Genetics Flashcards by caitlin stewart

What is a somatic mutation?

Damage in single cell, then a second hit would happen, can develop metastatic potential. Not in gremlin tissue, cannot be passed on

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What is gremlin mutation?

Alteration in egg or sperm, higher chance of developing second hit in the cell. Cause cancer family syndromes

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Describe the cell cycle.

Resting ->
(tumour suppressor genes) ->
Synthesis ->
DNA repair genes ->
G2 ->
Mitosis ->
G1 cell growth (oncogenes)

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What occurs after 1 mutations of oncogene?

Accelerated cell division

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Give an example of a cancer caused by tumour suppressor related gene mutation.

Retinoblastoma

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What happens from 1st and 2nd mutations of tumour suppressor genes?

1st = susceptible carrier

2nd mutation or loss = leads to cancer

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What is the main mechanism for familial cancer?

Faulty DNA mismatch repair

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What causes Lynch syndrome?

Mutation in mismatch repair genes

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What is the sequence for polyp formation in Lynch syndrome/ HNPCC?

Adenoma - carcinoma sequence

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What cancers are likely in those with Lynch syndrome?

Colorectal
Endometrial 
Urinary tract 
Ovarian 
Gastric

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What are the chances of breast cancer in a female if you have BRCA1 and 2?

60-80%

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What do males with BRCA2 have an increased risk of?

Prostate and breast cancer

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When should you suspect hereditary cancer syndrome?

Cancer in 2 or more close relatives (on same side of family)

Early age of diagnosis

Multiple primary tumours

Bilateral or multiple rare cancers

Characteristic pattern of tumours

Evidence of autosomal dominant transmission

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What should be included in a clinical genetics consultation?

FH, risk estimation, explain risk, genetic testing, interventions (increased awareness of symptoms/signs, lifestyle e.g diet and exercise, prevention, screening, prophylactic surgery)

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What is the recommendation for CRC surveillance?

2 yearly for gene carriers ages 25/35

5 yearly from 50 if moderate risk

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What tests are available for Lynch syndrome?

IHC (immunohistochemistry) for mismatch repair gene proteins or MSI

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Discuss some benefits of genetic testing?

Identifies high risk
Identifies non-carriers in families with a known mutation
Early detection
Relive anxiety

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Discuss some risks of genetic testing?

Doesn’t detect all mutations
Continued risk of sporadic cancer
Psychosocial or economic harm

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Who is referred for genetic testing?

1st, 2nd and 3rd degree relatives

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What are potential modes of inheritance in multi-system disorders?

Chromosomal
Single gene disorders (dominant, receive, X-linked)
Multifactorial (polygenic, environmental)

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What are common problems in multi-system disease?

Variable expression within as well as between families

Present to a large variety of different specialists

Family history easily missed

What is neurofibromatosis?

Autosomal dominnant multisystems disease

What is the diagnostic criteria for neurofibromatosis?

Need 2+ of…

Cafe au last spots (6 or more)
Neurofirbromas
Axillary freckling
Lisch nodules (on iris)
Optic glioma
Thinning of long bone cortex
FH

What are other features of NF1?

Macrocephaly
Short stature
Dysmorphic (Noonan look)
Learning difficulties
Epilepsy 
Scoliosis
Raised BP
Neoplasia

How is NF1 managed?

``` BP Spine for scoliosis Tibia for unusual angulation Visual acuity and visual fields Educational assessment Asp patient to report any unusual symptoms ```

What do we worry about in patients with NF1?

Tumour growth

What are the genetics of NF1?

``` Autosomal dominant Variable expression Gene identified (17q) Mutations different in different families 50% due to new mutations ```

What are the main features of NF2?

Acoustic neuromas CNS and spinal tumours a few CAL spots

What gene is NF2 mutation on?

What is the classic triad for tuberous sclerosis?

Epilepsy Learning difficulty Skin lesions

What is the pathology of tuberous sclerosis?

Harmatomas (overgrowth) in different organs

How do you investigate tuberous sclerosis?

Clinical examination Cranial MRI (if seizures) Renal ultrasound Echo

What are signs of myotonic dystrophy?

``` Bilateral late onset cataract Muscle weakness, stiffness and myotonia Low motivation Bowel problems DIabetes Heart block Congenital myotonic dystrophy ```

Discuss the genetic change in myotonic dystrophy.

Autosomal dominant in CAG repeat

Why are adults referred to genetics?

``` Diagnosis Predictive etesting Carrier testing FH Fetal loss or recurrent miscarriage ```

What are the mechanisms of adult onset genetic disease?

Single gene Chromosomal Mitochondiral Multifactorial

What are causes of genetic diseases?

Environmental + genetics | on a spectrum, can be mix of both factors

What genetic diseases are easier to predict?

Single gene disorders with high penetrance. Multifactorial conditions harder to predict

What is shared genetic heritage?

Genetic disease affects families, not individuals discovery of a genetic disorder implies risk for relatives

Give an example of a single gene disorder with high penetrance

Huntington's

Discuss the genetics of motor neuron disease.

Autosomal dominant male-male transmission seen at least 2 non-penetrative individuals

What % of ALS is familial?

5-10%

What are features of ALS?

Progressive muscle weakness, wasting and increased reflexes (upper and lower neuron signs), limb and bulbar muscles involved, cognition spared, pure motor signs with fasciculations

Would you test someone for motor neuron?

No cure, no satisfactory treatment, incomplete penetrance Impact on insurance? Risks to employment? Variability in condition

What is the mutation that causes Huntington's?

Mutation in CAG repeat

What are benefits of Huntington's genetic testing?

If negative - concerns about self and offspring reduced If positive - can make plans for future, arrange surveillance/treatment, inform children or decide whether to have children

What are the disadvantages of predictive testing if test are positive?

``` Removes hope Continues uncertainty Known risk to offspring Impact on self/partner/family/friends Potential problems with insurance/mortgage ```

What are the disadvantages of predictive testing if test are negative?

Expectations of a good result | Survivor guilt

What are the principles of ethics in medicine that need to be considered for genetic testing?

Respect for autonomy Beneficence Non-maleficence Justice

When should you carry out genetic testing on children and adults?

Only if there is potential medical benefits