Chromosome Abnormalities

The interpretation of the karyotype requires distinguishing between life-altering pathology, benign population variation, and laboratory error

Abnormalities (Constitutional vs. Acquired)

Numerical (Aneuploidy)
- Constitutional: Affects development. Trisomy 21 (Down), Trisomy 13/18 (Lethal), Monosomy X (Turner), XXY (Klinefelter)
- Acquired: Affects prognosis in cancer. Trisomy 8 (MDS), Monosomy 7 (Poor prognosis in AML), Hyperdiploidy (Good prognosis in ALL)
Structural
- Translocations
  - Constitutional: Balanced carriers are healthy but risk infertility/miscarriage
  - Acquired: Fusion genes drive cancer (e.g., t(9;22) in CML; t(15;17) in APL)
- Deletions
  - Constitutional: Microdeletion syndromes (e.g., del(22q) DiGeorge, del(5p) Cri-du-Chat)
  - Acquired: Tumor suppressor loss (e.g., del(5q) in MDS, del(17p) in CLL)
Mosaicism
- Constitutional: Post-zygotic error. Phenotype is typically milder than the full syndrome (e.g., Mosaic Down Syndrome)
- Acquired: Standard in cancer. We track the clone size to monitor treatment response (Residual Disease)

Cultural Artifacts (Pseudomosaicism)
- Abnormalities arising in vitro (flask error), not present in the patient
- Defined as a single abnormal cell/colony (“Random Loss” or “Single Cell +8”)
- Ignored if not reproducible in a second culture
Chromosomal Instability Syndromes
- Inherited DNA repair defects characterized by spontaneous breakage
- Fanconi Anemia: Radial figures (induced by Mitomycin C)
- Bloom Syndrome: High Sister Chromatid Exchange (SCE)
- Ataxia Telangiectasia: Spontaneous rearrangements of immune genes (Ch 7/14)
Normal Variants (Heteromorphisms)
- Benign, heritable polymorphisms in heterochromatin regions. Not: associated with disease
- inv(9)(p11q13): Most common variant
- 1qh+, 9qh+, 16qh+: Variable heterochromatin size
- Acromatic Satellites (ps+): Large satellites on 13, 14, 15, 21, 22