U01.01.050 Genetic terms

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Learning Objectives

  • Distinguish between Variable Expressivity and Incomplete Penetrance.
  • Understand the concepts of Pleiotropy and Heterogeneity.
  • Master high-yield inheritance patterns like Mosaicism and Uniparental Disomy.

1. Core Phenotypic Terms

  • Codominance: Both alleles contribute to the phenotype.
    Example: Blood groups A, B, AB; alpha-1 antitrypsin deficiency.
  • Variable Expressivity: Same genotype, but the severity of the phenotype varies between patients.
    Example: Two patients with NF1 (one has only café-au-lait spots, the other has extensive neurofibromas).
  • Incomplete Penetrance: Not everyone with the genotype expresses the disease.
    Formula: % penetrance × probability of inheriting genotype = risk.
    Example: BRCA1 mutations do not always lead to cancer.
  • Pleiotropy: One gene mutation causes multiple seemingly unrelated phenotypic effects.
    Example: Cystic Fibrosis (affects lungs, GI tract, and male fertility).

2. Advanced Genetic Concepts

  • Anticipation: Earlier onset or increased severity in future generations. Common in trinucleotide repeat diseases (e.g., Huntington’s).
  • Loss of Heterozygosity: Seen in tumor suppressor genes. The second “wild type” allele must be lost for cancer to develop.
    Example: Retinoblastoma (two-hit hypothesis) and Li-Fraumeni syndrome.
  • Dominant Negative Mutation: A nonfunctional protein prevents the normal protein from working.
    Example: Mutated p53 blocks the wild-type p53.
  • Linkage Disequilibrium: Alleles occur together more often than expected by chance. This is measured in a population, not a family.

3. Heterogeneity & Mosaicism

  • Locus Heterogeneity: Mutations at different loci cause the same disease (e.g., Albinism).
  • Allelic Heterogeneity: Different mutations at the same locus cause the same disease (e.g., Beta-thalassemia).
  • Mosaicism: Genetically distinct cell lines in one individual.
    • Somatic: Mitotic error after fertilization.
    • Gonadal: Mutation restricted to gametes. Suspect this if a child has a disease but parents/relatives do not.
    • McCune-Albright Syndrome: Gs-protein mutation. Presents with unilateral café-au-lait spots (ragged edges), fibrous dysplasia, and endocrinopathies. Survivable only due to mosaicism.

4. Mitochondrial and Uniparental Issues

  • Heteroplasmy: A mix of normal and mutated mtDNA. Leads to variable expression in mitochondrial diseases.
  • Uniparental Disomy (UPD): Two copies of a chromosome from one parent.
    • Heterodisomy: Meiosis I error.
    • Isodisomy: Meiosis II error.
    • Classic Examples: Prader-Willi and Angelman syndromes.

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