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PODT Disease S2 > Clinical Genetics 4 Genetics in General Medicine and Surgery > Flashcards

Clinical Genetics 4 Genetics in General Medicine and Surgery Flashcards

1
Q

What are the characteristics of Autosomal Dominant inheritance?

A
  • Vertical transmission through generations
  • Male to male transmission possible
  • Males and females equally affected
  • Offspring risk is 1 in 2
  • Reduced penetrance and variable expression possible
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2
Q

Give three examples of cardiac genetics:

A
  1. Syndromic disorders with multi system involvement e.g. Marfan Syndrome
  2. Conduction disorders - hereditary conduction defects e.g. long QT syndrome
  3. Cardiac structural disorders e.g. cardiomyopathy may cause Sudden Adult Death (SAD)
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3
Q
  1. What is the mechanism of Marfan Disorder?
  2. How is it diagnosed?
  3. What are the features of Marfan syndrome?
A
  1. Mutation in the Fibrillar (FBN1) gene - connective tissue disorder.
  2. Ghent criteria
  3. Involvement of ocular, skeletal and cardiovascular systems.
    - Skeletal features - tall stature with wide arm span and arachnodactylyl - long fingers and toes.
    - Others - joint flexibility, crowded teeth, high arched palate, scoliosis, skin striae
    - Congenital valve abnormalities
    - Aortic dissection - can be prevented by screening (ECHO/ MRI) and drug treatment or surgery.
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4
Q
  1. What is the mechanism of inheritance of Loeys-Dietz Syndrome?
  2. What are the genes involved?
  3. What are the features?
A
  1. Autosomal Dominant
  2. TGFBR1, TGFBR2, SMAD3 (some phenotype/genotype correlation)
  3. Valvular and skeletal involvement, dysmorphic features.
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5
Q
  1. What is the mechanism of inheritance of Ehlers-Dalos Syndrome?
  2. Describe the two subtypes
A
  1. Autosomal dominant, connective tissue disorder.
  2. Classic - skin is hyperextensible, joint hypermobility, abnormal wound cleaning.
    Vascular - hypermobility, kyphoscoliosis, progeroid features etc.

Villefranche diagnostic criteria.

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6
Q
  1. What is the mechanism of inheritance of sudden cardiac death?
  2. What is caused by a conduction disorder?
  3. What is caused by cardiomyopathy?
  4. Where do mutations come from?
  5. How to detect these?
A
  1. Autosomal Dominant
  2. Fatal arrhythmias
  3. Sudden Adult Death
  4. De novo mutations when patient has previously been fit and well.
    Inherited with family Hx of cardiac disease/sudden death/drowning.
  5. ‘Molecular autopsy’ possible.
    Screening identifies gene carriers and then treatment with pacemaker and other cardiac stabilising drugs.
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7
Q
  1. What is the mode of inheritance of Neurofibromatosis type I?
  2. Where is the mutation?
  3. What are the features of NF1?
A
  1. Autosomal dominant
  2. NF gene on chromosome 17
  3. Cafe-au-lait spots, neurofibromas, lisch nodules, scoliosis, learning difficulties, tumour risk (CNS, breast, pheochromocytoma) - screening important
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8
Q

HD

A

Other lectures covered

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9
Q
  1. What percentage of breast and colon cancer has a familial bias?
  2. What actions are taken?
  3. Give two examples of cancer predisposition syndromes that present in childhood.
A
  1. 10% - usually autosomal dominant
  2. Early screening of gene carriers may allow prevention and early diagnosis may help treatment.
  3. Multiple Endocrine Neoplasia 2 (MEN2) or Familial Adenomatous Polypoptosis (FAP)
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10
Q

SPORADIC CANCER

What are the causes of genetic mutations?

A
  • Age
  • Smoking
  • Radiation
  • Unknown factors
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11
Q

Describe the genetic changes involved in the progression of colon cancer (Adenoma Carcinoma Sequence)

  1. Normal –> Tubular adenoma
  2. –> Villus adenoma
  3. –> Invasive Carcinoma
A
  1. Loss of the ‘gatekeeper’ APC
  2. Activation of k-RAS, Loss of TGF-B RII or SMAD4
  3. Loss of p53. Activation of PRL-3
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12
Q
  1. What percentage of colorectal cancer is hereditary?
  2. What fraction of the population are affected?
  3. How does risk increase with family history?
A
  1. 5-10%
  2. 1 in 50 of general population
  3. 1 relative - 1 in 17
    2 relatives - 1 in 6
    3 relatives - 1 in 3
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13
Q
  1. Where is the mutation for FAP?
  2. What is the lifetime risk of Colorectal Cancer?
  3. How is this prevented?
A
  1. APC gene on chromosome 5
  2. Almost 100% risk - mean age is 39 years. Causes 100-1000s colonic polyps which starts in 2nd decade.
  3. Screening from teenage years, annual colonoscopy and then large bowel removed
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14
Q

What is CHRPE?

A

Congenital Hypertrophy of the Retinal Pigment Epithelium.

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15
Q
  1. What is the mode of inheritance of Hereditary Non-polyposis Colon Cancer (HNPCC)?
  2. What is the normal function of these genes? Why does abnormal function cause disease?
  3. What genes are involved?
  4. How does this cancer present?
  5. How is screening for HNPCC carried out?
  6. How can Colon Cancer be prevented?
A
  1. Autosomal Dominant
  2. MLH1, MLH 2 in 80%
    also MSH6 and pMS2
    Mismatch repair genes and MMR system which ‘proof read’ DNA. Proteins bind to incorrectly copied DNA and initiate repair. When there is damage to this system DNA repair is prevented and mutations accumulate.
  3. Awareness of symptoms - abdominal pain, change in bowel habit, PR bleeding etc
    - Regular colonoscopy every 2-3 years allows early diagnosis and polyp removal
    - Females - ovary and endometrial screened with yearly USS, also option of prophylactic surgery
    - Non-gene carriers don’t need screening
    - Affected cases may have specific treatments depending on the gene involved
  4. Diet - fruit and veg. Reduce constipation and obesity. Smoking cessation. Chemoprevention- aspirin and resistant starch which stop polyps turning malignant through the COX-2 pathway and apoptosis.
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16
Q
  1. What were the findings of the colorectal adenoma/ carcinoma prevention programme (CAPP) trials?
  2. What is the mode of action of this?
  3. Why is aspirin not prescribed for general population?
A
  1. CAPP1 - FAP.
    Aspirin trend towards reduction in size of largest polyp and reduction in polyp number.
    CAPP2 - HNPCC
    Risk of CRC halved with aspirin > 2 years and endometrial cancer risk halved
  2. Pro-Apoptotic in cells with MMR deficiency?
    Does this deficiency precede adenoma formation?
    Does aspirin ‘delete’ the cells most likely to progress to cancer?
  3. Side effect profile - risk benefit ratio
17
Q
  1. What is the incidence of breast cancer?
  2. What percentage of breast cancer is hereditary?
  3. What are the risk factors?
  4. What genes are involved?
  5. What is the Manchester score?
  6. What are the risks of breast cancer with mutations?
  7. What other cancers do these mutations put people at risk of?
A
  1. 1 in 10
  2. 5-10%
  3. Age, family history, carcinogens, oestrogen (early menarche, fewer children, late menopause)
  4. Multiple genes, both syndromic and non-syndromic. At least 13 genes.
    BRCA1 & 2 - 1000s of loss of function mutations, each individually rare. Most mutations lie within DNA repair pathways.
  5. Proportion of pathogenic mutations identified and given a score.
  6. Female breast cancer lifetime risk:
    BRCA1 - 60-90%
    BRCA2 - 5-10%
    Male breast cancer by 80 years:
    BRCA2 5-10%
    Lifetime risk of 2nd breast cancer:
    50%
  7. Ovary (BRCA1 40-60%, BRCA2 10-30%), Prostate (BRCA1 12?, BRCA2 25? - yearly PR exam), Pancreatic cancer, melanoma
18
Q

1How often are high risk patients with a BRCA mutation screened for breast cancer?
Ovarian cancer?

A

Breast MRI and clinical examinations:

  • Yearly if 30–50 years old
  • 18-24 months if 50-60 years old
  • 3 yearly from >60 years old

Ovarian - USS yearly 35-70 years old

19
Q

How do you reduce your risk of breast cancer with mutations?

A
  • Consider family planning, breast feeding, social issues, breast reconstruction
  • Prophylactic double mastectomy reduce risk by 90-95%
  • Bilateral sapingo-oopherectomy (BSO) can reduce ovarian cancer risk by around 5% (pre-menopausal by 50%)
  • Chemoprevention e.g. tamoxifen can reduce risk by 50%
20
Q

What are the characteristics of Autosomal Recessive Inheritance

A
  • Present in childhood
  • Severe
  • Males and females equally likely to be affected
21
Q
  1. What is the mode of inheritance of Cystic fibrosis?
  2. What gene is involved?
  3. What is the prevalence in Northern Ireland?
  4. What are the symptoms and signs of CF
A
  1. Autosomal recessive
  2. CFTR gene - cystic fibrosis transmembrane conductance regulator. >1000 known mutations (some can be very mild and cause virtually no symptoms or present with infertility.
  3. Incidence is 1 in 1850 and carrier frequency is 1 in 20 (carrier testing carried out if affected 1st or 2nd degree relative).
    The commonest mutation is deletion of 3bp encoding phenylalanine at residue 508 in exon 10.
  4. Thickened secretions:
    - Saliva causing tooth decay
    - Bronchiectasis, asthma, emphysema
    - Pancreatic insufficiency/ chronic pancreatitis, constipation
    - Infertility
    - CBAVD - congenital bilateral absence of the vas deferens
22
Q

How is CF managed?

A
  • Most diagnosed through neonatal screening
  • 10-15% requiring abdominal surgery to remove meconium plugs
  • Intensive management with antibiotics for chest
  • Pancreatic enzymes to help reverse malabsorption
  • Heart/lung transplants later in life
  • Life expectancy around 40+ years
23
Q

What are the features of X-linked inheritance

A
  • Males usually affected
  • Females are usually carriers and unaffected because they have two X chromosomes
  • All daughters of affected males are carriers
  • No male-to-male transmission
24
Q
  1. What is the mutation in haemophilia B?

2. What is the prognosis?

A
  1. Affects F9 gene - F9 binds to F8 so apparent loss of factor VIII (Haem-A)
  2. Affected males die early unless facts IX replacement therapy instigated
25
Q

What are the characteristics of X linked DOMINANT

A
  • All daughters of affected males are affected

- All sons of affected males are unaffected

26
Q

What are the features of mitochondrial inheritance?

How does Heteroplasmy arise?

A
  • Mitochondria inherited from mother
  • All offspring of an affected female are at risk of being affected
  • All daughters of an affected or a carrier female are at risk of transmitting the condition
  • Affected males cannot pass the condition on to any of their children.

Mitochondrial DNA replicates but is not equally and randomly partitioned into daughter cells. High variability and so mutational load may influence prognosis

  • 0-30% low
  • 30-70% moderate
  • 70%+ high
27
Q
  1. What does MELAS stand for?

2. What are the features?

A
  1. Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke Like Episodes.
  2. Multi-system and onset in childhood. Short stature, sensorineural hearing loss
    2-10 years: seizures, headaches, exercise intolerance
    Teens-20s: recurrent ‘stroke-like’ episodes of transient hemiparesis or cortical blindness
    Later: gradual impairment of motor abilities, vision, IQ
28
Q

Give 4 signs that someone may have a mitochondrial disorder?

A
  1. Multisystem involvement - CNS, cardiac, DM
  2. Variable phenotype
  3. ALL symptoms at risk of symptoms
  4. Surveillance often required: blood glucose monitoring
29
Q

What are the advantages of making a genetic diagnosis?

A

MANAGEMENT:

  • greater knowledge of phenotypic spectrum, natural history and recurrence risk
  • Accurate counselling information
  • Prognosis - longterm developmental outcome, other risks e.g. cancer, cardiac
  • Possible treatment

SUPPORT GROUPS

REASON ‘WHY’ - Important for the parents in many situations.

30
Q

How do you help patients to cope?

A

Positive predictive test:

  • Reproductive choices
  • Referral to appropriate specialists
  • Appropriate surveillance/ screening
  • Patient self-help groups - local, national, international

Negative predictive test:
- ‘Survivor guilt’

PODT Disease S2 (6 decks)

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