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Medicine Year 3 > Week 1 - Medical Genetics > Flashcards

Week 1 - Medical Genetics Flashcards

1
Q

Give an example of targeted therapy used in non-small cell lung cancer

A
  • Majority of patients present with inoperable or metastatic disease
  • New targeted therapies include epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors e.g. Erlotinib
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2
Q

How many genes are there?

A

22,000 genes, can produce approx. 6 primary transcripts per gene

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3
Q

Describe the mutations which cause Duchenne and Becker muscular dystrophy

A
  • Mutation on DMD gene - located on Xp21, largest human gene (2.4 million base pairs)
  • DMD gene codes for dystrophin protein
    • Dystrophin forms link between F-actin intracellulary and the dystroglycan complex (protein complex on cell surface)
  • Dysfunction causes faulty connection between inside of cell and outside of cell (to other cells)
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4
Q

Give an example of genetic screening tests done neonatally

A
  • On Guthrie card, blood spot from heel e.g.
    • Mass spectrometry - phenylketonuria, MCADD
    • Immunoassay - congenital hypothyroidism, cystic fibrosis
    • HPLC - sickle cell disorder
  • All conditions that benefit from early, presymptomatic treatment
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5
Q

How can sub-microscopic duplications and deletions be detected?

A
  • MLPA - PCR based method that targets a group of specific known chromosomal loci where there might be a deletion (commonly around 1.5-2 million base pair deletions)
  • Chromosomal micro-array - now using large number (e.g. 850,000) of single nucleotide polymorphisms
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6
Q

Describe anticipation in SCA

A
  • Earlier onset and increasing severity of disease in subsequent generations
  • Expansion in number of CAG repeats that occurs with transmission of the gene - especially when transmitted by father
  • May be so extreme that children w/ early onset, severe disease die of disease complications long before affected parent or grandparent is symptomatic
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7
Q

What mutation causes Rubenstein Taybi syndrome?

A
  • Microdeletion syndrome involving chromosomal segment 16p13.3
  • Characterised by mutations in the CREB-binding protein gene
    • CREB-binding protein is important in regulating cell cycle - acts like a transcription factor
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8
Q

How many copies of

a) Tumour supressor genes
b) Proto-oncogenes

need to be faulty for loss of function?

A

a) Need two faulty TSGs for loss of function
b) Only need one faulty proto-oncogene for loss of function

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9
Q

Describe the effects of mutation in mitochondrial DNA

A
  • Only inherited from mother
  • All children will inherit faulty mitochondrial DNA from mother but to variable extents
  • Syndromes often affect muscle, brain and eyes
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10
Q

List the main principles of a screening programme

A
  1. Clearly defined disorder
  2. With appreciable frequency
  3. Advantage to early diagnosis
  4. Few false positives (specificity)
  5. Few false negatives (sensitivities)
  6. Benefits outweigh costs
  7. Important health problem
  8. Natural history of condition should be understood
  9. Recognisable latent or early symptomatic stage
  10. Test that is easy to perform and interpret, acceptable, accurate, reliable
  11. Accepted treatment recognised
  12. Policy on who should be treated
  13. Diagnoes and treatment should be cost-effective
  14. Case-finding should be a continuous process
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11
Q

Define variable expression/expressivity in AD conditions

A

Same genetic mutation can affect individual members of a family in different ways/to a different extent

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12
Q

Define genetic anticipation

A

Increasing severity and earlier age of onset of disease in successive generations

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13
Q

Give examples of genetic screening tests done in adulthood

A
  • Tay Sachs disease screening for Jewish populations - pre-pregnancy
    • Much higher risk in Ashkenazi Jew population, in US approx 1 in 27 Ashkenazi Jews are recessive carriers (Orthodox Jewish organisations offer anonymous screening programmes so carriers avoid marrying each other)
  • Thalassaemia - population carrier screening for thalassaemia (inadequate haemoglobin production, destruction of RBC, anaemia)
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14
Q

Describe the normal role and cancers associated with dysfunction in :

  1. MLH1
  2. MSH2
  3. MSH6
  4. BRCA1
  5. BRCA2
A
  1. Tumour suppressor gene, associated w/ bowel cancer (Lynch syndrome)
  2. Tumour suppressor gene, associated w/ bowel cancer
  3. Tumour suppressor gene, associated w/ bowel cancer (Lynch syndrome)
  4. Tumour suppressor gene, associated w/ breast and ovarian cancer
  5. Tumour suppressor gene, associated w/ breast and ovarian cancer (esp. male breast cancer)
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15
Q

How can aneuploidies be rapidly detected?

A

By quantitative fluorescent PCR (QF-PCR)

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16
Q

List the symptoms and complications associated with myotonic dystrophy

A
  • Progressive muscle weakness
  • Myotonia - difficulty relaxing muscles after contraction
  • Cataracts
  • Increased risk of developing diabetes and cardiac conductino defects - need regular ECGs and blood sugar monitoring
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17
Q

Define obligate carriers

A
  • Seen in X-linked recessive disorders
  • Females who must be carriers based on the individuals affected, e.g. mother of an affected individual, grandmother of an affected individual
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18
Q

How does the mutation which causes myotonic dystrophy cause its phenotypic affects?

A
  • Abnormal DMPK mRNA - CTG repeat downsteam of coding region
  • Indirect toxic effect upon splicing of other genes e.g. CLCN1 and insulin receptor gene (predisposition to diabetes)
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19
Q

Describe the mutation which causes fragile X syndrome

A
  • Repeatsin the 5’ UTR region of the FMR1 gene
  • If full mutation (>200 repeats)
    • Phenotype in males can be severe
    • Some carrier females also affected (but more mildly)
  • Repeats not in coding sequence, upstream
    • Promoter sequence, controls transcription
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20
Q

Mutation of what gene causes familial adenomatous polyposis (FAP)?

A

APC gene - chromosome 5

>100 polyps

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21
Q

List the features of Neurofibromatosis type 1

A
  • Cafe au lait macules - flat light-brown coloured patches
  • Neurofibromas - tumours on or under the skin, develop from nerves, start in teens
  • Short stature
  • Macrocephaly
  • Learning difficulties in 30% (severe in 3% or less)
  • Vary variable expressivity
  • Lisch nodules in iris, can be seen using slit lamp
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22
Q

Should a child with myotonic dystrophy in their family be tested?

A
  • Adult onset condition, no treatment available
  • Shouldn’t test for in children, wait until they are able to consent
  • Different in disease where there is treatment available - test in younger and provide therapy if diagnosed
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23
Q

How should an individual who is concerned about familial cancer be counselled in a genetic clinic?

A
  1. Draw out family tree and verify diagnoses (e.g. tummy cancer - stomach, pancreatic, colon?)
  2. Estimate likelihood of a predisposing gene mutation
  3. Discuss screening, risk factors, preventative measures
  4. Testing
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24
Q

What is the CRISPR-CAS9 system?

A
  • Possible future therapy = gene editing with CRISPR-CAS9 system
    • Mutation correction - CRISPR is a guide RNA that finds the target sequence
    • E.g. correct FBN1 in Marfan’s syndrome
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25
Q

Describe the usual pattern of inheritance of the most common cancer predisposition syndromes

A
  • Most are inherited in autosomal dominant fashion
    • MUTYH is exception - autosomal recessive
  • Most are due to inheritance of an altered TSG
    • Involve subsequent inactivation of the wild-type allele
    • Two hits - Knudson’s hypothesis 1971 (both normal copies of the gene have to be knocked out)
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26
Q

Describe the dysmorphic features seen in velocardiofacial syndrome (DiGeorge syndrome)

A
  • Prominent nose with narrow nasal passage
  • Cleft palate
  • Up-slanting palpebral fissures
  • Long thin upper lip and down-slanting mouth
  • Long face with prominent upper jaw
  • Underdeveloped lower jaw
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27
Q

List the pros and cons of PGD

A
  • Pros
    • Permits implantation of unaffected embryos
    • Termination of pregnancy then unnecessary
  • Cons
    • Possible long wait
    • Not available to all women (may restrict by age or by AMH level as an indicator of no. of remaining follicles)
    • Difficulty with multiple visits and procedures
    • ‘Take-home baby rate’ - likelihood of having live birth low - 1 in 3 PGD cycles result in pregnancy progressing to term
      • Once a healthy embryo acquired, there is an approx. 50% chance for each transferred embryo resulting in a pregnancy
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28
Q

How is a patient assessed in a genetic clinic?

A
  • Patient’s clinical history
    • With age of onset of symptoms, progression?
  • Family history
    • Consanguinity? Miscarriages? Stillbirths?
  • Examination
    • Any dysmorphic features
    • Normal growth (height, occipital-frontal circumference)
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29
Q

How can the risk of CRC in those with the MMR gene mutation present be reduced?

A

Aspirin

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30
Q

What are the principles of genetic counselling?

A
  • Provides genetics-related advice and information
  • Advice should be non-directive - should remain neutral, avoid taking a side, just give facts
  • Information re-investigation and interpretation
  • Thinking about implications for relatives
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31
Q

Boy has CF, what is his approximate chance of his mother’s brother being a carrier?

A
  • Cf is autosomal recessive - both parents are carriers
  • 25% chance of getting the disease, 50% chance of being a carrier, 25% unaffected
  • If one grandparent is a carrier - 50% chance of being a carrier
  • 50% chance of being a carrier
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32
Q

Describe the features of HNPCC (Lynch syndrome)

A
  • Usually only a few polyps (less than 10)
  • +/- uterus, stomach, ovary
  • Due to inheritance of mutation in MMR system of genes (mis-match repair) - important for accurate DNA replication
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33
Q

Describe the dysmorphic features seen in Rubenstein Taybi syndrome

A
  • Down-slanting palpebral fissures
  • Microcephaly
  • Broad thumbs and big toes
  • Short stature
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34
Q

Describe the mutation which causes myotonic dystrophy

A
  • Unstable length mutation of CTG repeat
  • In the 3’ region (i.e. downstream end of the gene, not in the coding region) - transcribed but not translated part of the DMPK gene
  • Affected if 50+ repeats
  • Higher chance of expansion when transmitted by females
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35
Q

Are proto-oncogenes only expressed in malignant tissues?

A
  • No - also expressed in healthy tissues
  • Participate in the normal cellular response to growth factors, stimulate proliferation
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36
Q

How are genetic screening tests used?

A
  • Whole population is offered test but each person has a low individual risk
  • Tests need to be cheap and non-invasive so they may not be 100% sensitive
  • Currently offered at 3 stages in life
    • Pregnancy
    • Neonatally
    • Adulthood
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37
Q

Define specificity

A

Proportion of healthy people who are correctly identified as not being affected

Specificity = true negatives/(false positives + true negatives)

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38
Q

Define a haplotype

A

A collection of specific alleles in a cluster of tightly linked genes on a chromosome that are likely to be inherited together - likely to be conserved as a sequence that survives the descent of many generations of reproduction

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39
Q

Define the genome

A
  • All DNA - nuclear (3 billion base pairs) and mitochondrial (17k base pairs) genomes
  • 1.5% protein encoding, rest are inter-genic regions
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40
Q

Describe the pattern of inheritance of spinocerebellar ataxia

A
  • Have different modes of inheritance - autosomal dominant, autosomal recessive or rarely mitochondrial or X-linked
  • Onset mostly adulthood, rarely childhood
  • Genetic anticipation - earlier onset and worsening severity in subsequent generations due to expansion in number of CAG repeats
    • May be so extreme that children w/ early onset severe disease die long before parents/grandparents are symptomatic
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41
Q

Explain how DMD may be treated in the future using gene therapies

A
  1. Exon skipping - convert DMD to BMD phenotype by altering splicing patterns
  • Correct the reading frame (out-of-frame to in-frame deletions) with antisense oligonucleotides, skips the exons with mutations (45 and 53 in DMD gene)
  • Synthesise nucleic acid (or chemical analogue) that will bind to mRNA produced by gene and inactivate it, effectively turning that gene off (skipping it)
  • OR - targeted to bind a splicing site on pre-mRNA and modify the exon content of an mRNA (as in AON)
  • AON therapy works in cells and mouse models of DMD
  1. Use a drug to permit read-through of premature stop codons (e.g. Ataluren or PTC124)
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42
Q

Give an example of the two hit hypothesis

A
  • MEN1 - example of a TSG
  • Patient with MEN1
    • 1st hit - inheritance of one faulty MEN1 gene from parent
    • 2nd hit - development of second faulty MEN1 gene throughout lifetime
    • = cancer
  • Patient without MEN1
    • Both hits due to mutation of normal MEN1 genes throughout lifetime - takes longer so cancer develops later in lifetime
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43
Q

What is the affect of mutations to proto-oncogenes?

A
  • Mutation leads to gain of function - unsual stimulation of the cell cycle
  • Only need one faulty allele to have irregular
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44
Q

Which methods of DNA analysis can provide whole chromosome analysis?

A

Karyotyping using light microscope

QF-PCR - specific aneuploidies

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45
Q

Define sensitivity

A

Ability of the test to identify those with the disease

Sensitivity = true positive / (true positive + false negative)

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46
Q

Why should DNA of affected individuals with a family history of cancer be stored?

A

For future mutation analysis used in testing of relatives

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47
Q

How can point mutations be detected?

A
  • DNA sequencing
    • Automated fluorecent dideoxy (Sanger) sequencing - 1 gene at a time
    • Massively parallel (‘next-generation’) sequencing (many or all genes)
  • Allele specific (ARMS) PCR
    • Special PCR then analysis only for specific point mutations
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48
Q

Describe the low penetrance loci for breast cancer

A
  • At least 72 mutations confer an increased susceptibility to breast cancer
  • Common - >5% of the population
  • Each genetic variant generally confers a small effect e.g. a 10-20% increased risk
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49
Q

A mutation on which gene is responsible for SCA?

A
  • SCA caused by mutation in AXTN gene on chromosome 12 - CAG trinucleotide repeat
    • E.g. SCA type 2 caused by abnormal CAG trinucleotide repeats on ATXN2 gene
  • ATXN gene codes for ataxin protein
  • Affected have alleles with more than 33 CAG trinucleotide repeats
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50
Q

What proportion of offspring of a male with an X-linked recessive condition will be affected/carriers?

A
  • None of his sons are affected (passes on Y chromosome)
  • All of his daughters are carriers (must pass on affected X chromosome)
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51
Q

Give an example of the use of FISH in practice

A
  • E.g. to detect William’s syndrome - mutation on elastin gene at 7q
    • Deletion of elastin gene on one chromosome 7
    • Need to know the position on chromosome where gene may be missing (to design the probe)
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52
Q

When is PGD used?

A
  • Used in patients with serious genetic conditions in their family, need to do IVF even if no fertility problems
  • Transfer only unaffected embryos to the patient - up to two embryos
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53
Q

Which methods of DNA analysis can detect point mutations?

A

DNA sequencing or ARMS

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54
Q

Give examples of diseases which show X-linked dominant inheritance

A
  • Vitamin D resistant rickets - hypophosphataemia (can be AD sometimes)
  • Incontinentia pigmenti - male lethality
  • Rett syndrome - usually male lethality
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55
Q

How can known substitutions, deletions or insertions be detected?

A

Allele specific (ARMS) PCR

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56
Q

How can disorders of mitochondrial DNA be prevented from being passed on

A
  • ‘Three person baby’
  • If mother has mitochondrial DNA damage - use donor mitochondrial DNA and mothers nuclear DNA + father’s sperm
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57
Q

Describe the mutation which causes cystic fibrosis

A
  • Mutation in the CFTR gene means chloride ion channels are defective, secretions are thicker
  • Over 1000 different mutations in CFTR gene, most common is F508del
    • In-frame deletion of 3 base pairs (one codon)
    • Deletion of a phenylalanine at position 508
    • Prevents normal folding of protein and insertion into plasma membrane
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58
Q

What is the normal function of proto-oncogenes?

A
  • Normally stimulate the cell cycle
  • Activation from onco-genes –> proto-oncogenes w/ gain of function
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59
Q

What usually causes trisomies e.g. trisomy 21 (Down’s)?

A

Maternal non-disjunction (failure of normal separation of the two chromosomes number 21, 18 or 13) in meiosis

Trisomies more frequent with increased maternal age

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60
Q

How can breast cancer be treated using targeted therapies?

A

If HER2 positive (duplication of gene) can use trastuzumab (Herceptin)

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61
Q

Describe how skewed X inactivation can lead to manifesting carriers in X-linked recessive disorders

A
  • Normally - X inactivation occurs in female embryos, X switched off to leave one active X per cell
    • If inherits mutated X chromosome, usually 50% switched off will be mutated, 50% normal - balances out
  • Skewed X inactivation - more normal X’s switched off than mutated, more mutated X’s expressed, carrier can be mildly affected
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62
Q

How is FAP screened for?

A

Annual bowel screening from age 11

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63
Q

How does genetic anticipation occur in Huntington’s disease?

A
  • Huntington’s is caused by a duplication of triplet repeat base sequences
  • Increasing sequence repeats in subsequent generations worsens severity of disease and causes earlier onset
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64
Q

How is spinocerebellar ataxia diagnosed?

A
  • Single blood test to check for many ataxia genes
  • Prenatal testing - available in families who have been proven to have mutations in some genetic ataxias
    • CVS available in 1st trimester, amniocentesis early 1st trimester or later in 2nd
  • Advice from clinical geneticist needed as soon as family is being planned/early in pregnancy as possible
  • Hard to distinguish between types because of overlap of symptoms/onset
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65
Q

What is thought to cause the differences in penetrance/severity of genetic disorders?

A

Modifier genetic variants - genes other than the disease causing gene which affect severity or penetrance e.g. FGFR2 variants in BRCA2 mutation carriers

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66
Q

Define gonadal mosaicism

A

Mixture of mutated and unaffected gametes

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67
Q

Describe the chromosomal abnormality which causes Down syndrome

A
  • Trisomy 21
  • Translocation e.g. 14:21 translocation
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68
Q

What proportion of breast cancers are familial?

A

5-10%

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69
Q

List the capabilites which must be acquired for a cell to develop into cancer? (Hallmarks of cancer)

A
  • Evading apoptosis
  • Inducing angiogenesis
  • Avoiding immune destruction
  • Enabling replicative immortality - bypassing replicative senescence
  • Tumour promoting inflammation
  • Activating invasion and metastases
  • Genome instability and mutation
  • Deregulating cellular energetics
  • Insensitivity to anti-growth signals
  • Sustaining proliferative signalling
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70
Q

How are non-invasive prenatal tests being used in the diagnosis of genetic disorders?

A
  • Recently introduced for foetal sex determination (e.g. for X-linked conditions) and paternal mutations e.g. for FGFR3 mutations (achondroplasia)
  • Latest - testing for aneuploidy
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71
Q

What chromosomal abnormality causes Edward’s syndrome?

A

Trisomy 18

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72
Q

Define cascade screening

A

Identification of mutations permits prenatal diagnosis is desired and the subsequent identification of carrier relatives.

Cascade screening = mechanism for identifying those at risk of genetic disorder by systematic family tracing

73
Q

Describe the pattern of inheritance of fragile-X syndrome

A
  • X-linked recessive (females can be affected mildly)
  • Genetic anticipation - due to repeats in the 5’ UTR region of the FMR1 gene
  • Most common inherited cause of significant learning disability
74
Q

Give example of diseases which could be treated using medicine tailored to a specific disease-causing mutation

A
  • In CF - inherited mutation
    • G551D is the 3rd most common CF mutation (present in 4% of patients)
    • Blocks the opening of CFTR chloride ion channel
    • Ivacaftor (Kalydeco) - re-opens the channel
  • In tumour cells - somatically acquired
    • Can tailor cancer treatment to a tumour’s genotype - example of precision/stratified medicine (use of one or more clinical biomarkers to identify therapies more suited for specific patients)
    • E.g. EGFR in lung cancer - specific mutations can make tumour more or less sensitive to inhibitor (Gefitinib - Iressa)
75
Q

Compared in and out-of-frame deletions

A
  • 3 nucleotides encode 1 amino acid = a codon
  • In-frame deletion - multiples of 3 nucleotides (whole codons) deleted
  • If deletion is not a multiple of 3, reading frame is shifted downstream, whole chain is wrong - protein completely disrupted, more severe phenotype
76
Q

What mutation leads to Huntington’s disease?

A
  • Unstable length mutation in Huntingtin (HTT) gene - on short arm of chromosome 4
    • Up to 35 repeats = unaffected
    • 36-39 repeats = incomplete penetrance
    • More than 39 = complete penetrance
  • CAG repeat unit within the coding sequence - encodes a polyglutamine tract, expansion of tract causes insoluble protein aggregates and neurotoxicity
77
Q

List the preventative measures which can be taken when an indidvual has a family history of familial breast cancer

A
  • Examinations
  • Screenings by mammography or MRI
  • BRCA1/2 mutation carriers may be offered
    • Prophylactic mastectomies
    • Prophylactic oophorectomies
78
Q

Define X-linked dominant inheritance

A
  • Mutated gene on the X chromosome
  • Males (XY) will be affected
  • Females (XX) with one mutated X will be affected
79
Q

What proportion of colon cancers are familial?

A

Strong genetic basis in 5-10%

80
Q

Compare Duchenne and Becker muscular dystrophy

A
  • DMD
    • Onset - 3 years
    • Wheelchair by 12 years
    • 65% deletions out-of-frame
  • BMD
    • Onset - 11 years
    • Wheelchair much later, or not at all
    • 85% deletions in-frame
81
Q

Describe the pattern of inheritance of Huntington’s disease

A
  • Autosomal dominant with genetic anticipation
  • Prone to expansion of mutation during meiosis, especially if inherited from father
82
Q

What is the normal function of the BRCA1/2 genes?

A

BRCA1/2 proteins cause transcriptional activation - proteins produced that carry out DNA repair by homologous recombination of double-strand breaks

83
Q

Give examples of diseases which show:

A) Complete penetrance

B) Incomplete penetrance

A

A) Huntington’s disease

B) Breast cancer caused by BRCA1 gene

84
Q

Describe the mutation which causes MYH polyposis

A
  • MYH gene mutation
    • Normal function = base excision repair gene - DNA glycosylase
85
Q

Give an example of a genetic screening test done prenatally

A
  • Down’s syndrome, affects 1/700 pregnancies
    • CUBS screening in 1st trimester - early enough to offer a 1st trimester termination if DS confirmed by diagnostic test
    • Maternal blood biochemical markers
    • Ultrasound - nuchal translucency increases in DS
86
Q

Why is Duchenne muscular dystrophy more severe than Becker?

A
  • Mutation which causes Becker often has in-frame deletions, doesn’t ruin reading frame downstream
  • Duchenne - deletion is out-of-frame, all amino acids after deletion are wrong
    • Inappropriate stop codons, protein is cut short (failure of nonsense mediated decay - usually stops mRNA chains with premature stop codons from being translated)
87
Q

List the characteristics of X-linked dominant inheritance which may be seen on a pedigree chart

A
  • Autosomal dominant-like but no male-to-male transition
  • Vertical transmission
88
Q

The presence of male breast cancer in a family with other breast cancers, suggests which gene may be mutated?

A

BRCA2 - tumour suppressor gene associated w/ breast and ovarian cancer (especially male breast cancer)

89
Q

Describe the general pattern of inheritance of familial colon cancers

A
  • Mostly autosomal dominant
  • Except MYH (2-3% of colorectal cancer)
90
Q

If a condition is autosomal recessive and both parents are carriers, what is the chance that their child will be:

A) Affected

B) A carrier

C) Unaffected?

A

A) 25%

B) 50%

C) 25%

91
Q

For the detection of what is QF-PCR used most often (in the diagnostic lab)?

A
  • Rapid detection of aneuploidies
    • By quantitative fluorescent PCR (QF-PCR)
    • Aneuploidy = abnormal number of chromosomes, that is not a multiple of 23 e.g. trisomy 18
  • Also for sex chromosome abnormalities
92
Q

What proportion of offspring of a female heterozygote for an X-linked recessive condition will be affected/carriers?

A
  • 50% of sons affected
  • 50% of daughters carriers
93
Q

What tests may become available in the future for prenatal diagnosis of genetic disorders?

A
  • aCGH for fetuses with abnormal ultrasound scans
  • Non-invasive prenatal diagnosis (NIPD) for achondroplasia and for foetal sex determination
  • ‘NIPT’ for aneuploidy e.g. Down’s syndrome using NGS, available privately (‘NIPT’ as still requires an invasive test)
94
Q

Define X-linked recessive inheritance

A
  • A mutation on the X chromosome causes the disease in males (XY) and in females who are homozygous for the mutation (XX)
  • Females who have the mutation on one X chromosome are carriers for the disease (not affected)
95
Q

What is the affect of mutations to tumour suppressor genes?

A

Mutations cause loss of function and usually require loss of wild-type allele (need both alleles to be faulty to have irregular function)

96
Q

List characteristics of autosomal dominant inheritance which could be seen on a pedigree chart

A
  • Vertical pattern of inheritance
  • Affects males and females equally
  • Can be passed from father to son (distinguishes from X-linked)
97
Q

Define triploidy

A

3 full sets of chromosomes (69 chromosomes)

98
Q

Describe heteroplasmy in mitochondrial DNA

A
  • Mixture of mutated and normal mitochondrial chromosomes = heteroplasmy
  • Threshold affect - need certain percentage of heteroplasmy before disease is seen
99
Q

Define autosomal recessive inheritance

A

Affected individual has inherited the faulty gene from both parents - need two copies of the mutated gene to be affected

100
Q

What are the risks of developing cancer if there is a mutated MMR gene?

A

MMR gene present:

  • Males - 80-90% lifetime risk of colon cancer
  • Females - 40% risk of colon cancer, 50% risk of endometrial cancer and approx. 4% risk of ovarian cancer
  • Gastric approx 5%
  • Glioma small risk
101
Q

Define penetrance, incomplete penetrance and complete penetrance

A
  • Penetrance - the proportion of individuals carrying a particular allele of a gene that also express the associated trait
  • Incomplete penetrance - can inherit the mutation but not have the disease
  • Complete penetrance - if the mutation is inherited the individual is guaranteed to have the disease to some extent
102
Q

What causes NF1?

A
  • Mutation of gene on chromosome 17, overproduction of neurofibromin
  • Autosomal dominant disorder
103
Q

Give an example of a technique for next generation sequencing

A

Illumina method - hundreds of millions of DNA fragments sequenced at once, on a ‘flow cell’

104
Q

Give an example of a disorder with X-linked recessive inheritance

A

Duchenne muscular dystrophy, Becker muscular dystrophy

105
Q

What is MLPA most commonly used to detect?

A

MLPA = PCR-based method that targets a group of specific known chromosomal loci where there might be a deletion

106
Q

Which of the following is not a tumour suppressor gene?

  1. MSH2
  2. MLH1
  3. BRCA2
  4. RET
  5. APC
A

RET is not a TSG - proto-oncogene

107
Q

List the main symptoms of cystic fibrosis

A

Recurrent lung infections, exocrine pancreas insufficiency, male infertility (vas deferens problem)

108
Q

What chromosomal abnormality causes Patau’s syndrome

A

Trisomy 13

109
Q

Describe the pattern of inheritance of MYH polyposis

A

Autosomal recessive

110
Q

How is SCA treated?

A

No specific treatments can prevent, delay or reverse major clinical features of dominant SCA, some manifestations e.g. seizures can be treated, certain rehabilitative measures can be of benefit

111
Q

List the features of Down’s syndrome

A
  • Learning difficulties
  • Heart malformations in >40%
  • Hypothyroidism in 30%
  • Single palmar crease
  • Typical facies
112
Q

When are genetic diagnosis tests used?

A
  • Individuals with high genetic risk
  • Need high sensitivity and specificity
  • Done after e.g. positive screening test or if there is a family history
113
Q

How are those at risk of HNPCC screened for colon cancer?

A

If at high risk - 2-yearly colonoscopies from age of 25, 2-yearly upper GI endoscopy from age 50

114
Q

What should be reviewed in an annual follow-up for NF1?

A
  • BP - phaeochromocytomas produce adrenaline
  • Vision, esp. loss of peripheral - optic pathway gliomas
115
Q

How can X-linked recessive conditions be tested for in embryos?

A

Embryo sexing for X-recessive conditions possible by FISH or PCR

Red probe detects Y, green prove detects X, blue probe acts as a control

116
Q

If a woman has a familial breast cancer in her family, and her mother has the BRCA1/2 gene, what is her risk of developing breast cancer?

A
  • 50% chance of her mother passing on the BRCA1/2 gene
  • BRCA1/2 has incomplete penetrance - 80% chance of developing cancer if you have the gene
  • Her chance of developing breast cancer = 50 x 80 = 40%
117
Q

Give examples of genetic conditions which show autosomal dominant inheritance

A
  • Achondroplasia
  • Most inherited cancers e.g. breast, colon
  • Adult polycystic kidney disease (children usually recessive)
  • Neurofibromatosis type 1 (NF1)
118
Q

How does translocation cause Down’s syndrome?

A
  • Parent has one chromosome 21 attached to chromosome 14 - still has the right amount of genetic material
  • When has children could result in spontaneous abortion, Down’s syndrome or could have no affect
  • Child with Down’s syndrome - becomes translocation carrier, like the parent
  • Translocation Down’s syndrome = familial Down’s syndrome
  • Have to test parents of child with Down’s for translocation - higher risk of other children also having Down’s
119
Q

Describe the pattern of inheritance of cystic fibrosis

A

Autosomal recessive

120
Q

What is the normal function of tumour supressor genes?

A
  • Normally inhibit progression through the cell cycle
  • Promote apoptosis
  • Some act as stability genes - carry out repair to damaged DNA to minimise genetic alterations (account for commonest hereditary cancer predisposition syndromes)
121
Q

Why are patients with Huntington’s disease often underweight?

A
  • Constant involuntary movements - always burning calories
  • Difficulty eating
122
Q

List the possible complications of NF1

A

Uncommon, but increased risk of:

  • Hypertension
  • Scoliosis requiring surgery
  • Pathological tibial fractures
  • Significant tumours e.g. phaeochromocytomas (from adrenal cortex, overproduction of adrenaline, BP goes up), optic pathway gliomas
123
Q

What is pseudo-dominant inheritance?

Give an example

A
  • Unusually - if an autosomal recessive condition but a very high carrier frequency or consanguinity so appears like autosomal dominant
  • Many affected in one family
  • E.g. Gilbert’s syndrome
    • Carrier frequency = 50% (high)
    • Causes intermittent jaundice, due to hyperbilirubinaemia
124
Q

Describe the data analysis of DNA test results

A
  • Machine produces a FASTQ (raw data) file
  • Align sequencing ‘reads’ to the reference genome sequence
  • Produces a BAM file as a result
  • Use a computer to identify the variants compared to the reference sequence
  • Produces a variant call format (VCF) file - list of all variants
  • Software then filters the list to the variants that are not common variants e.g. polymorphisms, and are predicted to be damaging the protein
125
Q

How is Huntington’s disease diagnosed?

A
  • DNA testing possible - testing unaffected relatives can be performed
  • Presymptomatic test i.e. predictive
  • Test only done after full discussion of pros and cons + with full written consent
126
Q

12 year old boy has CF, what is the approximate chance that his healthy older sister is a carrier?

A

67% chance of being a carrier - doesn’t have the disease so 2/3 chance of being a carrier, 1/3 chance unaffected

127
Q

In individuals with the BRCA2 gene, what is the risk of breast/ovarian cancer and male breast cancer?

A

By age 70:

  • 18-88% for breast cancer
  • 10-35% for ovarian cancer
  • 5-6% for breast cancer in men
128
Q

List the features of an autosomal recessive disorder which could be seen on a pedigree chart

A
  • Usually horizontal not vertical pattern - may skip generations
    • I.e. affected individuals in one sibship
  • Both males and females may be affected
  • There may be consanginuity in the family
  • Parents of affected children are both carriers
129
Q

Describe chromosome-based analysis methods

A
  • Karyotyping - examining chromosomes under a light microscope
  • Fluorescence in-situ hybridisation (FISH) - uses a specific DNA probe that binds to location on a chromsome
130
Q

Compare the differences between sporadic and familial cancers

A
  • Sporadic
    • Common
    • Late onset
    • One primary tumour - can have metastases
  • Familial
    • Uncommon
    • Early onset
    • Often multiple primaries
131
Q

What biochemical marker can be used in the diagnosis of DMD?

A
  • Serum creatine kinase (SCK)
    • CK leaks out of damaged muscle fibres into serum
    • Boys with DMD will have massively increased levels of SCK from birth - before any other symptoms are noticeable
132
Q

Give an example of a genetic disorder which shows reduced occipital-frontal circumference

A

Down’s syndrome

133
Q

List characteristics which indicate a high risk breast cancer family

A
  • BRCA1/2 in 84% of families with 4 breast cancers younger than 60 y/o
  • Less commonly - TP53 (involved in other tumours), PALB2, PTEN (also causes Cowden’s syndrome)
  • Presence of ovarian cancer? Male breast cancer in family?
134
Q

Describe the differences between nuclear and mitochondrial DNA

A
  • Mitochondrial DNA has much smaller genome - only 16.6k base pairs, 37 genes
  • Mitochondrial DNA is circular rather than linear (nuclear)
  • No introns in mitochondrial DNA
  • Mitochondrial DNA is only inherited from the mother
135
Q

In individuals with the BRCA1 gene, what is their risk of developing breast/ovarian cancer?

A

40-87% risk of breast cancer by 70 y/o, 22-65% of ovarian cancer

136
Q

Summarise the similarities and differences between autosomal dominant and autosomal recessive inheritance

A

Autosomal dominant and autosomal recessive:

  • Equal frequency in males and females

Autosomal dominant only:

  • Vertical pedigree pattern
  • Disease expressed in heterozygotes
  • Offspring of affected individuals usually have a 50:50 risk of being affected
  • Variable expressivity
  • There may be incomplete penetrance

Autosomal recessive only:

  • Horizontal pedigree pattern
  • Disease expressed in homozygotes (2 identical mutated alleles) or compound heterozygotes (2 different mutations)
  • Offspring of affected individuals have low risk of being affected
  • Expressivity more constant within a family
  • Importance of consanguinity
137
Q

Give an example of a disorder inherited through mitochondrial DNA

A
  • Leigh’s disease
    • In mitochondrial DNA - MT-ATP6 gene
    • Affects ATP synthase
138
Q

Define the term compound heterozygous

A

Faults which cause the disease are different on each gene

139
Q

Summarise the characteristics of X-linked recessive and X-linked dominant inheritance

A

X-linked recessive and dominant:

  • No male to male transmission

X-linked recessive only:

  • Knight’s move
  • Male-to-female - all daughters carriers
  • Female-to-female - 50% daughters carriers
  • More males affected than females

X-linked dominant only:

  • Vertical transmission
  • Male-to-female - all daughters affected
  • Female-to-female - 50% daughters affected
  • F:M is 2:1
140
Q

List the genes which cause HNPCC

A
  • MLH1 - 50%
  • MSH2 - 40%
  • MSH6 - 7-10%
  • PMS2 - <5%
141
Q

List the dysmorphic features which may be seen in those with a genetic condition

A
  • Head shape and size (micro or macrocephaly)
  • Eyes
    • Palpebral fissures (size? slant?)
    • Spacing (hypertelorism means pupils too far apart e.g. Edward’s syndrome)
  • Ears
    • Size, shape, position (low-set? - Down’s syndrome, Turner’s syndrome)
    • Rotated anteriorly or posteriorly
  • Nose (size, nares - nostrils)
  • Philtrum (smooth) e.g. in FAS (foetal alcohol syndrome)
  • Mouth - size, lips, teeth
  • Limp - disproportion
  • Skin - lumps, abnormal pigmentation
  • Hands and feet
    • Palmar creases - Down syndrome
    • Fingers and toes - correct number, polydactyly, syndactyly
142
Q

When is disclosure of information regarding genetic testing acceptable?

A

Patient confidentiality is always crucial, but GMC guidance suggests that in exceptional circumstances, where there is risk of ‘serious harm’ to others (e.g. relatives) from non-disclosure, the doctor must make a judgement, balancing there issues. Where possible, identity should not be disclosed.

143
Q

What causes the range in risk of familial cancers caused by the same genes?

A

Range in risk of penetrance due to modifier genes

144
Q

What is the function of the intergenic regions of the genome?

A
  • Function largely unknown
    • Some are enhancers, some are silencers (enhance or slow transcription rate)
145
Q

Define autosomal dominant inheritance

A

If the abnormal gene is passed down from one parent, you can get the disease (only need one faulty copy)

146
Q

List the features of Edward’s syndrome

A
  • Small chin
  • Clenched hands with overlapping fingers
  • Malformations of the heart, kidney and other organs
  • If survive first year, generally have profound learning difficulties
147
Q

List the symptoms of spinocerebellar ataxia

A
  • Broad-based gait - feet wider when walking
    • Can also be when sitting/standing, due to balance problem
  • Lack of purposeful coordination in hands (intention tremor), imprecision when trying to reach a target with fingers (past pointing), difficulties with fast and alternating actions (dysdiadochokineasia) and slurred speach (dysarthria) = clumsy
148
Q

Define the term double heterozygous

A

Disease is caused by faults on two separate genetic loci

149
Q

Which methods of DNA analysis can detect submicroscopic deletions/duplications <5mb?

A

FISH or MLPA - if position known

Chromosomal microarray - if position not known

150
Q

List the main symptoms of Huntington’s disease

A

Progressive chorea (involuntary movements), dementia and psychiatric symptoms

151
Q

List the mutations which predispose to ovarian cancer

A
  • BRCA1/2
  • HNPCC gene - MLH1 or MSH2
  • More rarely - RAD51C, PTEN, STK11 (causes Peutz-Jeghers syndrome), PTCH
152
Q

Give examples of conditions which show autosomal recessive inheritance

A
  • Cystic fibrosis
  • Phenylketonuria (PKU)
  • Spinal muscular atrophy
  • Congenital adrenal hyperplasia (hypoplasia is X-linked)
153
Q

Describe the features of Li Fraumeni Syndrome

A
  • Rare autosomal dominant cancer predisposition syndrome
    • Breast cancer
    • Brain tumours
    • Sarcoma
    • Leukaemia
    • Adrenocortical carcinoma
  • Chance of cancer - 50% by age 30, 90% by 50
  • Mutations in master control gene, TP53
154
Q

What kind of mutations is next generation sequencing be used to detect?

A
  • Single gene - like Sanger sequencing
  • Several genes at once - gene panel
  • Exome - all coding regions of genome
  • Genome - coding and non-coding regions
155
Q

Give an example of expressivity in an AD condition

A

BRCA1 gene - inherited in an AD manner, can cause breast cancer, ovarian cancer or the individual can be unaffected

156
Q

How is cystic fibrosis diagnosed?

A
  • Screening of newborns by immunoreactive trypsin (IRT) level
  • Confirmation by DNA testing (for CF mutations) and/or sweat testing (for increased chloride concentration)
157
Q

Define spinocerebellar ataxia

A
  • Group of genetic disorders characterised by a slowly progressive incoordination of gait, often associated with poor coordination of hands, speech and eye movements
158
Q

How common is cystic fibrosis?

A
  • 1 in 2500 newborns in the UK
  • Carrier frequency of 1 in 2 –> 1 in 25
  • Commonest life-limiting autosomal disease in Caucasians
159
Q

Why are more females than males affected by X-linked dominant disorders?

A

Females have 2 X chromosomes, 2x the chance to inherit a faulty gene

160
Q

What DNA testing could be done in an undiagnosed dysmorphic child with intellectual disability?

A
  1. Look for deletions/duplications w/ microarray
  2. Use next generation sequencing to find small mutations somewhere in exome
161
Q

List the features of Patau’s syndrome

A
  • Congenital heart disease is usual
  • About 50% die within a month
  • Like in Edward’s syndrome, approx only 10% survive 1st year, generally with profound learning difficulties
  • Features
    • Cleft lip and palate
    • Micro-ophthalmia
    • Abnormal ears
    • Clenched fists
    • Post-axial polydactyly
162
Q

What is ARMS commonly used for detecting?

A

Single nucleotide substitution in a known position in a gene

163
Q

What is the pattern of inheritance of Duchenne muscular dystrophy?

A

X-linked recessive

164
Q

What preventative measures can be taken in those with familial ovarian cancer?

A
  • Screening difficult
  • Prophylactic surgery
  • Possible treatment - PARP (poly ADP ribose polymerase) inhibitioin (olaparib)
165
Q

Describe the pattern of inheritance of myotonic dystrophy

A

Autosomal dominant with genetic anticipation

166
Q

What is the risk of having a second child with Down’s syndrome?

A
  • Trisomy 21 - for young parents, low risk at birth of 1/100
  • Translocation - higher risk
167
Q

When are the symptoms of Huntington’s disease usually first seen?

A

Onset between 30-50, occasionally younger

168
Q

Define aneuploidy

A

Abnormal number of chromosomes that is not a multiple of 23 e.g. trisomy 18

169
Q

How is MYH polyposis screened for?

A

2 yearly colonoscopy

170
Q

How can embryos be tested for genetic disorders?

A

Pre-implantation diagnosis

  • One/two cells removed for testing, at three days when embryo contains 6-10 cells (blastomere stage)
  • Then QF-PCR or PCR - for mutation of just for a set of neighbouring DNA markers i.e. haplotype
  • Or FISH

More recently:

  • Trophoectoderm biopsy at 5-6 days (blastocyst stage - approx. 100 cells) - now being done in Scotland
  • Cells collected from trophectoderm cells - which will form the placenta (not from inner cell mass - will form foetus itself)
171
Q

What is a gene panel used to detect?

A

Look for several genes at once which all cause disease

172
Q

List the characteristics of X-linked recessive disorders which may be seen on a pedigree chart

A
  • Not vertical or horizontal pattern - knights move inheritance
  • No male to male transition - father only passes Y chromosome to son
  • Mostly or only males affected
    • Chances of females inheriting two mutated X chromosomes is very low
    • Occasional manifesting carriers due to ‘skewed X inactivation’
173
Q

When examining an individuals pedigree chart, what suggests they are at a high risk of familial cancer?

A
  • 2+ first degree relatives affected
  • Relatives who have had more than one type of primary cancer (esp. e.g. breast and ovarian)
  • Relatives have had cancer young
174
Q

List the DNA-based methods of detecting mutations

A

DNA extracted and tested for:

  1. Detection of point mutations
  2. Detection of sub-microscopic duplications and deletions
  3. Rapid detection of aneuploidies
175
Q

What is PTC124?

A

Oral drug, trials still ongoing

Small molecule that may cause ‘read-through’ of premature stop codons

176
Q

When are prenatal genetic tests used?

A
  • If family history of serious disorder or high risk from a prenatal screening test
  • Chorionic villous sampling e.g. at 10-12 weeks, up to a 1/50 miscarriage rate, result <1 week
  • Amniocentesis e.g. @16-18 weeks, up to 1/100 miscarriage rate, result 1-2 weeks
177
Q

Give examples of disorders which show genetic anticipation

A

Huntington’s disease, fragile X syndrome, myotonic dystrophy

178
Q

List the features of MYH polyposis

A
  • 15-200 polyps (like a mild form of FAP)
  • High risk of carcinoma
179
Q

How can familial cancer be recognised?

A
  • Family history
    • More than one individual in same family affected by similar cancers or cancers at related sites e.g. breast and ovarian/colon and endometrial) with early age of onset
  • Individual
    • Multiple primary tumours
    • Early age of onset

Medicine Year 3 (15 decks)

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