Chromosomal Abnormalities: Aneuploidy and Structural Rearrangements
Concept Name
Chromosomal Abnormalities
Genetic Loci
Down syndrome (trisomy 21): DSCR1 (21q22.3), DYRK1A (21q22.13). Philadelphia chromosome: t(9;22)(q34;q11) → BCR‑ABL1 fusion. Cri‑du‑chat syndrome: 5p deletion.
Intracellular Cascade
Nondisjunction during meiosis I or II → aneuploidy. Reciprocal translocations result from double‑strand breaks and aberrant non‑homologous end joining (NHEJ). Spindle assembly checkpoint (SAC) failure can lead to chromosomal missegregation.
Required Cofactors
No specific cofactors; folate deficiency is associated with increased risk of nondisjunction (chromosome 21).
Histology Stains
Karyotyping (G‑banding) identifies numerical and structural abnormalities. FISH with locus‑specific probes detects microdeletions and translocations. SKY (spectral karyotyping) paints each chromosome in a different color.
EM Findings
Not applicable; chromosomal abnormalities are studied at the light microscopy level in metaphase spreads.
Knockout Phenotype
Mice trisomic for chromosome 16 (homologous to human chromosome 21) exhibit cognitive deficits and neuropathological features of Alzheimer disease. Conditional knockout of Mad2 (SAC component) leads to aneuploidy and tumorigenesis.
Specific Toxins
Colchicine arrests cells in metaphase by inhibiting microtubule polymerization, used for karyotyping. Radiation and chemotherapy can cause DNA double‑strand breaks, leading to structural rearrangements.