Week 02 Genetics

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mewinstanley@googlemail.com
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Week 02 Genetics
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2012-02-01 12:03:54
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medicine week gengetics
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Genetics & inheritance lectures from week 2
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  1. Outline Autosomal Dominant [AD] Inheritance
    • AD
    • Vertical pattern of inheritance
    • passed from father to son
    • Disease expression in heterozygotes
    • 50% risk to offspring
    • variable expressivity
    • incomplete penetrance
    • e.g. Achondroplasia [short stature]

    • Genetic modifier variant
    • Other genes that affect severity of phenotype
    • [FGFR2 Mt effects BrCa2 penetrance]
  2. Outline Autosomal Recessive [AR] Inheritance
    • AR
    • Only affected if have 2 copies of affected gene, 1 copy = carrier
    • Horizontal pattern [in same sib-ship]
    • only expressed in homozygotes/ compound heterozygotes [2Mt in same gene]
    • Lower risk of TMx to children [n.b. carrier rate]
    • More constant within family
    • Consaguinuity ^^ risk [double line in pedigree]
  3. Outline X-linked recessive [XLR] inheritance
    • Never Male → male TMx
    • Females are carriers [obligate = circle w dot]
    • Features
    • Knights move inheritance
    • All daughters carriers
    • occaisional manifesting carriers [skewed x-inactivation]
  4. Outline X-linked dominant [XLD] inheritance
    • Looks like AD, but no Male → Male TMx
    • Vertical Pattern
    • all daughters affected
    • F:M 2:1
  5. Weirder mendelian inheritance
    -Y-linked inheritance [Holandric]
    -Pseudo-Autosomal Inheritance
    -Pseudo-Dominant Inheritance
    • Y-linked inheritance [Holandric]
    • Mt in sex det region Y [SRY] - male infertility

    • Pseudo-Autosomal Inheritance
    • similarity of X & Y on PAR of Xp, escape X inactivation, appears AD

    • Pseudo-Dominant Inheritance
    • AR inherited, but ^^ carrier freq appears AD [e.g. gilbert syndrome]
  6. Weirder inheritance [cont.]
    -Mosaicism
    -Imprinting Disorders
    -Mitochondrial Inheritance
    • Mosaicism
    • Somatic → not affecting gonads e.g. Mcune-Albright syndrome [skin & hormone Probs]
    • Gonadal → Mt in gonads

    • Imprinting Disorders
    • Gene expressed from just 1 allele due to methylation 'imprinting' of DNA
    • e.g. angelman syndrome, prader willi syndrome [hypotonia, overeat, LDs]

    • Mitochondrial Inheritance
    • smaller genome [37] no introns
    • maternal inheritance only
    • often affect muscle, brain & eyes
  7. What are the clinical features and molecular basis of Huntingdons Disease [HD]
    Huntingtons DiseaseAD w genetic anticipation

    • CF
    • adult onset [30-50yo]
    • progressive chorea [involuntary movements → weight loss]
    • dementia
    • psych symtoms
    • Poor prognosis [death in 17y] worse if juvenile onset
    • Nueurpathology → atrophy of small neurones [caudate & petumen]
    • Dx → clinical & FH, Imaging & DNA test to confirm

    • Molecular Basis
    • CAG [glutamine] reps in HD gene → num of repeats det severity [>39 = phenotype]
    • Shows genetic anticipation → ea gen CAG-r ^^ esp if paternal TMx
    • CAG → polyglutamine tract [huntingtin]→ insoluable, aggregates → neurotixic → symptoms
  8. What are the clinical features and molecular basis of Myotonic Dystrophy [MD]?
    Myotonic DystrophyAD w anticipation

    • CF
    • progressive muscle weakness
    • myotonia [grip to hard]
    • susceptible to → DM, cardiac conduction defects
    • Congenital → floppy baby, resp probs, poss neonatal death

    • Molecular Basis
    • CTG repeat on DMPK [Affected 50-2000 rpts]
    • abnormal mRAN indirect toxic effect on splcing of other genes → Cl ion channels → myotonia
    • Shows anticipation, worse if maternal TMx
  9. What is the CF and molecular basis of Cystic fibrosis [CF]
    Cystic FibrosisAR ^^carrier freq

    • CF
    • Bronchiectusis & obstructive lung disease
    • Meconium Ileus [obstruction at birth]
    • Pancreas → exocrine & endocrine failure

    • Molecular Basis
    • CFTR Mt → defective Cl channel
    • ^thickness of secretions
    • screen neonates on guthrie card [imunoreactive trypsin - IRT]
  10. What is the CF and molecular basis of Haemochromatosis
    HaemochromatosisAR compound heterozygotes

    • CF
    • Progressive Fe accumulation
    • Untreated → DM, cirrhosis, arthropathy, cardiomyopathy, HCC
    • Tx → therapeutic venesection

    • Molecular basis
    • HFe on C6 → C282Y & H63D [milder] Mt
    • Clinical in C282Y homozygotes & C282Y/ H63D compound heterozygotes
  11. What are the CF & molecular basis of DMD [also some BMD]
    DMDXL-R inheritance

    • CF
    • onset ~3y, wheelchair ~12y
    • Progressive muscle weakness [voluntary intially]
    • Toe walking, Gowers Sign [stand up using hands]

    • Molecular Basis
    • out of frame deletion in Xp21 [no dystrophin produced]
    • Dystrophin links F-actin w dystroglycan [structural intact during contraction]
    • CK leaks out of muscles

    • BMD
    • in frame deletion, some dystrophin made
    • onset ~11y
    • Wheelchair late/not at all
  12. What are the genetics & CF of Neurofibromatosis 1
    NF1AD inheritance, variable expression

    • CF
    • Cafe au lait spots & neurofibromas → teenage
    • Iris lisch nodules → adults [dont affect vision]
    • General → short stature w macrocephaly
    • ~mild LDs
    • Complications → scoliosis, patho tibial #, HBP, tumours [phaechromocytoma, sarcoma, optic pathway gliomas, CNS tumours]

    • Genetics
    • Mt of GTPase regulating RAS [normal] in growth factor receptor transduction p way
    • in NF1 RAS linked to GTP → ongoing activation of pathway →tumours
  13. What are the genetics and clinical consequences of fragile X?
    Fragile XXL-R genetic anticipation

    • CF
    • Severe phenotype in males
    • long face, large ears, enlarged testes
    • LDs

    • Genetics
    • CCG repeats in FMR1 gene
    • Phenotype → >200rpts, CF present 50% carrier fem = affected
    • Pre-Mt → 55-200rpts, No LDs, but can get ataxia/ tremor
  14. Outline the CF and basis of the following polysomy diseases
    -Trisomy 21
    -Edwards Syndrome
    -Trisomy 13 [Patua syndrome]
    • Trisomy 21
    • causes DS, young parents, low risk [but more births]
    • 14-21 translocation = ^^risk
    • CF → heart malformations, hypothyroidism, single palmar crease

    • Edwards Syndrome → trisomy 18
    • CF → small chin, clenched hands overlapping fingers, heart defects, severe LDs

    • Trisomy 13 → Patua Syndrome
    • CF → congenital heart defects, extra pinky finger, severe LD. ^^neonatal mortality
  15. Define
    -Tumour Suppressor Gene
    -Proto-oncogene
    -Oncogene
    • Tumour Supressor Gene [TSG]
    • inhibit progression through cell cycle e.g. p53, NF1
    • promote apoptosis e.g. p53, BAX
    • Loss of function Mt
    • Recessive → req 2 Mt

    • Proto-oncogene
    • produce proteins that stimulate cell cycle
    • Activated → oncogenes
    • dominant
    • Mt = gain of function

    • Oncogene
    • gene that has potential to cause cancer
  16. What are;
    -Loss of function Mt
    -Gain of function Mt
    Loss of function Mt → Mt causes gene to stop doing something e.g. TSG dont suppress tumours

    Gain of function → Mt causes gene to start doing something e.g. protooncogenes become oncogenes
  17. What are the functions of BRCA1 & 2 and what is their importance?
    • Functions
    • Caretake genes
    • repair via homologous recombination of double strand breaks → good, low error
    • if Mt dont work need to use → NHEJ

    • NHEJ
    • Non-homologous end joining → repair double strand breaks, not as good →mistakes → cancer
  18. What is HNPCC?
    Why is it important?
    • Hereditary Nonpolyposis colorectal Ca
    • AD inherited Mt in MSH1 & 2 [mismatch repair system genes MMR]
    • CF → few polyps [<10] +/- uterus/stomach/ovarian Ca
    • Males → 80-90% risk CRCa
    • Females → 40% CRCa

    • Screening
    • moderate risk → 1st degree relative, <45yo, colonoscopy ea 5yr 55-75
    • High risk [MMR Mt present] 2 yearly colonoscopy, 25-30yo
  19. What is FAP?
    What are the implications for the Pt?
    • Familial Adenomatous Polyposis
    • AD inherited Mt TSG
    • Congenital hypertrophy of retinal pigment [eyes]
    • >100 polyps in bowel

    • Implications?
    • Bowel screening from age 11
    • ^^risk of colon Ca
  20. What is ARMS?
    How does it work?
    What is it used for?
    • ARMS → amplifications refractory Mt System [Allele specific PCr
    • uses primers that match Mt/Wt
    • Works like PCR
    • No amplification of sequence if primers dont match
    • shows presence of known Mt
  21. What is QF-PCR?
    How does it work?
    What is it used for?
    • Quantitive Flourescant PCR
    • DNA markers from sample are amplified + tagged w flourescant
    • Amount of DNA measured by electrophoreisis
    • Used to detect aneuploidies [abn num of chromosomes]
  22. Outline a Hx and exam for clinical genetics? [Hx to toes]
    • Pts Clinical Hx → Age of onset, progression?
    • FH? → consaguinuity, miscarriage, still births?
    • Examination
    • Dysmorphic Features?
    • head to toes

    • Normal Growth
    • Height
    • Occipital-frontal circumference

    • Investigations
    • Biochem → DNA [EDTA tube] Chromosomes [Heparinised tube]
  23. What are the genetic screening tests offered in pregnancy?
    Genetic screening →whole pop, not v invasive, ?specificity

    • Downs Syndrome → 1/700pregnancies
    • 1st trimester CUBs [combined U/S & biochem]
    • hCG ^, PAPPA low, U/S → nuchal translucency
    • 2nd Trimesterquadruple biochem
    • AFP &UE3 = low
    • ^hCG & Inhibin-A
  24. What are the genetic screening tests offered for neonates?
    • Guthrie Card → heel blood spot
    • PKU
    • Congenital Hypothyroidism
    • Cystic Fibrosis
    • Sickle Cell Disease
  25. What post-natal genetic screening tests are offered?
    • Tay-sachs disease → jewish pop, pre-regnancy
    • Thalassaemia → marriage prereq in some countries
  26. What makes a good screening program? [6]
    • Clearly defined disorder
    • appreciable frequency
    • advantage to early diagnosis
    • ^specificity [few false positive, only shows what it tests for]
    • ^sensitivity [ few false negatives, always gets the answer right]
    • Benefits > costs

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