
Mitochondrial
Imprinted

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27
Q

What is the point of pharmacogenetics

A

To understand who will respond to different treatments and in what way

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28
Q

What are the three routes of determining a genetic diagnosis

A

Family tree
Physical examination
Genetic tests

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29
Q

What are the two ways of testing for genetic disorders

A

Non-genetic tests

Genetic tests

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30
Q

What are examples of non-genetic tests

A

Blood tests

Xrays

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31
Q

What are the advantages of testing for genetic disorders

A

Early diagnosis allowing for early interventions
Carrier testing to inform of reproductive choices
Prenatal testing to inform of reproductive choices

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32
Q

What are disadvantages of testing for genetic disorders

A

Is the information something which the patient actually wants to know?
Will it affect other things in life such as insurance prospects?

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33
Q

What is genetic counselling

A

An education process which seeks to assist affected or at risk individuals to understand the nature of the genetic disorder, its transmission and the options open to them in management and family planning

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34
Q

What are pharmacogenomics

A

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

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35
Q

What are pharmacogenetics

A

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

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36
Q

What is multifactorial/ complex genetic classification and an example

A

The interaction of multiple genes in combination with environmental factors
EG: type II diabetes

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37
Q

What is single gene genetic classification and an example

A

A mutation in a single gene
Mendelian inheritance
EG: cystic fibrosis

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38
Q

What is chromosomal genetic classification and an example

A

An imbalance or rearrangement in chromosome structure

EG: aneuploidy, deletion, translocation

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39
Q

What is mitochondrial genetic classification

A

A mutation in mitochondrial DNA

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40
Q

What is somatic mutation genetic classification and an example

A

Mutation within a gene in a defined population of cells that results in disease
EG Breast cancer

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41
Q

What are the single gene modes of inheritance

A

Autosomal dominant
Autosomal recessive
X-linked
Mitochondrial

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42
Q

What is autosomal dominant inheritance

A

A trait or disease runs from one generation to the next

Males and females are equally affected

Chance of offspring affected 50%

Affected individuals are heterozygous for the mutation

Affects structural proteins, receptors, transcription factors

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43
Q

What are examples of autosomal dominant inheritance

A

Myotonic dystrophy
Marfan syndrome
Huntington disease

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44
Q

What is penetrance

A

The frequency with which a specific genotype is expressed by those individuals that possess it, usually given as a percentage

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45
Q

What is expressivity

A

Variation in expression between different people

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46
Q

What is anticipation

A

The symptoms of a genetic disorder become apparent at an earlier age as it is passed from one generation to the next.

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47
Q

What is a new dominant or de novo mutation

A

New mutation that has occurred during gametogenesis or in early embryonic development

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48
Q

What is autosomal recessive inheritance

A

Disease seen in one generation
Does not tend to pass from one generation to the next
Offspring of affected individual has low risk of disease
Relatives may be asymptomatic carriers of disease
Affects males and females equally
Gene mutations, not chromosomes
Affected individuals are homozygous or compound heterozygous for the mutation

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49
Q

What is the difference between being homozygous and compound heterozygous for a mutation

A

Homozygous: same type of mutation for same gene

Compound heterozygous: Same gene disrupted but it’s a different mutation but still means they have the disease

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50
Q

What are examples of autosomal recessive inheritance

A

Cystic fibrosis
Many of the metabolic disorders
Haemachromatosis
Sickle cell disease

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51
Q

What is X-linked inheritance

A

Males more severely affected
Females may be unaffected, mildly through to fully affected
Cannot have male to male transmission
Gene mutations and chromosome deletions/ duplications
Carrier mother: 1/4 normal girl and 1/4 carrier girl, 1/4 normal boy and 1/4 affected boy
Affected father: all daughters are carriers, all sons are unaffected

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52
Q

What are examples of X- linked inheritance

A

Duchenne Muscular dystrophy
Fragile X syndrome
Red/green colour blindness
Haemophilia

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53
Q

What are the two main factors for why females can have such variable phenotypes with x linked inheritance

A

X inactivation

X linked dominant vs X linked recessive inheritance

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54
Q

What are examples of X linked dominant and recessive inheritance

A

Dominant:
Rett syndrome
Fragile X syndrome

Recessive:
Red-green colour blindness
Haemophilia
Duchene musclular dystrophy

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55
Q

How are mitochondria inherited

A

All from our mother

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56
Q

How do you draw a family pedigree

A

Build up the tree from the bottom starting with affected child and siblings
Record names, dates of birth and maiden names
Choose one parent, ask about sibling and their children, then parents
Always create a key with the symbols used
Date and sign

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57
Q

What is consanguinity

A

Couples who are blood relatives
Potentially share recessive gene mutations
Risk of congenital birth defect 5-6% (2-3% general population) if no family history of genetic condition
Seen in all ethnic groups

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58
Q

What are genome analysis methods

A 
PCR
DNA sequencing
Array CGH
Karyotyping
FISH
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59
Q

What pathologies are analysed in genome analysis methods

A

Single-gene variants
Copy number variants
Chromosome number
Structural changes

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60
Q

What is the hybridisation principle

A

Two DNA molecules will anneal (hybridise) into a duplex only if their sequences are complimentary according to the Watson-Crick base-pairing rules

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61
Q

What are the steps of PCR

A 
Target strands forced apart by heating 94 degrees 
Primer anneals at 55 degrees
Primer extension at 72 degrees
Heat denaturation at 94 degrees
Repetition
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62
Q

What are some applications of PCR

A

Detect presence or absence of a genetic sequence

Generate template for analysis of specific mutations

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63
Q

What is allele-specific mutation detection

A

Distinguishes two alleles that may only differ by a single nucleotide

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64
Q

What happens when the identity of a disease-causing mutation is unknown

A

It must be searched for by sequencing of DNA of the region of interest
Pathogenic changes must be distinguished from harmless ones

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65
Q

What is an exome

A

The smaller, more interesting, coding part of the genome

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66
Q

What are the methods for detecting copy number variation

A

Whole genome: G-banding, next generation sequencing, microarrays
Targeted testing: FISH, MLPA, QF-PCR

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67
Q

What are the phases of mitosis

A

Interphase, prophase, metaphase, anaphase, telophase, cytokinesis

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68
Q

What is karyotyping

A

Determination of a karyotype by:
Cell culture
G-banding
Variable resolution >5Mbp

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69
Q

What are the DNA-based methods for copy number

A

Array comparative genomic hybridisation
Whole genome sequencing
MLPA: multiplex ligation-dependent probe amplification
Quantitative fluorescent PCR

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70
Q

Why is DNA nor always used

A

DNA based methods are good for dosage as cheaper and heavier and provide higher resolution
Cytogenetic analysis is still needed for genome rearrangements such as translocations

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71
Q

What is cytogenetics

A

Study of chromosomes

Anything more than a single gene

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72
Q

What are the types of CNV

A

Copy number variations

Numerical:

aneuploidy: gain (trisomy) or loss (monosomy)
polyploidy: gain whole sets (triploidy or tetraploidy)
mosaicism: diploidy and aneuploidy

Structural:
deletion
duplication

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73
Q

How do cytogenetic abnormalities produce an abnormal phenotype

A 
Dosage effect (loss is worse than gain)
Disruption of a gene at a breakpoint/ inappropriate activation or inactivation of genes
Position effect: gene in a new chromosomal environment functions inappropriately 
Unmasking of a recessive disorder
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74
Q

What are the consequences of mosaicism

A 
Variable phenotype
Variable lethality
Non-identical identical twins
Tissue-specificity lateral asymmetry
Recurrence risk if gonadal
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75
Q

What is a microarray CGH

A

Genome-wide screen
Hybridise sample and control DNA to a microarray BACs or SNPs or oligonucleotides
Genomic imbalances at high resolution
Has replaced some karyotyping as 1st line test

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76
Q

Which patients would an array CGH be used for

A

Moderate to severe learning and developmental disability
Dysmorphic infants
Pregnancies with abnormal ultrasound

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77
Q

What are the advantages of array CGH

A

Early diagnosis 1st line test, reduces need for other tests and avoids the diagnostic odyssey
High resolution = increased diagnostic hit rate
Greater accuracy of location/ size of imbalances
Information on relevant genes

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78
Q

What are the disadvantages of array CGH

A 
Dosage changes only
Not balanced rearrangements or mutations
Low level mosaics not detected
Non-pathogenic and uncertain pathogenic changes detected
Needs good quality DNA
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79
Q

What are application of molecular cytogenetics

A

Non-invasive prenatal testing
Pregnancy loss
Pre-implatation ctudies
Cancer

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80
Q

What is NIPT

A 
Non-invasive prenatal testing
Maternal blood sample
Extract circulating free foetal DNA
Assess aneuploidy of 13, 18, 21
Risk of aneuploidy - invasive test to confirm
Reduces number of invasive tests
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81
Q

How is cytogenetics used in cancer

A

Disease specific acquired chromosome changes:
Mostly translocation
Several different acquired abnormal clones
Diagnosis
Prognosis
Treatment

Leukaemia: bone marrow

Solid tumour: tumour tissue

82
Q

What are the two types of translocation

A

Reciprocal:
Break and exchange
Robertsonian:
Whole arm fusion

83
Q

What is genetic bottleneck effect

A

Caused by:
Speciation, migration, environment, disease
Diversity in the form of genetic variation is reduced

84
Q

What are exogenous and endogenous factors causing uncorrected errors

A

Exogenous factors: radiation, chemicals

Endogenous factors: segregation (e.g. Downs syndrome, Edwards syndrome)
Recombination (translocation)
DNA replication errors (mispaired bases, slippage)
Inadequate DNA repair mechanisms (mismatch repair, base excision repair)

85
Q

What are the two classes of genetic variation

A

Variation that does not alter the DNA content as number of nucleotides is unchanged (single nucleotide replacements, balanced translocations or inversions)

Variation that results in a net loss or gain of DNA sequence (can by whole chromosome or single nucleotides)

86
Q

What is a neutral variation

A

DNA changes are small scale and have no obvious effect on phenotype
Is common but detrimental variation is rare

87
Q

What are the types of normal genetic variation

A

Single nucleotide variants (SNVs)
Single nucleotide polymorphisms (SNPs)
Copy number variation (CNVs)
Indels (insertion or deletion of one or more nucleotides)

88
Q

What is minor allele frequency

A

The frequency of the less common variant in a population

89
Q

What are the types of exotic variants

A

Missense mutation: an amino acid change
Nonsense mutation: change of amino acid to a stop codon
Silent mutation: The codon for an amino acid is changed but the same amino acid is still coded for

90
Q

What is the meaning of a Mendelian genetic condition

A

Obey Mendel’s laws of segregation
Dominant, recessive, X-linked
Single gene influencers

91
Q

What is the meaning of a complex genetic condition

A

Tends to be used vaguely to describe something with an inherited but non-mendelian component

92
Q

What is polygenic genetics

A

The result of the action of multiple genes

93
Q

What are multifactorial genetics

A

The result of multiple factors, usually including both genetic and environmental factors

94
Q

What does lamna s mean

A

Relative risk to second children

Comparison of risk of having condition to the population risk

95
Q

What are examples of congenital malformations which are multifactorial

A

Cleft lip
Congenital hip dislocation
Congenital heart defects
Neural tube defects

96
Q

What are examples of acquired diseases pf childhood and adult life which are multifactorial

A 
Asthma
Autism
Cancer
Diabetes
Epilipsy
Hypertension
Inflammatory bowel disease
97
Q

What is a genome wide association study

A

Detects common genetic variants conferring susceptibility to complex phenotypes
Controls should match cases and be a representative sample of the population

98
Q

What is a Manhattan plot

A

Visualisation of GWAS results
All SNP results are plotted on one graph
X-axis shows the position in the genome
Y-axis shows the significance (-log10 of the p-value)

99
Q

What is Alzheimer disease

A

Most common form of dementia after 40yr
Symptoms:
inability to cope, loss of memory, brain damage
Shrinkage of brain, tangles of B-amyloid protein in nerve fibres of hippocampus
Different genes involved in different families bur give same end result

100
Q

What are the genetics of Alzheimer disease

A

Sequence variants at a polymorphic locus have a large effect on the age of onset
Much of that is due to a gene implicated in heart disease (apo-lipoprotein E)

101
Q

What are the three haplotypes of APOE and what do these confer in the genetics of Alzheimer disease

A

APOEE2: protective effect
APOEE3
APOE*E4: increase in susceptibility

102
Q

What is an allele

A

A variant form of genes or genetic marker

103
Q

What is a genetic anticipation

A

A phenomenon whereby as a genetic disorder is passed on to the next generation, the symptoms become apparent at an earlier age with each generation

104
Q

What is a genetic association

A

When one or more genotypes within a population co-occur with a phenotypic trait, more often than it would be expected by chance

105
Q

What is a haplotype

A

A set of DNA variants or polymorphisms that tend to be inherited together

106
Q

What is Hardy Weinberg Equilibrium

A

The situation where allele and genotype frequencies in a population remain constant from generation to generation in the absence of other evolutionary influences

107
Q

What is heritability

A

A statistic used in breeding and genetics work that estimates how much variation in a phenotypic trait in a population is due to genetic variation among individuals in that population

108
Q

What are hyper normal controls

A

Unaffected individuals selected from the extreme of a quantitative trait

109
Q

What is linkage disequilibrium

A

The occurrence in members of a population of combinations of linked genes in non-random proportions

110
Q

What is microsatellite

A

A tract of repetitive DNA in which certain DNA motifs are repeated typically 5-50 times

111
Q

What is the minor allele frequency

A

The frequency of the less common variant in a population

112
Q

What does monomorphic mean

A

Existing in one form only

113
Q

What is population genetics

A

The branch of science that deals with the statistical analysis of the inheritance and prevalence of genes in a population

114
Q

What is a quantitative trait

A

A measurable phenotype that depends on the cumulative actions of many genes and the environment. These traits can vary among individuals, over a range, to produce a continuous distribution of phenotypes

115
Q

What is a genetic trio

A

A set of individuals comprising of a father, a mother and their child.

116
Q

What are the different types of mutations in a gen

A

Large deletions or insertions
Gross rearrangements
Point mutations
Trinucleotide repeat expansions

117
Q

What are the types of point mutations

A

Silent: Change in nucleotide still codes for the same amino acid
Missense: Change in nucleotide results in change in amino acid coded for
Nonsense: Change in nucleotide results in formation of a stop codon causing a truncated protein to be produced
Frameshift mutation: deletion/insertion of one nucleotide alters protein sequence beyond mutation

118
Q

What is Huntington’s disease

A 
Neurodegenerative disorder 
Symptoms:
Involuntary movement
Psychiatric changes
Cognitive loss -> dementia
Neuronal loss

Autosomal dominant:
Heterozygous CAG repeat expansions
Mutational instability
Anticipation

119
Q

What is fragile X syndrome

A 
One of the more common single-gene causes of mental handicap
X-linked
Semi dominant 
males severely affected 
Females less so
Peculiar inheritance
120
Q

What is a germlin mutation

A

Inherited from parents at birth

121
Q

What is a somatic cell mutation

A

A mutation that develops in one particular cell that has divided and cloned

122
Q

What is the function of caretaker genes

A

Improve genomic stability

123
Q

What is the function of gatekeeper genes

A

Monitor and control cell division and death, preventing accumulation of mutations

124
Q

What is the function of Landscaper genes

A

Control the surrounding environment

125
Q

What is the penetrance of a cancer gene

A

Percentage of people with a gene change who develop the condition
May be modified by other genetic variations
May be modified by environmental factors

126
Q

What are tumour suppressor genes

A

Protects cells from becoming cancerous

Loss of function increases the risk of cancer

127
Q

What are oncogenes

A

Regulate cell growth and differentiation

Gain of function/activating mutations increase the risk of cancer

128
Q

What is Knudson’s two hit hypothesis

A

Recessive at the cellular level so both copies of the gene inactivated to have the effect
Most cancer syndromes show autosomal dominant inheritance pattern

129
Q

What are sporadic vs familial cancers

A

Sporadic:
Onset at older age
One cancer in individual
Unaffected family members

Familial:
Onset at younger age 
Multiple primaries in individual
Other family members affected
Same type/ genetically-related cancers
130
Q

What is the purpose of genetic assessment

A 
Diagnosis/explanation of family history
Counselling of advantages and disadvantages of testing
Risk of further cancers for affected case
Risk of cancer for unaffected relatives
Screening
Prevention
Treatment
Research
131
Q

What is retinoblastoma

A 
Childhood ocular cancer
Very rare
30-50 children/year in uk
Classic example following Knudson 2-hit hypothesis
Retinoblastoma (Rb1) gene
132
Q

What is familial adenomatous polyposis

A

Hundreds of bowel polyps from teens onwards
Accounts for about 1% of bowel cancers
High risk of bowel cancer if untreated
APC tumour suppressor gene
Autosomal dominant inheritance
Colonoscopies, total colectomy late teens/early 20s

133
Q

What is hereditary non-polyposis colorectal cancer

A 
Accounts for about 2-3% of bowel cancers
Polyps are common but not polyposis
60-80% risk of bowel adenomas or cancer from mid 20s onwards
Other cancer risks
Mismatch repair genes 
Autosomal dominant inheritance
134
Q

What is the Amsterdam criteria of HNPCC

A

One member diagnosed with colorectal cancer before 50
Two affected generations
Three affected relatives, one first-degree relative of the other two
FAP should be excluded
Tumours should be verified by pathologic examination

135
Q

What is the BRCA1 and BRCA2 gene

A

BRCA1 and 2 are involved in DNA repair
Around 10% of cases of breast under 40 and around 25% of those with strong FH
Common mutations in Jewish and some other founder populations
Autosomal dominant inheritance
Risk of breast cancer 80%, ovarian BRCA1 40%, BRCA2 10-20%
Some increased risk of other cancers

136
Q

What is Morphology

A

The scientific study of the structure and form of either animals and plants or words and phrases

137
Q

What are congenital malformations

A 
2-3% of births
Single malformations often isolated events
More likely to be genetic if:
Multiple malformations
Dysmorphic
Family history of similar problems
138
Q

What is achondroplasia

A 
around 1 in 20,000
Autosomal dominant- often new mutation
Risk increases with paternal age
Rhizomelic limb shortening
Short stature
Foramen magnum compression/hydrocephalus
139
Q

What is Beckwith- Wiedemann syndrome

A 
around 1 in 10,000
Large tongue
Ear pits/ creases 
Exomphalos
Hemihypertrophy
Neonatal hypoglycaemia
Increased risk of Wilms tumour (nephroblastoma)
140
Q

What is down syndrome

A 
Commonest chromosomal disorder
around 1 in 800 live births
Learning difficulties 
Congenital heart disease
Hypotonia in neonates
Single palmar cease
Cataracts
Hearing impairment
Hypothyroidism
Leukaemia
Atlanta-axial instability
Alzheimer's disease
141
Q

What is Kabuki syndrome

A 
around 1 in 30,000
Learning difficulties
Congenital heart disease (50%)
Poor growth
Hearing impairment
Cleft palate
Premature breast development
Persistent fetal finger pads (96%)
142
Q

What is mosaicism

A

Hypo- and/or hyper- pigmented patches
May follow Blaschko’s lines
Diagnosis often requires skin biopsy

143
Q

What is Peutz Jeghers syndrome

A 
<1 in 50,000
Gastointestinal polyps: 
Bleeding
Obstruction
Malignancies:
Colorectal 
Gastric
Pancreatic
Breast
Ovarian
144
Q

What is Treacher-collins syndrome

A 
around 1 in 50,000
Autosomal dominant
Very variable
Cleft palate
Hearing impairment
145
Q

What is Waardenburg syndrome

A 
Around 1 in 250,000
Sensorineural hearing impairment
Iris heterochromia
Premature greying
White forelock
Areas of skin hypo pigmentation
Congenital malformations
146
Q

What is William’s syndrome

A 
7q11 deletion
Around 1 in 20,000
Learning difficulties
Hypercalcaemia
Congenital heart disease:
Supravalvular aortic stenosis
Peripheral pulmonary artery stenosis
147
Q

What is androgenesis

A

Initiation of development using only paternal genetic material

148
Q

What is parthenogenesis

A

Initiation of development using only maternal genetic material
Common in some other animals: insects, fish and reptiles

149
Q

What is a hydatidiform mole

A

Androgenetic
Mostly homozygous 46, XX
Proliferation of abnormal trophoblast tissue
Can develop into malignant trophoblastic tumour
No remaining embryo

150
Q

What is an ovarian teratoma

A 
Parthenogenetic conceptions
Derive from oocytes which have completed first or both meiotic divisions
Diploid
Wide spectrum of differentiated tissues:
-predominantly epithelial
-no skeletal muscle
-no membranes/ placenta
151
Q

Why do uniparental conceptions fail

A

Different roles of maternal and paternal genes in determining developmental fate
Karyotype and gene dosage are normal
Genomic imprinting

152
Q

What is genomic imprinting

A

Mothers and fathers somehow imprint their genes with a memory of their paternal or maternal origin
Mechanism ensures the functional non-equivalence of m and p genomes
Not encoded in the DNA nucleotide sequence (epigenetic)
Depends on modification to the genome laid down during gametogenesis (spermatogenesis vs oogenesis)

153
Q

What is angelman syndrome

A

Facial dysmorphism (prognathism, wide mouth, drooling, smiling/laughing appearance)
Mental handicap (microcephaly, absent speech)
Seizure disorder
Ataxic, jerky movements

154
Q

What is prader-willi syndrome

A 
Infantile hypotonia (feeding problems, gross motor delay)
Mental handicap
Male hypogenitalism/ cryptorchidism
Small hands and feet
Hyperphagia (resulting in obesity)
Stereotypic behaviour
155
Q

What causes prader-willi and angelman syndrome

A

Deletion of chromosome 15 (q11-q13)
De novo
Recurrence risk is very low
Deletion on maternal copy in angelman syndrome
Deletion on paternal copy in Prader-Willi syndrome

156
Q

What is uniparental disomy

A

When an offspring inherits two copies of one gene from now parent and none of that gene from the other parent

157
Q

What is DNA methylation

A 
Post-synthetic DNA modification
Epigenetic (does not alter DNA sequence)
DNA methyltransferases
Reversible
Has to be maintained after replication
Occurs at CG dinucleotides
Involved in gene regulation
Usually unmethylated CG islands at promotor region but if methylated then gene is silenced
158
Q

What is Beckwith-Wiedemann syndrome

A 
Fetal overgrowth (high birthweight >5kg)
Organomegaly (exomphalos)
Asymmetry
Tumour risk
Sporadic occurence
Epigenetic abnormalities
Too much IGF2 in pregnancy
159
Q

What is Russel-silver syndrome

A

Growth retardation (fatal, persistent postnatal growth failure)
Triangular face (brain size more preserved
Asymmetry
Sporadic occurrence
Too little IGF2 in pregnancy

160
Q

What is hypothesis independent genetic research

A

Without any prior knowledge we can identify which genes, proteins and pathways are involved in development and disease
Gene identification allows accurate diagnosis and counselling
Gene identification gives us a starting point for deciphering its function
Identifies targets for therapy

161
Q

How is genetics used in medicine

A 
Diagnosis: presymptomatic, prenatal, preimplantation
Counselling
Treatment
Therapy
Personalised medicine
Prevention
162
Q

What are the types of prenatal diagnosis

A

Amniocentesis (17 weeks)
Chorionic villus sampling (11 weeks)
NIPD- New non-invasive method based on NGS of mothers blood (10 weeks)

163
Q

What is classic gene therapy

A

Introduction of functional genes, in the form of DNA to replace mutated genes
Can repair mutated genes, silence overactive genes, provide immune cells with the tools needed to recognise and kill cancer cells and infections

164
Q

What is genetic counselling

A

A communication process which deals with human problems associated with the occurrence or the risk of occurrence of a genetic disorder in a family

165
Q

What is hypertrophic cardiomyopathy

A

Thickening of the heart muscle due to irregular pattern of muscle cells, can obstruct valves or affect heart rhythm
Not same as hypertrophy
Lifestyle implications
Medications, implantable devices, surgery
Small risk of sudden death from arrhythmia usually
Screening from 10-12
Autosomal dominant

166
Q

What is human genetics

A

The science of heredity and variation in humans

167
Q

What is medical genetics

A

The subset of human genetics that is important in medicine and medical research

168
Q

What is molecular genetics

A

The study of the structure and function of individual genes

169
Q

What is clinical genetics

A

The application of genetics to diagnosis and patient care in individuals and families

170
Q

What does nt mean

A

Nucleotide

171
Q

What does bp mean

A

Base pair

172
Q

What is a karyotype

A

The number and visual appearance of the chromosomes in the cell nuclei of an organism

173
Q

What are the chromosome landmarks

A

Centromere: middle bit
Arms: Short (p) and long (q)
Telomere: ptel and qte

174
Q

What is a telomere

A

TTAGGG telomeric repeat sequence
Made by telomerase (TERT) which is inactive in somatic cells
Telomeres shorten somatic cell division so finite number of cell division to senescence
Chromosomes are unstable without telomeres

175
Q

How do cancer cells bypass senescence

A

Telomerase (TERT) reactivation

176
Q

What are pseudoautosomal regions

A

Regions that are present on the X and the Y chromosomes

177
Q

What is the SRY gene

A

Sex determining region which determine production of testis and male traits

178
Q

What is the mitochondrial genome layout

A

Circular not linear

Cytoplasmic not nuclear

179
Q

What is in the human genome

A 
Single copy sequences:
-genes
Repetitive sequences:
-interspersed repeats
-satellite DNA: large blocks of repetitive sequences, heterochromatin
180
Q

What are Genes comprised of

A 
Functional units of DNA:
-Genes are expressed :
-transcribed into RNA
-Translate RNA into protein (not all)
Components (exons, introns, regulatory sequences - promoters, enhancers, locus control regions)
181
Q

What is the Alphoid DNA’s role

A

Required for assembly of centromere

182
Q

What is an example of intragenic pathology

A

Duchenne Muscular dystrophy

183
Q

What are the features of large deletions or insertions

A

Effects may vary
May be missed by PCR based screening methods if heterozygous
Examples:
Duchenne Muscular Dystrophy (deletion)
Charcot-Marie-tooth disease (duplication)

184
Q

What is an example of a gross rearrangement mutation

A

Haemophilia A

185
Q

What is a single-nucleotide indel

A

Insertion or deletion of a single nucleotide

186
Q

What is the hyper mutability of CG dinucleotides

A

C is methylated in to C-CH3
Undergoes deamination to T
Mismatch repair turns G to A so it matches T

187
Q

How is a molecular change described unambiguously

A

Reference sequence needed
Genomic DNA (g.)
cDNA (c.)
Protein (p.)

188
Q

What is a polymorphism

A

Variant that’s more common than 1%

189
Q

What is a rare variant

A

Variant that’s less common than 1%

190
Q

What is the process of FISH

A

1 Prepare short sequences of single stranded DNA that match a portion of the gene desired (called probes)

2 Label probes by attaching colours of fluorescent dye

3 Probes are able to bind to the complementary strand of DNA wherever it may reside on a person’s chromosomes

4 When a probe bends to a chromosome, the fluorescent tag provides a way to see that DNA location

191
Q

What is FISH used for

A

Locus specific probes: used to determine on which chromosome the gene is located or how many copies of a gene exist in a particular genome

Alphoid or centromeric repeat probes: Used to determine if individual has correct number of chromosomes. Can be used in combination with locus specific probes to determine whether individual is missing genetic material.

Whole chromosome probes are collections of smaller probes which each bind to different sequences along the length of chromosome. Allows each chromosome to be labelled unique colour resulting in a full colour map of the chromosome known as a spectral karyotype. Useful for examining chromosomal abnormalities.

192
Q

What is array CGH

A

An ultra high resolution way of objectively and quantitatively detecting whether a patient’s DNA has losses (deletions) or gains (duplications, triplications etc) which are pathogenic and therefore explain clinical problems

193
Q

What is the process of array CGH

A

Genomic BAC, P1, cosmic or cDNA clones are used for hybridisation and fluorescence ratios along the length of chromosomes provide a cytogenetic representation of the relative DNA CNVs

Fluorescence ratios at arrayed DNA elements provide a locus by locus measure of DNA Copy number variation and represent a means of achieving increased mapping resolution

194
Q

What are the two methods of prenatal testing

A

Amniocentesis

Chorionic villus sampling

195
Q

How is an amniocentesis performed

A

A sample of amniotic fluid is removed from uterus by insertion of a long thin needle through abdomen into uterus to withdraw a small amount of fluid which is then sent to lab for evaluation. It can be tested for genetic abnormalities, infection, signs of lung development

196
Q

How is Chorionic villus sampling performed

A

CVS removes a small sample of placenta tissue from uterus which is sent to the lab for testing. Sample can be taken by:
-A catheter through vagina, passed through the cervix and into uterus
-A needle through the abdomen which withdraws placenta tissue
Ultrasound used in both methods to guide.

197
Q

What is non disjunction in meiosis

A

Failure of chromosome or chromatid to separate

198
Q

What are the advantages and disadvantages of array CGH

A

Advantages:

  • Early diagnosis
  • High resolution (increased diagnostic hit rate)
  • Greater accuracy of location/size of imbalances
  • Information on relevant genes

Disadvantages:

  • Dosage changes only not balanced rearrangements or mutations
  • Low level mosaics not detected
  • Non pathogenic and uncertain pathogenic changes detected
  • Needs good quality DNA
199
Q

What happens in Quantitative fluorescent PCR

A

PCR amplification of short tandem repeats using fluorescent primers

200
Q

What is locus heterogeneity

A

A single disorder, trait or pattern of traits caused by mutations in genes at different chromosomal loci

201
Q

What is allelic heterogeneity

A

Different mutations at the same locus lead to the same or very similar phenotypes

202
Q

What is dysmorphology

A

The study of human congenital malformations (birth defects) particularly those affecting the anatomy (morphology) of the individual

Y2 Essential Medical Science (2 decks)

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