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year 4 CDM 2 > Case 16: Genetic variant > Flashcards

Case 16: Genetic variant Flashcards

1
Q

What tests are done before a referral to a cancer genetics clinic

A
  • Tumour genetic testing in patient
  • Germline genetic tests in other family members
  • MSI (Microsatellite instability)/IHC (Immunohisto chemical) testing – particularly on colorectal / endometrial tumours – particularly if suspect Lynch
  • Histopathology on other lesions e.g. benign skin tumours can be a clue into some rare inherited cancer predisposition syndromes (e.g. trichilemmomas in PTEN)
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2
Q

What tests are done at/after a Cancer Genetic testing clinic

A
  • To determine how likely the patient is to have a strong familial disposition to cancer
  • Germline single gene test
  • Germline gene panel test (i.e. renal cancer)
  • MSI / IHC on tumour DNA: Lynch syndrome
  • Pedigree chart: make sure cases are confirmed and you age of disease presentation
  • To more fully explore phenotype i.e isolated cerebellar haemangioblastoma organising an eye review to check for VHL
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3
Q

When will someone have an increased risk of cancer

A
  • Based on family history
  • Having a mutation in a known cancer predisposition gene
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4
Q

Management options if at increased risk of cancer

A
  • Extra screening
  • Lifestyle advice
  • Chemoprophylaxis e.g. tamoxifen (breast take for 5 years), aspirin (colorectal cancer- Lynch syndrome)
  • Risk reducing surgery options e.g. bilateral or completion mastectomy; gynaecological surgery (Lynch or BRCA)
  • Radiation advice in TP53 (avoid CT or radiotherapy if possible)
  • Research studies
  • Patient support groups
  • Predictive genetic test for relatives
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5
Q

What is a normal genome

A
  • 23 pairs of chromosomes - all chromosomes are separate from each other. 2 copies of each autosomal chromosomes
  • All genes present: no missing or duplicated copies of genes
  • The nucleic acid sequence is the same as the reference sequence
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6
Q

What is a genomic test

A

Any test that analyses DNA, whether its a single nucleotide or the entire genome. May be diagnostic or predictive.

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7
Q

Karyotyping

A
  • Method for looking at chromosomes
  • Cells are grown in culture and arrested during mitosis then stained with Giemsa dye and viewed under a microscope
  • Can detect whole chromosome changes like trisomy, monosomy or translocation
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8
Q

Genetic variants: Aneuploidy

A
  • Aneuploidy: too few (1- monosomy) or too many (3-trisomy) chromosomes
  • Common ones: Trisomy 21 (downs), Trisomy 13, Trisomy 18, Sex chromosome aneuploidy i.e. 45 X0 (Turners), Klinefelter XXY
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9
Q

Genetic variation: Translocation

A
  • One Chromosome stuck onto another chromosome
  • Balanced translocation: There are no missing or extra parts of the chromosome. Wouldn’t have a phenotypic effect but their offspring may have an unbalanced translocation
  • Unbalanced translocation: where there is excess or missing genetic material, there is expected to be a phenotypic effect
  • Karyotype detects unbalanced translocation
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10
Q

Examples of balanced and unbalanced translocations

A
  • Balanced: one copy of chromosome 14 stuck on chromosome 13
  • Unbalanced: one copy of chromosome 14 stuck on chromosome 13 but there is also two normal copies of chromosome 14 so there is excess genetic material
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11
Q

How can unbalanced translocations cause disease

A
  • dose effect of the genes that are present in abnormal quantity
  • aberrant activation or interruption of gene at the breakpoint
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12
Q

Copy number variants

A
  • Large chunks of DNA that are either duplicated or deleted
  • Identified by SNP array
  • The structure of the genome predisposes some chunks of DNA to be deleted or duplicated: can cause phenotype or be normal
  • extra or missing copies of genes within the chromosome causes a dose effect which can cause a genetic disease
  • Both deletions and duplications can be pathogenic
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13
Q

Examples of copy number variants

A
  • 22q11.2 deletion = DiGeorge syndrome. 78 genes deleted on chromosome 22
  • 22q11.2 duplication syndrome. 78 genes duplicated = Has phenotypic effect but less clear cut
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14
Q

Structure of a gene

A
  • Introns: the non-protein coding DNA between exons. Regulatory functions and splice sites
  • Exons: code for proteins. Contains the majority of disease causing variants
  • When a gene is transcribed both the introns and exons are transcribed into RNA together. Through splicing the introns are removed so just the exons RNA is translated into protein
  • 3 nucleic acids code for a single protein and together form a codon
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15
Q

Single nucleotide variant (SNV) in DNA: Synonymous substitution and Missense mutation

A
  • A change in a single nucleotide (base pair)
  • Synonymous substitution: the nucleotide change still codes for the same amino acid. Low likelihood of causing a disease
  • Missense mutation: where you change one amino acid for another. May alter biochemical properties of translated protein affecting its function. For example, if the original protein was hydrophobic and the new one is hydrophilic.
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16
Q

SNV (single nucleotide variant) in DNA: Nonsense mutation, Frameshift mutation

A
  • Nonsense mutation: insertion of a premature stop codon, leading to a prematurely truncated protein. High chance of death
  • Frameshift mutation: An insertion of an extra nucleic acid which shifts the reading frame meaning every codon afterwards is altered. Stop codon is altered causing an elongated protein. Can also result in a new stop codon before then. The protein is either shortened or elongated. High likelihood of disease
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17
Q

Single nucleotide variation (SNV) in DNA: Splice sites

A

Sequences important for correct splicing. Changes in nucleic acids at these position can be pathogenic after splicing. Changes to the DNA just before and after the exons (-1, -2, +1, +2 position). High likelihood of disease

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18
Q

How pathogenic are genetic variants

A
  • Synonymous: less likely to be pathogenic
  • Missense: might be pathogenic
  • Nonsense, Frameshift and Splice shift: high likelihood of being pathogenic
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19
Q

Other classes of genetic variants

A
  • Insertions or deletions of more than one nucleic acid: cause frameshift effects
  • Triplet repeat:
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20
Q

Genetic variation: Triple repeat

A
  • Repeat of an amino acid motif at a particular locus. Can be unstable i.e. get bigger on transmission Parent might have premutation and child has full mutation
  • Causes anticipation where subsequent generations are affected at a younger age
  • Myotonic dystrophy type 1 (DM1):(CTG)n repeat in a non-coding part of the DMPK gene. Number of repeats corresponds with phenotype
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21
Q

Genetic variation: Candidate gene approach

A
  • Select gene to sequence based on phenotype
  • Sanger sequencing of that gene
  • very few variants to classify- could look at less genes, considered fewer genes to be pathogenic
22
Q

Genetic variation: Genomic era approach

A
  • Gather phenotype information
  • Genome sequencing (or large panel of genes, or exome): sequence hundreds of genes
  • Genome sequencing, exome sequencing or sequencing large panels of genes
  • Huge number of variants to classify: hard to distinguish what’s normal and what’s dangerous
23
Q

The significance of a genetic diagnosis

A
  • May alter clinical management: access to specific treatments or screening. May cause withdrawal of care particularly in paediatrics/neonates
  • Enrolment in clinical trials or disease registries
  • Implication for wider family: predictive testing for family or counselling about reproductive option
  • Reproduction options: selection of embryos or foetuses with or without specific genetic diagnosis for prenatal testing or pre-implantation
24
Q

Criteria for classifying variants

A
  • Phenotype: Do variants in this gene cause the same symptoms / family history that my patient has?
  • Population data: Is this variant common or rare, or totally novel?
  • In silico or computational data: What does computer program predict will be the effect of the mutation?
  • Family studies: Testing other family members
  • Reported in a disease database: has the variant been reported to be associated with the disease?
  • Functional data: Experiments to model this gene change e.g. in cells or in animal models (mice, zebrafish etc)
25
Q

Variant classification: Phenotype

A
  • Need to meet the patient and take a full history- may need to do further investigations i.e. MRI once gene has been found to match pathophysiology
  • Matching the gene variant to the phenotype is useful depending on: How specific the features are to the gene? How many different genes cause the same phenotype?
  • For example, in learning disability these are hundreds of genes involved so less useful
  • Genetic heterogeneity: many different genes can cause the same phenotype
  • Online Mendelian Inheritance in Man (OMIM) database: catalogue of genes and their associated phenotypes
  • If they don’t have the phenotype its unlikely the gene causes the disease
26
Q

Population data: variant classification

A
  • Big population genome/exome sequencing studies have generated massive databases on genetic variation that are used as the control to compare mutations to
  • gnomAD is the largest and most referred to
  • Dominant highly penetrance disease – would not expect to find these variants in population databases
  • Autosomal recessive disease – may find these variants in population databases but note frequency
  • If its dominant you would not expect any healthy individuals to carry the gene
27
Q

Variant classification: in silico / computational data- data found

A
  • Tells you what type of genetic variant it is i.e. nonsense, missense, synonymous, whole gene deletion or duplication
  • Compare DNA sequence to reference one. For example, in missense variation which DNA has been substituted and what’s the new protein
  • Can then look in research articles if the genetic variation is common in the disease
  • Pathogenic: genetic variation type is common in the disease
28
Q

Variant classification: In silico or computational data- questions answere

A
  • What type of variant is it?
  • Is the variant expected to affect an important part of the protein (‘domain’)?- computer models can predict the structure of the protein encoded by the gene and predict possible effects of the amino acid change
  • Does the variant affect an evolutionarily conserved region?- if lots of different animals have that gene sequence
  • How big is the biochemical difference between the substituted amino acids? (only relevant for missense variants)
  • Computer prediction programs amalgamate all of the above data
29
Q

Variant classification: Computer prediction programmes

A
  • PolyPhen and SIFT are commonly used prediction programmes they predict the effect of genetic variants
  • Used as part of a comprehensive assessment of a variation not in isolation
  • Genetic disease: highly conserved amino acid position
  • Normal variant: small biochemical distance between substituted amino acids (similar properties), conflicting prediction tools
30
Q

Variant classification: family data

A
  • Is the disease present or absent in other family members, is there an inheritance pattern (i.e. both parents carriers for a recessive pattern)
  • Consider reduced penetrance or variable expressivity
  • Don’t necessarily need to test other family members
31
Q

Variant classification: Reported in a disease/variant database

A
  • Disease or gene specific databases of variants
  • May need to ask a laboratory with expertise in analysing that gene
  • Determines whether a genetic variant is clinically significant
  • ClinVar is a commonly used database for all genetic variants (regardless is pathogenic)
32
Q

Variant classification: Functional data

A
  • Research - are there any experiments modelling this genetic variant
  • Look on pub med for research papers
33
Q

Variant of uncertain significance criteria

A
  • Phenotype doesn’t match the patient
  • Too common to be pathogenic?
  • Not previously reported as pathogenic
  • Small biochemical distance between substituted amino acids
  • Conflicting prediction tools
  • Reported as Variant of Uncertain Significance in ClinVar
  • Variant of uncertain significance: don’t use this result for clinical management
34
Q

Criteria for classifying variants

A
  • 1.Phenotype
  • 2.Population data
  • 3.In silico data
  • 4.Functional data
  • 5.Family studies
  • 6.Reported in a disease database
35
Q

Can finding a recessive gene confirm a disease?

A

Identifying one pathogenic/likely pathogenic variation is insufficient. Would need to confirm with phenotypic information

36
Q

What further tests might help classify if a genetic variant is benign or pathogenic?

A
  • gathering more info on the phenotype
  • testing other family members
  • undertaking more specialised lab investigations such as splicing studies
37
Q

What to do when there is a variation of uncertain significance

A
  • Doesn’t confirm the genetic disease
  • Cant be used for reproductive purposes like prenatal testing and cant counsel the family based on this variation
  • Might need further tests to confirm pathogenicity and association with variation
38
Q

What questions should be asked to explore family history of a genetic condition

A
  • any conditions that seem to run in family
  • anyone with major health problem
  • anyone ever had a serious illness or operation
  • any deaths (age and cause) inc miscarriages and stillbirths
  • gather info on first degree relatives minimum (parents, siblings, children)
39
Q

Autosomal dominant inheritance

A
  • Where a genetic change on only one copy of the allele causes the disease
  • Affected people in each generation
  • Males and females affected
  • All forms of transmission seen (including male to male transmission)
  • Variable penetrance e.g. the likelihood that disease will manifest if the gene change is present
40
Q

Autosomal recessive inheritance

A
  • Need two copy’s of the allele to cause the disease. If only have one copy then are carriers
  • Can’t always follow the disease through the family tress, skips generations
  • Males and females affected
41
Q

Autosomal recessive: both parents are carriers what chance do the kids have…

A
  • Having the condition: 25%
  • Being a carrier: 50%
  • Unaffected: 25%
42
Q

X linked recessive inheritance

A
  • More than one generation involved
  • Only males affected (usually)
  • No male to male transmission
  • Males with affected X chromosome have the disease whilst females are carriers. If they have two copy’s of the gene then they will have the disease
43
Q

Difficult information to include in a pedigree chart

A
  • Relationship breakdown (divorce/estrangement)
  • Adoption/other biological relationships/non paternity
  • Causes of death – other than ‘natural causes’ e.g. accidental, suicide, drug/alcohol related
  • Bereavement (including termination of a pregnancy)
  • Consanguinity
44
Q

How to draw a pedigree chart

A
  • Male = square
  • Female = circle
  • unknown sex = diamond
  • Affected individual = black (symbol coloured in)
  • Miscarriage = triangle
  • Partners are blood relatives (consanguineous relationship) = double line
  • Deceased: diagonal line cross (bottom left to top right) through the shape
45
Q

How to find out family history of cancer

A
  • By asking patient- though risk of diagnoses being misreported or misunderstood
  • Can check the National Cancer Registry, Clinical records, pathology records and death certificates
46
Q

Ovarian cancer

A

Ovarian cancer is the fifth most common malignancy in females. The peak age of incidence is 60 years and it generally carries a poor prognosis due to late diagnosis.

47
Q

Ovarian cancer: Pathophysiology

A
  • Around 90% of ovarian cancers are epithelial in origin, with 70-80% of cases being due to serous carcinomas
  • The distal end of the fallopian tube is often the site of origin of many ‘ovarian’ cancers
48
Q

Ovarian cancer: risk factors

A
  • family history: mutations of theBRCA1or theBRCA2 gene
  • many ovulations:early menarche,late menopause,nulliparity
49
Q

Clinical features for ovarian cancer

A
  • abdominal distension and bloating
  • abdominal and pelvic pain
  • urinary symptoms e.g. Urgency
  • early satiety
  • diarrhoea
50
Q

Ovarian cancer: Investigations

A
  • CA125: Endometriosis, menstruation, benign ovarian cysts and other conditions may also raise the CA125 level. Don’t do if asymptomatic.
  • Ultrasound of abdomen and pelvis: offered if raised CA125 (>35 IU/ml)

Diagnosis is difficult and usually involves diagnostic laparotomy

Management: usually a combination of surgery and platinum-based chemotherapy

year 4 CDM 2 (39 decks)

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