Genetics week

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  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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.
  12. 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)
  13. 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
  14. 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
  15. 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
  16. What are the characteristics of X linked dominant inheritance?
    • No male-male transmission
    • Female carriers always present the disease
    • Few examples exist
  17. What are the characteristics of autosomal dominant inheritance?
    • Vertical pattern
    • Offspring of affected parent have a 50% risk
    • Variable expressivity
    • May have incomplete penetrance
  18. What are the characteristics of autosomal recessive inheritance?
    • Horizontal pedigree (not seen in different generations as two carrier parents necessary)
    • Commonly found in consanguinity
  19. 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
  20. 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
  21. - 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
  22. 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
  23. Outline mitochondrial inheritance
    • Far smaller genome found in mitochondria
    • Only inherited through mother
    • Syndromes relate to muscle, brain and eye due to energy needs
  24. 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
  25. 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
Card Set
Genetics week
Genetic diseases, chromosome analysis
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