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  <head>
    <title>069-01 Mechanistic foundations, classification, normal variation, and clinical presentation</title>
    <ownerName>Integrated Medical Foundations</ownerName>
  </head>
  <body>
    <outline text="Genomic foundations and presentation">
      <outline text="Framing genomic medicine">
        <outline text="Links sequence, structure, regulation, environment, phenotype"/>
        <outline text="Genetic contribution does not mean inevitability"/>
        <outline text="Congenital is not necessarily inherited"/>
        <outline text="Build a defensible causal model from variation"/>
      </outline>
      <outline text="Genome organisation">
        <outline text="Antiparallel strands, complementary bases">
          <outline text="Support replication and repair"/>
        </outline>
        <outline text="Regulatory elements set when and where">
          <outline text="Promoters, enhancers, silencers, splice sites"/>
        </outline>
        <outline text="Alternative promoters, splicing, polyadenylation"/>
        <outline text="Chromatin states are dynamic">
          <outline text="Methylation, histone marks, 3D contacts"/>
          <outline text="Epigenetic states persist without sequence change"/>
        </outline>
        <outline text="Meiosis pairs, recombines, segregates homologues">
          <outline text="Nondisjunction gives aneuploid gametes"/>
          <outline text="Mitotic error after fertilisation gives mosaicism"/>
        </outline>
        <outline text="Mitochondrial genome inherited via the ovum">
          <outline text="Heteroplasmy and threshold effects"/>
          <outline text="High energy demand organs affected"/>
        </outline>
      </outline>
      <outline text="Variant scale and consequence">
        <outline text="Single-nucleotide variants and indels">
          <outline text="In-frame or frameshift"/>
        </outline>
        <outline text="Repeat expansions lengthen across generations"/>
        <outline text="Copy-number variants, inversions, translocations"/>
        <outline text="Synonymous is not always silent"/>
        <outline text="Non-coding variants disrupt regulation"/>
        <outline text="Structural variants change dosage or create fusions"/>
        <outline text="Loss of function">
          <outline text="Both copies lost, or haploinsufficiency"/>
        </outline>
        <outline text="Gain of function and dominant negative"/>
        <outline text="Same gene, different mechanisms, different disease"/>
        <outline text="Five-tier classification">
          <outline text="Uncertain significance is not a diagnosis"/>
        </outline>
      </outline>
      <outline text="Inheritance patterns">
        <outline text="Autosomal dominant">
          <outline text="One-in-two transmission"/>
          <outline text="Reduced penetrance, variable expressivity"/>
          <outline text="Germline mosaicism raises recurrence"/>
        </outline>
        <outline text="Autosomal recessive">
          <outline text="One-in-four each pregnancy, independent"/>
          <outline text="Consanguinity raises shared rare allele chance"/>
        </outline>
        <outline text="X-linked">
          <outline text="Hemizygous individuals express recessive variant"/>
          <outline text="Skewed X inactivation in heterozygotes"/>
        </outline>
        <outline text="Y-linked paternal, mitochondrial maternal"/>
        <outline text="Imprinting: parent of origin sets syndrome"/>
        <outline text="Anticipation from unstable repeats">
          <outline text="Ascertainment can mimic it"/>
        </outline>
      </outline>
      <outline text="Beyond single genes">
        <outline text="Polygenic traits: many small effects"/>
        <outline text="Heritability is population-specific">
          <outline text="Not individual determination"/>
        </outline>
        <outline text="Multifactorial threshold models">
          <outline text="Recurrence not a Mendelian ratio"/>
        </outline>
        <outline text="Polygenic scores modify probability">
          <outline text="Performance falls in unlike populations"/>
          <outline text="Risk of widening inequity"/>
        </outline>
      </outline>
      <outline text="Penetrance and variability">
        <outline text="Penetrance by defined phenotype and age"/>
        <outline text="Expressivity is degree or pattern"/>
        <outline text="Age-dependent penetrance: carriers may develop disease"/>
        <outline text="Modifiers, sex, environment, chance"/>
        <outline text="Pleiotropy across systems"/>
        <outline text="Locus versus allelic heterogeneity"/>
        <outline text="Somatic mosaicism">
          <outline text="Blood testing may miss tissue variants"/>
          <outline text="Earlier event, broader distribution"/>
        </outline>
        <outline text="Gonadal mosaicism allows recurrence"/>
      </outline>
      <outline text="Clinical presentations">
        <outline text="Prenatal: anomaly, growth, screening, fluid"/>
        <outline text="Childhood: anomalies, delay, seizures, crises"/>
        <outline text="Adult: cardiac, cancer, neurological, renal"/>
        <outline text="Negative family history can mislead"/>
        <outline text="Germline versus somatic tumour variants">
          <outline text="Confirm in a non-tumour sample"/>
        </outline>
        <outline text="Pharmacogenomics shapes metabolism and reactions">
          <outline text="Genotype does not replace monitoring"/>
        </outline>
      </outline>
      <outline text="Language and uncertainty">
        <outline text="Use neutral terms, never &quot;defective&quot;"/>
        <outline text="Separate carrier, predisposition, diagnosis, disease"/>
        <outline text="Probabilities per pregnancy or interval"/>
        <outline text="Reason from variant to presentation with evidence"/>
        <outline text="Bounded uncertainty with a plan">
          <outline text="Segregation, functional study, reinterpretation"/>
        </outline>
      </outline>
    </outline>
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