Abnormalities

Cytogenetic diagnosis hinges on the distinction between Constitutional (Germline) and Acquired (Somatic) abnormalities. While the chromosomal mechanics (deletions, gains, translocations) are physically identical, their clinical implications are radically different. Constitutional defects affect the entire body and typically cause developmental delays, congenital anomalies, or reproductive failure. Acquired defects are restricted to a specific tissue (e.g., bone marrow) and drive malignancy (cancer)

Numerical Abnormalities (Aneuploidy)

Aneuploidy is a deviation from the normal chromosome number (46), usually arising from Non-disjunction (failure of chromosomes to separate) during cell division

• Trisomy (Gain): 47 chromosomes (+1)
  • Constitutional
    • Trisomy 21 (Down Syndrome): The most common live-born autosomal trisomy. Implications: Intellectual disability, heart defects, early Alzheimer’s
    • Trisomy 18 (Edwards) / 13 (Patau): Severe life-limiting anomalies. Most die within the first year
    • Sex Chromosome Trisomy (XXY, XXX, XYY): Milder phenotypes. Klinefelter (XXY) causes infertility/hypogonadism; XXX and XYY often have normal phenotypes or mild learning issues
  • Acquired (Oncology)
    • Trisomy 8 (+8): Common in Myelodysplastic Syndromes (MDS) and AML. Intermediate prognosis
    • Trisomy 12 (+12): The most common trisomy in CLL. Intermediate prognosis
• Monosomy (Loss): 45 chromosomes (-1)
  • Constitutional
    • Monosomy X (Turner Syndrome): The only viable whole-chromosome monosomy in humans. Implications: Short stature, ovarian failure/infertility, heart defects (coarctation of aorta)
    • Autosomal Monosomy: Lethal in utero. Finding a full autosomal monosomy (e.g., -21) in a postnatal sample is almost always a technical artifact (broken cell), not a biological reality
  • Acquired (Oncology)
    • Monosomy 7 (-7): A high-risk marker in MDS/AML (therapy-related myeloid neoplasms). Very poor prognosis

Structural Abnormalities

Structural defects involve breakage and reunion of chromosomes

• Translocation (t): Exchange of material between non-homologous chromosomes
  • Reciprocal (Balanced): No net gain/loss of DNA
    • Constitutional: Phenotypically normal carrier. Clinical Implication: High risk of Infertility: or Recurrent Miscarriage because meiosis produces unbalanced gametes
    • Acquired: Drivers of leukemia fusion genes
      • t(9;22) BCR:ABL1: CML (Chronic Myeloid Leukemia). Treatable with Tyrosine Kinase Inhibitors (Gleevec)
      • t(15;17) PML:RARA: APL (Acute Promyelocytic Leukemia). Medical emergency (coagulopathy). Highly curable with ATRA/Arsenic
  • Robertsonian: Fusion of two acrocentric chromosomes (13, 14, 15, 21, 22) at the centromere
    • Constitutional: der(13;14) is the most common. Carriers are normal (45 chromosomes) but risk having Trisomy 13 offspring. der(14;21) carriers have a high risk of Down Syndrome offspring
• Deletion (del): Loss of a segment
  • Constitutional (Microdeletion Syndromes)
    • del(22q11.2): DiGeorge/VCFS. Heart defects, immune deficiency, cleft palate
    • del(5p): Cri-du-Chat. Cat-like cry, severe intellectual disability
  • Acquired: Tumor Suppressor Gene loss
    • del(5q): “5q- Syndrome” in MDS. Good prognosis; responds to Lenalidomide
    • del(17p) (TP53): High risk in CLL and Myeloma. Resistance to standard chemo; requires novel agents
• Inversion (inv): Reversal of a segment
  • Pericentric (Includes Centromere)
    • Constitutional: inv(9)(p12q13) is a common benign polymorphism (normal variant). No clinical significance
  • Acquired
    • inv(16): Acute Myeloid Leukemia (AML M4Eo). Good prognosis (Core Binding Factor Leukemia)

Mosaicism

The presence of two or more genetically distinct cell lines in the same individual

• Constitutional Mosaicism
  • Arises from a mitotic error after fertilization (post-zygotic)
  • Clinical Implication: The phenotype is often milder than the full syndrome
    • Example: Mosaic Trisomy 21 (46,XX/47,XX,+21) individuals may have higher IQs and fewer physical stigmata than full Down Syndrome patients
    • Example: Mosaic Turner (45,X/46,XX) individuals may have spontaneous puberty and fertility, unlike pure 45,X
• Acquired Mosaicism (Clonality)
  • In cancer, “Mosaicism” is the default state (Tumor vs. Normal Host cells)
  • Clinical Implication: We track the percentage of abnormal cells (Clone Size) to monitor Residual Disease
    • Example: At diagnosis, 100% of cells are Ph+ (t(9;22)). After treatment, 0% are Ph+ (Cytogenetic Remission)

Imprinting Disorders (UPD)

While technically structural/numerical, these often appear normal on a karyotype and require Microarray/Methylation testing

• Uniparental Disomy (UPD): Inheritance of both homologs from one parent
• Prader-Willi / Angelman (Ch 15): Can be caused by deletion 15q11-q13 (visible by FISH/Karyotype) OR by UPD 15 (invisible by Karyotype)

Summary of Clinical Implications

Abnormality	Constitutional Impact	Acquired (Oncology) Impact
Trisomy 21	Down Syndrome	Rare in cancer
Trisomy 8	Mosaic Warkany Syndrome (Severe)	MDS/AML (Intermediate Risk)
Monosomy 7	Lethal	High Risk MDS/AML (Poor Prognosis)
t(9;22)	Carrier (Normal)	CML (Defines the disease)
del(5q)	Cri-du-Chat	MDS 5q- Syndrome (Good Prognosis)
inv(16)	Carrier (Risk of unbalanced offspring)	AML M4Eo (Good Prognosis)