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  <head>
    <title>092-01 Chromosomes, meiosis, Mendelian inheritance, mosaicism, penetrance, and pedigrees</title>
    <ownerName>Integrated Medical Foundations</ownerName>
  </head>
  <body>
    <outline text="Chromosomes, meiosis, Mendelian inheritance, and pedigrees">
      <outline text="Framing and chromosome structure">
        <outline text="Many mechanisms of genetic disease">
          <outline text="Single nucleotides, copy number, rearrangements, repeats"/>
          <outline text="Mitochondrial variants, epigenetic errors"/>
        </outline>
        <outline text="Inheritance is transmission, not mechanism or severity"/>
        <outline text="22 autosome pairs plus two sex chromosomes"/>
        <outline text="Sister chromatids joined at the centromere">
          <outline text="Telomeres cap ends, kinetochore binds spindle"/>
        </outline>
        <outline text="Band address runs outward from the centromere"/>
        <outline text="Genomic coordinates need the assembly version"/>
      </outline>
      <outline text="Meiosis and aneuploidy">
        <outline text="Homologues pair and recombine at chiasmata"/>
        <outline text="Homologues split in meiosis one, chromatids in two"/>
        <outline text="Nondisjunction yields aneuploid gametes">
          <outline text="Trisomy or monosomy after fertilisation"/>
          <outline text="Mitotic error after fertilisation gives mosaicism"/>
        </outline>
        <outline text="Phenotype: chromosome, fraction, tissue, dosage"/>
        <outline text="Most monosomies and many trisomies are lethal">
          <outline text="Viable: trisomy 21, 18, 13 and sex chromosomes"/>
        </outline>
        <outline text="Maternal age: arrested oocytes lose cohesion"/>
        <outline text="Paternal age: new variants via spermatogonial divisions"/>
      </outline>
      <outline text="Polyploidy and structural rearrangement">
        <outline text="Triploidy from two sperm or a diploid gamete">
          <outline text="Parental origin shapes placenta and fetus"/>
        </outline>
        <outline text="Tetraploidy lethal unless mosaic"/>
        <outline text="Balanced: no major net copy-number change">
          <outline text="May disrupt a gene or regulatory domain"/>
          <outline text="Can create unbalanced gametes"/>
        </outline>
        <outline text="Unbalanced: dosage change and phenotype"/>
      </outline>
      <outline text="Translocations, inversions, rings">
        <outline text="Reciprocal: exchange between nonhomologues"/>
        <outline text="Robertsonian: fused acrocentric long arms">
          <outline text="Miscarriage or translocation trisomy"/>
          <outline text="Recurrence differs from free trisomy, test parents"/>
        </outline>
        <outline text="Inversion rotates a chromosome segment">
          <outline text="Paracentric excludes centromere, pericentric includes"/>
          <outline text="Loop recombination yields abnormal products"/>
        </outline>
        <outline text="Ring from terminal breaks and fusion"/>
        <outline text="Isochromosome: one arm duplicated, other lost"/>
      </outline>
      <outline text="Autosomal inheritance">
        <outline text="Dominant: vertical, all sexes, one-half risk">
          <outline text="De novo variant gives an isolated case"/>
          <outline text="Reduced penetrance mimics a skipped generation"/>
          <outline text="Haploinsufficiency, dominant negative, gain, toxicity"/>
        </outline>
        <outline text="Recessive: variants in both gene copies">
          <outline text="Carrier parents, one-quarter sibling risk"/>
          <outline text="Consanguinity raises shared rare alleles"/>
          <outline text="Compound heterozygosity: two different variants"/>
          <outline text="Pseudodominance where the allele is frequent"/>
        </outline>
      </outline>
      <outline text="Sex-linked and mitochondrial inheritance">
        <outline text="X-linked recessive affects hemizygous males">
          <outline text="No father-to-son transmission"/>
          <outline text="Symptomatic females: skewing, dosage, tissue"/>
        </outline>
        <outline text="X-linked dominant: father to all daughters">
          <outline text="Heterozygous mother: one-half to each child"/>
        </outline>
        <outline text="Pseudoautosomal genes recombine"/>
        <outline text="Mitochondrial DNA is maternally inherited">
          <outline text="Heteroplasmy: normal and variant genomes coexist"/>
          <outline text="Bottleneck, segregation, thresholds vary severity"/>
        </outline>
      </outline>
      <outline text="Imprinting and repeat expansion">
        <outline text="Expression depends on parent of origin"/>
        <outline text="Uniparental disomy: both homologues from one parent">
          <outline text="Imprinting disease or unmasked recessive"/>
        </outline>
        <outline text="Imprinting-centre and methylation defects mimic deletion">
          <outline text="Recurrence follows mechanism, not syndrome name"/>
        </outline>
        <outline text="Anticipation: earlier or more severe each generation">
          <outline text="Repeats expand during gametogenesis"/>
          <outline text="Coding CAG expansion gives polyglutamine"/>
          <outline text="Noncoding expansion silences genes or alters RNA"/>
        </outline>
      </outline>
      <outline text="Penetrance, heterogeneity, mosaicism">
        <outline text="Penetrance: proportion affected by a set age"/>
        <outline text="Expressivity: degree or pattern among affected"/>
        <outline text="Modifiers, environment, ascertainment alter both">
          <outline text="Clinic estimates may not fit screening"/>
        </outline>
        <outline text="Pleiotropy, locus and allelic heterogeneity"/>
        <outline text="Phenocopy from a non-genetic cause"/>
        <outline text="Mosaicism from postzygotic change">
          <outline text="Earlier events involve more tissues"/>
          <outline text="Gonadal mosaicism: repeated affected children"/>
          <outline text="Low-level mosaicism missed in blood"/>
        </outline>
      </outline>
      <outline text="Pedigrees and counselling">
        <outline text="Record three generations when possible"/>
        <outline text="Respectful language and confidentiality"/>
        <outline text="Bayesian update of prior risk">
          <outline text="Negative result limited by assay sensitivity"/>
          <outline text="Young unaffected status is weak evidence"/>
        </outline>
        <outline text="Transmission, disease risk, severity are distinct"/>
        <outline text="Discordance prompts reconsideration">
          <outline text="Phenotype, mosaicism, penetrance, second diagnosis"/>
        </outline>
      </outline>
    </outline>
  </body>
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