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Phase 3 > Week 1 > Flashcards

Week 1 Flashcards

1
Q

What do TSGs require to exert their tumorigenic effect?

A

The inactivation of both alleles (two hit hypothesis; inheritance and deletion, recombination, epigenetic transcriptional repression)

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2
Q

How are most of the common cancer predisposition syndromes inherited?

A

Autosomal dominant, due to inheritance of an altered TSG

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3
Q

What is the normal function of proto-oncogenes?

A

They participate in the normal cellular response to growth factors (driving cell cycle forwards)

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4
Q

What are stability genes?

A
  • A type of TSG
  • Act to minimise genetic alterations
  • Account for commonest hereditary predisposition syndromes (BRCA2 and colon cancer)
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5
Q

Differences between sporadic and familiar cancer:

A 
Sporadic:
- common
- late onset
- single primary tumour
Familial:
- uncommon
- early onset
- often multiple primary tumours (BRC and OVC)
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6
Q

What should you look for in a family history to establish risk of familial cancer?

A

More than one individual in same family (4 makes high risk) affected by similar cancers or cancers at related sites (breast & ovaries) with early age of onset

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7
Q

What genes cause familial breast cancer

A
  • BRCA1
  • BRCA2 (evident in male BRC)
    less commonly
  • TP53
  • PALB2
  • PTEN
    (at least 72 loci that confer an increased susceptibility to BRC)
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8
Q

What are the main features of HNPCC?

A
  • Usually only a few polyps (less than 10)
  • +/- uterus, stomach, ovary
  • Due to inheritance of mutation in mismatch repair system genes
  • 2 yearly colonoscopies from 25, plus 2 yearly upper GI endoscopies from 50
  • MLH1 in ~50%, MSH2 ~40%
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9
Q

What are the main features of Familial Adenomatous Polyposis?

A
  • Congenital hypertrophy of the retinal pigment epithelium in 80%
  • Caused by APC (TSG) gene
  • Annual bowel screening from age 11
  • Many polyps (>100)
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10
Q

What are the main features of Li Fraumeni syndrome?

A
  • Autosomal dominant
    • BRC
    • Brain tumours
    • Sarcoma
    • Leukaemia
    • Adrenocortical carcinoma
  • Chance of cancer 50% by 30, 90% by 50
  • Mutations in master control gene, TP53
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11
Q

What does male-male transmission of genetic disease indicate?

A

The condition is not X linked

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12
Q

What is a vertical pattern of inheritance?

A

Condition inherited over generations

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13
Q

What is a horizontal pattern of inheritance?

A

Condition present in sibship (single generation)

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14
Q

What are the typical features of autosomal dominant?

A
  • Vertical inheritance pattern
  • Generally equal frequency and severity in M and F
  • Variable expressivity
  • Disease expressed in heterozygotes
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15
Q

What are the typical features of autosomal recessive?

A
  • Carriers unaffected
  • Equal frequency in males and females
  • Disease expressed in homozygotes or cpd heterozygotes
  • Expressivity more constant within a family
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16
Q

What is genetic anticipation?

A
  • Increasing severity and earlier age of onset in successive generations
  • Due to increasing repeats of trinucleotide as gene is passed from one generation to the next
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17
Q

What is pseudo-dominant inheritance?

A

Recessive inheritance with very high carrier frequency (or consanguinity) so appears like AD

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18
Q

What are the main features of X linked recessive?

A
  • No male-male transmission
  • Knight’s move inheritance pattern
  • All daughters are carriers in male-female transmission
  • 50% daughters carriers in female-female transmission
  • M»F sex ratio
19
Q

What are the main features of X linked dominant?

A
  • No male-male transmission
  • Vertical inheritance pattern
  • All daughters affected in male-female transmission
  • 50% daughters carriers in female-female transmission
  • F:M = 2:1
20
Q

What is the genetic basis for Huntington disease (HD)?

A
  • AD with genetic anticipation
  • Mutation in gene causes expansion of polyglutamine tract, which causes insoluble protein aggregates and neurotoxicity
  • Genetic anticipation, prone to expansion during meiosis especially from father
21
Q

What is the genetic basis for myotonic dystrophy?

A
  • AD with genetic anticipation
  • Unstable length mutation of a CTG repeat
  • In the 3’ (transcribed but not translated) region of DMPK gene causing faulty DMPK mRNA
  • Abnormal mRNA has toxic effect on other genes (CLCN1- chloride channel)
  • Affected if 50 or more repeats
  • Higher chance of expansion when transmitted by females
22
Q

How does the genetic mutation cause myotonic dystrophy?

A
  • Abnormal DMPK mRNA
  • Indirect toxic effect upon splicing of other genes, e.g. CLCN1 gene causing myotonia
  • Also affects insulin receptor
23
Q

What is the pathogenic mechanism of cystic fibrosis?

A
  • AR
  • CFTR mutation, single codon deletion most common, causes defective chloride ion channel
  • Increased thickness of secretions
24
Q

What is the difference between in frame and out of frame deletion?

A

In frame is deletion of whole codon(s), out of frame deletion of base pairs

25
Q

What explains the difference in severity of DMD and BMD?

A 
DMD
- 65% deletions
  - most out of frame
BMD
 - 85% deletions
  - in-frame
Genotype-phenotype correlation
26
Q

Describe neurofibromatosis:

A

Commonly

  • Cafe au lait macules and neurofibromas (from teens), short stature and macrocephaly
  • LDs in 30% (severe in 3% or less)
  • Very variable expressivity due to modifier genes
27
Q

What are the possible complications of NF1?

A
  • Hypertension
  • Scoliosis (requiring surgery)
  • Pathological tibial fractures
  • Significant tumours
    • Phaeochromocytomas
    • Sarcomas
    • Optic pathway gliomas
28
Q

What is fragile X syndrome?

A
  • X linked
  • Genetic anticipation (due to repeats in the 5’ UTR region of FMR1 gene)
  • Most common inherited cause of significant LD
  • Phenotype can be severe in males, some carrier females also affected but more mildly
29
Q

Describe Edwards syndrome:

A
  • Trisomy 18
  • Small chin
  • Clenched hands with overlapping fingers
  • Malformations of heart, kidney and other organs
  • If strive first year, generally have profound LD
30
Q

Describe Patau syndrome:

A
  • Trisomy 13
  • Congenital HD is usual
  • About 50% die within 1 month
  • Approx only 10% survive first year, generally profound LD
31
Q

What are the clinical features of Patau syndrome ?

A
  • Cleft lip and palate
  • Micropthalmia
  • Abnormal ears
  • Clenched fists
  • Post-axial polydactyly
32
Q

How do trisomies normally arise?

A
  • Maternal non-disjunction in meiosis
  • Trisomies more frequent with increased maternal age
  • Potential mutation of enzyme or protein factors that help in separation
33
Q

Which aspects of clinical history are helpful for clinical genetic purposes?

A
  • Patient’s clinical history
    • with age of onset of symptoms, progression?
  • Family history
    • consanguinity, miscarriages or stillbirths
  • Examination
    • any dysmorphic features
    • normal growth (height; occipital-frontal circumference)
34
Q

Which aspects of clinical exam are helpful for clinical genetic purposes?

A

Dysmorphic features:

  • head shape and size (micro or macrocephaly)
  • eyes
    • palpebral fissures (slant?)
    • spacing (hypertelorism- pupils too far apart)
  • ears
    • size, shape, position (low-set?)
    • rotated anteriorly or posteriorly (top of ear)
  • nose: size, nares
  • mouth (size, lips, teeth)
  • limbs: disproportion
  • skin (lumps, abnormal pigmentation)
  • hands and feet
    • palmar creases
    • fingers and toes (correct number? poly and syndactly)
    • normal palmar creases
35
Q

What is pre-implantation genetic diagnosis (PGD)?

A

One or two cells removed from embryo when it contains 6-10 cells, then tested by FISH or (QF-) PCR

36
Q

What are 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
- difficulty with multiple visits and procedures
- “take home baby rate” usually <50% per cycle

37
Q

Which genetic conditions is screening currently carried out for during pregnancy and which tests are used?

A
  • DS: CUBS screening in 1st trimester with maternal blood biochemical markers
  • Ultrasound: nuchal translucency increased in DS
  • Prenatal if family history of serious disorder, or a high risk from a prenatal screening test
    • amniocentesis
    • CVS
38
Q

Which genetic conditions is screening currently carried out for neonatally and which tests are used?

A

Blood spot from a heel

  • Mass spectrometry
    1. phenylketonuria
    2. MCADD
  • Immuno-assay
    1. congenital hypothyroidism
    2. cystic fibrosis
  • HPLC
    1. sickle cell disorder
39
Q

Which genetic conditions is screening currently carried out for postnatally and which tests are used?

A
  • Tay Sachs disease screening for Jewish people

- Thalassaemia, population carrier screening for thalassameia

40
Q

What are the basic principles of PCR-related sequencing?

A

PCR requires template DNA, two oligonucleotide primers that are complementary to sequences flanking the target DNA sequence, deoxyribose and a thermostable DNA polymerase. The PCR product can then be analysed by DNA sequencing, or other methods to detect small scale deletions

41
Q

What are the applications and limitations of fluorescent Sanger DNA sequencing?

A

Applications:
- Single gene
Limitations:
- Single gene

42
Q

What is aCGH and what is it used for?

A

Array comparative genomic hybridisation, used for whole chromosome analysis

43
Q

What is non-invasive prenatal testing?

A
  • Maternal plasma and free fetal DNA
  • Tests for fetal sex determination (for X linked conditions)
  • Tests soon to be introduced for paternal mutations (eg FGFR3)
  • Also test aneuploidy

Phase 3 (14 decks)

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