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Huntington's disease:
- Age of onset
- Clinical features
- Pathophysiology
- Inheritance
- Between 30 and 40 yoa
- Progressive chorea, dementia and psychiatric symptoms
- CAG repeats in polyglutamine = huntingtin protein (amyloid, hydrophobic + insoluble) = toxicity to basal ganglia
- Autosomal dominant: genetic anticipation with up to 39 repeats asymptomatic
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Myotonic dystrophy:
- Clinical features
- Pathophysiology
- Inheritance
- Investigations
- Progressive muscle weakness in early adulthood
- CTG repeats in myotonin protein kinase = chromatin condense = defunct L type calcium channels
- Autosomal dominant, genetic anticipation.
- ECG and eye checks for diabetes and cardiac conduction risk. PCR
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Cystic fibrosis:
- Clinical features
- Pathophysiology
- Inheritance
- Investigations
- Recurrent lung infections, bronchiectasis and obstructive lung disease. Pancreatic insufficiency and cyst formation
- Mutation = codon deletion = phenylalanine loss = normal protein insertion onto membrane. Also defunct chloride ion channel = more mucous thickness in resp + exocrine pancreas
- Autosomal recessive; carrier frequency 1 in 20-25
- Immunoreactive trypsinogen test, DNA testing and sweat chloride concentration
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Hereditary haemochromatosis
- Clinical features
- Pathophysiology
- Inheritance
- DM, cirrhosis, arthropathy, hepatocarcinoma, cardiomyopathy
- HFE mutation in GI + liver = disulphide bond = less stabilisation = less transferrin receptor iron uptake
- Autosomal recessive, carrier 1 in 10 with low penetrance
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Neurofibromatosis type 1
- Clinical features
- Pathophysiology
- Inheritance
- Cafe au lait spots, skeletal nerve root impingement and scoliosis
- Neurofibromin a tumour suppressor. Mutation = neural crest cells proliferate = tumour formation around melanocytes and Schwann cells
- Autosomal dominant; 50% de novo
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Duchenne's
- Onset/prognosis
- Clinical features
- Pathophysiology
- Inheritance
- Onset in 4th year. Death by 20th
- Difficulty walking and breathing. Gower's sign: using hands when standing up.
- Dystrophin absent = membrane instability = calcium and H2O enter mitochondria = lysis = oxidative stress = muscle fibre necrosis and fibrosis
- X linked recessive; 1/3 de novo
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Becker's muscular dystrophy
- Difference from Duchenne's
- Clinical features
- Inheritance
- Some functional dystrophin is produced, reducing severity
- Mainly affects legs and pelvis
- Many more cases are spontaneous
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Fragile X syndrome
- Clinical features
- Pathophysiology
- Inheritance
- Macroorchidism, low muscle tone, elongated face, protruding ears, social problems (e.g. shyness, memory and eye contact problems)
- CGG repeat = expansion + methylation in FMR gene on X chromosome = abnormal neural development.
- Premutation stage: less than 100 repeats
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What are the common criteria used to determine a screening programme's efficacy?
- - Clearly defined disorder
- - Appreciable frequency
- - Advantage to early diagnosis
- - High specificity and sensitivity
- - Benefits should outweigh costs
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Screening for Down syndrome
- What is CUBS
- What does it detect?
- When should it be performed
- Combined ultrasound and biochemical screening
- 95% of DS cases: Nuchal transparency (US), f beta hCG and PAPP-A
- Offered early enough to allow first trimester termination
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Neonatal tests
- What is a Guthrie card?
- What does it test for?
- What other conditions are investigated?
- Heel-prick used to put neonate blood onto filter paper, which is then examined by biochemists
- Hypothyroidism (TSH immunoassay); cystic fibrosis (IRT assay); sickle cell disorder; PKU.
- Medium chain acyl coA dehydrogenase deficiency (mass spectrometry). Beta-thalassaemia major.
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What are the indications for genetic investigation in adulthood?
- Individuals with a high genetic risk (family history or positive screening test)
- Diseases with a high carrier frequency (e.g. Tay sachs in Jewish communities)
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What is a modifier gene variant?
- When other mild alterations are found in a gene, along with a main pathogenic mutation.
- These can contribute to the severity of the phenotype
- E.g. FGFR-2 mutation can increase the likelihood of breast cancer in BRCA2 mutation carriers
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What are:
- Variable expression
- Incomplete penetrance
- Gonadal mosaicism
- Variable expression: when a gene is inherited, but diplays different clinical features and severity from the parent's disease
- When an autosomal gene is 'absent' in a generation; only notable in dominant genes. Parent has children with mutation, but does not express it himself
- When a mutation is present in more than one sperm or egg cell, but not all: means a dominant disease may have reduced frequency in the next generation
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What are the characteristics of X-linked recessive inheritance?
- Knight's move (uncle and nephew affected)
- No male-male transmission
- Predominantly males affected, rarely females
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What are the characteristics of X linked dominant inheritance?
- No male-male transmission
- Female carriers always present the disease
- Few examples exist
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What are the characteristics of autosomal dominant inheritance?
- Vertical pattern
- Offspring of affected parent have a 50% risk
- Variable expressivity
- May have incomplete penetrance
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What are the characteristics of autosomal recessive inheritance?
- Horizontal pedigree (not seen in different generations as two carrier parents necessary)
- Commonly found in consanguinity
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What is the significance of:
- Y SRy region
- AZF
- X inactivation
- The sex determining region: mutations can cause phenoytpic females with male genotypes
- Found on Y. Microdeletions can cause infertility: oligospermia
- One X chromosome gets inactivated in females to reduce gene expression
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Atypical inheritance
- Explain pseudoautosomal inheritance
- Explain pseudodominant inheritance
- Close homology between X and y chromosomes in PAR region means recombination can occur: PAR genes escape x inactivation in females, making them inherit in an autosomal fashion.
- When a recessive gene behaves like a dominant; e.g. an AR condition with very high carrier frequency. Gilbert syndrome has 5% carrier frequency
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- What is somatic mosaicism?
- What is gonadal mosaicism?
- Somatic: when mutation found in part of a body exclusively. Occurs after conception, where a fetal cell mutates, proliferates and develops into tissue
- Gonadal: when egg or sperm precursor cells are a mixture of two genotypes due to a mutation
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What is an imprinting disorder?
- When DNA methylation deactivates either a maternal or paternal allele
- Angelman syndrome a common example: deletion of maternal allele. If paternal allelle; Prader willi
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Outline mitochondrial inheritance
- Far smaller genome found in mitochondria
- Only inherited through mother
- Syndromes relate to muscle, brain and eye due to energy needs
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What are the key features when assessing a genetic disease?
- Clinical history: Age of onset, symptoms and progression
- Family history: Consanguinity, miscarriages, still births
- Examination: Dysmorphic features or growth defects
- Investigations: Biochemistry, DNA/chromosomal
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How is pre-implantation genetic diagnosis (PGD) performed?
- A single cell is taken and examined with PCR or QF-PCR.
- PCR examines for exact mutations
- QF-PCR detectes chromosomal number defects
- FISH can be used for specific mutations also
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