Variations in dominant phenotypes

Penetrance

  • Definition: The probability that a gene will have any phenotypic expression.

  • Non-penetrance: When a trait is not expressed even though the individual carries the gene, potentially causing a phenotype to skip a generation.

    • Risk Assessment Problems: Difficult to assess disease transmission risk in individuals with normal phenotypes if genotyping is unavailable.

Variable Expressivity

  • Definition: Variability in disease symptoms among individuals with the same genotype.

  • Example: Neurofibromatosis type 1 (NF-1) shows a range of symptoms from skin spots to tumors and skeletal deformities.

Anticipation

  • Definition: Genetic disorders that manifest earlier and/or become more severe with each generation.

  • Common in: Disorders like Huntington disease, myotonic dystrophy, and fragile X syndrome.

  • Mechanism: Often due to trinucleotide repeat expansions in the genome.

Single-Gene Disorders with Nonclassic Inheritance

  • Categories:

    1. Trinucleotide-repeat mutations

    2. Mitochondrial gene mutations

    3. Genomic imprinting

    4. Gonadal mosaicism

Trinucleotide Repeat Mutations

  • Mechanism: Repeats of a three-nucleotide sequence, often involving guanine and cytosine.

  • Examples:

    • Fragile X syndrome: 250 to 4000 repeats of CGG in the FMR-1 gene.

    • Myotonic dystrophy: Correlation between CTG repeat size and disease severity.

Genomic Imprinting

  • Definition: Differential expression of genes depending on the parent of origin.

  • Mechanism: Only one allele (either maternal or paternal) is expressed.

  • Examples:

    • Prader-Willi Syndrome: Deletion in paternally derived chromosome 15.

    • Angelman Syndrome: Deletion in maternally derived chromosome 15.

Parent-of-Origin Effect: Uniparental Disomy

  • Definition: Both copies of a chromosome are inherited from one parent.

  • Significance: Can lead to diseases if imprinted genes are involved.

De Novo Mutations

  • Definition: New mutations occurring in the egg or sperm, not inherited from parents.

  • Impact: No increased risk to siblings if parents are unaffected.

Gonadal Mosaicism

  • Definition: Mutations occurring during early embryogenesis affecting gonadal cells.

  • Impact: Can transmit to offspring despite normal parental phenotype.

Genetic Heterogeneity

  • Types:

    • Clinical Heterogeneity: Different disorders from mutations in the same gene (e.g., RET gene in MEN2 and Hirschsprung disease).

    • Allelic Heterogeneity: Different mutations within the same allele causing a disorder.

    • Locus Heterogeneity: Mutations in different genes leading to a similar phenotype (e.g., BRCA1 and BRCA2 in breast cancer).

Phenocopy

  • Definition: Environmental factors induce a trait that mimics a genetic disorder.

  • Example: A family with BRCA mutations but an individual develops breast cancer without the mutation.