Genetics in Medicine Flashcards

Question

What is the purpose of modern genetics

Answer 1

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

Answer 2

Single gene Chromosomal Mitochondrial Imprinted

Answer 3

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

Answer 4

Family tree Physical examination Genetic tests

Answer 5

Non-genetic tests | Genetic tests

Answer 6

Blood tests | Xrays

Answer 7

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

Answer 8

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

Answer 9

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

Answer 10

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

Answer 11

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

Answer 12

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

Answer 13

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

Answer 14

An imbalance or rearrangement in chromosome structure | EG: aneuploidy, deletion, translocation

Answer 15

A mutation in mitochondrial DNA

Answer 16

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

Answer 17

Autosomal dominant Autosomal recessive X-linked Mitochondrial

Answer 18

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

Answer 19

Myotonic dystrophy Marfan syndrome Huntington disease

Answer 20

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

Answer 21

Variation in expression between different people

Answer 22

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

Answer 23

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

Answer 24

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

Answer 25

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

Answer 26

Cystic fibrosis Many of the metabolic disorders Haemachromatosis Sickle cell disease

Answer 27

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

Answer 28

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

Answer 29

X inactivation | X linked dominant vs X linked recessive inheritance

Answer 30

Dominant: Rett syndrome Fragile X syndrome Recessive: Red-green colour blindness Haemophilia Duchene musclular dystrophy

Answer 31

All from our mother

Answer 32

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

Answer 33

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

Answer 34

``` PCR DNA sequencing Array CGH Karyotyping FISH ```

Answer 35

Single-gene variants Copy number variants Chromosome number Structural changes

Answer 36

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

Answer 37

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

Answer 38

Detect presence or absence of a genetic sequence | Generate template for analysis of specific mutations

Answer 39

Distinguishes two alleles that may only differ by a single nucleotide

Answer 40

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

Answer 41

The smaller, more interesting, coding part of the genome

Answer 42

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

Answer 43

Interphase, prophase, metaphase, anaphase, telophase, cytokinesis

Answer 44

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

Answer 45

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

Answer 46

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

Answer 47

Study of chromosomes | Anything more than a single gene

Answer 48

Copy number variations Numerical: aneuploidy: gain (trisomy) or loss (monosomy) polyploidy: gain whole sets (triploidy or tetraploidy) mosaicism: diploidy and aneuploidy Structural: deletion duplication

Answer 49

``` 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 ```

Answer 50

``` Variable phenotype Variable lethality Non-identical identical twins Tissue-specificity lateral asymmetry Recurrence risk if gonadal ```

Answer 51

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

Answer 52

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

Answer 53

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

Answer 54

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

Answer 55

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

Answer 56

``` 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 ```

Answer 57

Disease specific acquired chromosome changes: Mostly translocation Several different acquired abnormal clones Diagnosis Prognosis Treatment Leukaemia: bone marrow Solid tumour: tumour tissue

Answer 58

Reciprocal: Break and exchange Robertsonian: Whole arm fusion

Answer 59

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

Answer 60

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)

Answer 61

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)

Answer 62

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

Answer 63

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

Answer 64

The frequency of the less common variant in a population

Answer 65

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

Answer 66

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

Answer 67

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

Answer 68

The result of the action of multiple genes

Answer 69

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

Answer 70

Relative risk to second children | Comparison of risk of having condition to the population risk

Answer 71

Cleft lip Congenital hip dislocation Congenital heart defects Neural tube defects

Answer 72

``` Asthma Autism Cancer Diabetes Epilipsy Hypertension Inflammatory bowel disease ```

Answer 73

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

Answer 74

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)

Answer 75

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

Answer 76

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)

Answer 77

APOE*E2: protective effect APOE*E3 APOE*E4: increase in susceptibility

Answer 78

A variant form of genes or genetic marker

Answer 79

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

Answer 80

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

Answer 81

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

Answer 82

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

Answer 83

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

Answer 84

Unaffected individuals selected from the extreme of a quantitative trait

Answer 85

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

Answer 86

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

Answer 87

The frequency of the less common variant in a population

Answer 88

Existing in one form only

Answer 89

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

Answer 90

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

Answer 91

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

Answer 92

Large deletions or insertions Gross rearrangements Point mutations Trinucleotide repeat expansions

Answer 93

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

Answer 94

``` Neurodegenerative disorder Symptoms: Involuntary movement Psychiatric changes Cognitive loss -> dementia Neuronal loss ``` Autosomal dominant: Heterozygous CAG repeat expansions Mutational instability Anticipation

Answer 95

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

Answer 96

Inherited from parents at birth

Answer 97

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

Answer 98

Improve genomic stability

Answer 99

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

Answer 100

Control the surrounding environment

Answer 101

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

Answer 102

Protects cells from becoming cancerous | Loss of function increases the risk of cancer

Answer 103

Regulate cell growth and differentiation | Gain of function/activating mutations increase the risk of cancer

Answer 104

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

Answer 105

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 ```

Answer 106

``` 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 ```

Answer 107

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

Answer 108

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

Answer 109

``` 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 ```

Answer 110

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

Answer 111

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

Answer 112

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

Answer 113

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

Answer 114

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

Answer 115

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

Answer 116

``` 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 ```

Answer 117

``` 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%) ```

Answer 118

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

Answer 119

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

Answer 120

``` around 1 in 50,000 Autosomal dominant Very variable Cleft palate Hearing impairment ```

Answer 121

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

Answer 122

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

Answer 123

Initiation of development using only paternal genetic material

Answer 124

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

Answer 125

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

Answer 126

``` 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 ```

Answer 127

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

Answer 128

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)

Answer 129

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

Answer 130

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

Answer 131

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

Answer 132

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

Answer 133

``` 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 ```

Answer 134

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

Answer 135

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

Answer 136

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

Answer 137

``` Diagnosis: presymptomatic, prenatal, preimplantation Counselling Treatment Therapy Personalised medicine Prevention ```

Answer 138

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

Answer 139

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

Answer 140

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

Answer 141

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

Answer 142

The science of heredity and variation in humans

Answer 143

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

Answer 144

The study of the structure and function of individual genes

Answer 145

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

Answer 146

Nucleotide

Answer 147

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

Answer 148

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

Answer 149

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

Answer 150

Telomerase (TERT) reactivation

Answer 151

Regions that are present on the X and the Y chromosomes

Answer 152

Sex determining region which determine production of testis and male traits

Answer 153

Circular not linear | Cytoplasmic not nuclear

Answer 154

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

Answer 155

``` 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) ```

Answer 156

Required for assembly of centromere

Answer 157

Duchenne Muscular dystrophy

Answer 158

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

Answer 159

Haemophilia A

Answer 160

Insertion or deletion of a single nucleotide

Answer 161

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

Answer 162

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

Answer 163

Variant that's more common than 1%

Answer 164

Variant that's less common than 1%

Answer 165

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

Answer 166

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.

Answer 167

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

Answer 168

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

Answer 169

Amniocentesis | Chorionic villus sampling

Answer 170

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

Answer 171

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.

Answer 172

Failure of chromosome or chromatid to separate

Answer 173

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

Answer 174

PCR amplification of short tandem repeats using fluorescent primers

Answer 175

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

Answer 176

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

Answer 177

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