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  <head>
    <title>069-02 History, examination, diagnostic strategy, differential diagnosis, and common disease</title>
    <ownerName>Integrated Medical Foundations</ownerName>
  </head>
  <body>
    <outline text="Genomic diagnosis in practice">
      <outline text="Diagnostic approach">
        <outline text="Start with phenotype and family, not sequencing"/>
        <outline text="Define the question, document findings"/>
        <outline text="Match test to suspected variant class"/>
        <outline text="Prepare for results affecting relatives"/>
        <outline text="Negative may lower probability without excluding"/>
      </outline>
      <outline text="Three-generation pedigree">
        <outline text="Record relatives, pregnancies, ages, causes of death"/>
        <outline text="Ask consanguinity, donor conception, adoption"/>
        <outline text="Do not infer parentage or gender from role"/>
        <outline text="Look for transmission patterns">
          <outline text="Vertical, sibling, sex bias, maternal line"/>
          <outline text="Multiple primaries, early onset"/>
        </outline>
        <outline text="Family history is dynamic">
          <outline text="Small families, surgery, early death hide syndromes"/>
          <outline text="Records confirm whether diseases match"/>
        </outline>
        <outline text="Test the affected relative first">
          <outline text="Unaffected first may be uninformative"/>
        </outline>
      </outline>
      <outline text="Phenotyping and examination">
        <outline text="Record positive and relevant negative findings"/>
        <outline text="Measure growth, proportions, skin, neurology"/>
        <outline text="Photographs need specific consent"/>
        <outline text="Dysmorphology identifies patterns">
          <outline text="Many features are familial variants"/>
          <outline text="Coherent minor anomalies raise plausibility"/>
          <outline text="Compare with appropriate references and parents"/>
        </outline>
        <outline text="Search for treatable complications">
          <outline text="Diagnosis matters when it guides care"/>
        </outline>
      </outline>
      <outline text="Choosing the test">
        <outline text="Karyotype: aneuploidy, large rearrangements"/>
        <outline text="Microarray: submicroscopic copy-number change">
          <outline text="Misses balanced translocations, small variants"/>
        </outline>
        <outline text="Single gene when phenotype points to one"/>
        <outline text="Panels for heterogeneity, content varies"/>
        <outline text="Exome and genome sequencing">
          <outline text="Miss some repeats, methylation, mosaicism"/>
        </outline>
        <outline text="Specialised assays for specific classes"/>
        <outline text="Confirm report scope and parental samples"/>
      </outline>
      <outline text="Biochemical genetics">
        <outline text="Crises: encephalopathy, acidosis, hyperammonaemia"/>
        <outline text="Stabilise without waiting for molecular diagnosis"/>
        <outline text="Critical samples during illness">
          <outline text="Treatment takes priority over yield"/>
        </outline>
        <outline text="Normal newborn screen does not exclude"/>
        <outline text="Pattern guides substrate, cofactor, catabolism"/>
        <outline text="Functional evidence can establish pathogenicity"/>
      </outline>
      <outline text="Interpreting results">
        <outline text="Pathogenic result needs concordance">
          <outline text="Established gene, mechanism, zygosity, phenotype"/>
        </outline>
        <outline text="Pathogenicity differs from causality"/>
        <outline text="Segregation supports or weakens">
          <outline text="De novo strong, mosaicism possible"/>
          <outline text="Non-segregation does not disprove"/>
        </outline>
        <outline text="No predictive testing on a VUS"/>
        <outline text="Reanalysis and recontact policies"/>
        <outline text="True negative needs known familial variant">
          <outline text="Otherwise often uninformative"/>
        </outline>
      </outline>
      <outline text="Common presentations">
        <outline text="Delay with anomalies: microarray and sequencing">
          <outline text="Repeat testing may need separate assays"/>
        </outline>
        <outline text="Hereditary cancer assessment">
          <outline text="Tumour screening needs germline confirmation"/>
          <outline text="Moderate-risk genes, uncertain management"/>
        </outline>
        <outline text="Inherited cardiac disease">
          <outline text="Silent, age-dependent phenotype"/>
          <outline text="Negative panel does not stop surveillance"/>
        </outline>
        <outline text="Prenatal: screening versus diagnosis">
          <outline text="Cell-free DNA confounders"/>
          <outline text="Ultrasound phenotype guides test choice"/>
        </outline>
      </outline>
      <outline text="Incidental and uncertain findings">
        <outline text="Unrelated variants, carrier status, relationships"/>
        <outline text="Pre-test discussion of categories and records"/>
        <outline text="Benefits versus anxiety, insurance, conflict"/>
        <outline text="No childhood testing for adult-onset without benefit"/>
        <outline text="Diagnosis is iterative">
          <outline text="No assay compensates for an undefined question"/>
        </outline>
      </outline>
    </outline>
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