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Cytogenetics

Clinical Implications

When reviewing a karyogram, the cytogeneticist must translate the visual bands into a clinical prognosis. The “meaning” of a chromosomal change depends entirely on the context (Constitutional vs. Acquired)

Constitutional (Germline) Implications

These abnormalities are present in every cell of the body (or a mosaic fraction) from conception

  • Impact: Developmental Delay, Intellectual Disability (ID), Dysmorphic Features, Congenital Heart Defects, Infertility, Recurrent Pregnancy Loss
  • Examples
    • t(11;22)(q23;q11.2): The most common recurrent constitutional translocation (Emanuel Syndrome carrier). Balanced carriers are normal; unbalanced offspring have severe ID/heart defects
    • inv(9): Normal Variant. No clinical impact. Reviewers must ignore it as a cause of disease
    • 47,XXY (Klinefelter): Infertility (Azoospermia) is the primary feature. Often diagnosed in adults at fertility clinics
    • Balanced Translocations: The carrier is phenotypically normal but has a high risk of creating unbalanced gametes (miscarriage)

Acquired (Somatic) Implications

These abnormalities arise in a specific tissue (usually Bone Marrow/Blood) and drive malignancy

  • Impact: Diagnosis, Prognosis, and Therapy Selection for Leukemia/Lymphoma
  • Diagnostic Markers (Who has it?)
    • t(9;22): Defines CML
    • t(15;17): Defines APL (Acute Promyelocytic Leukemia)
    • t(8;14): Defines Burkitt Lymphoma
    • inv(16) or t(16;16): Defines AML M4Eo
  • Prognostic Markers (How bad is it?)
    • Good Risk: t(8;21), inv(16), t(15;17). (Respond well to chemo)
    • Intermediate Risk: Normal Karyotype, +8
    • Poor Risk: Monosomy 7, Complex Karyotype (>3 abnormalities), del(17p)/TP53 loss. (Need Stem Cell Transplant)
  • Therapeutic Targets
    • Ph+ (t(9;22)): Use Imatinib (TKI)
    • APL (t(15;17)): Use ATRA + Arsenic

Variants & Incidental Findings

Sometimes, you find something you weren’t looking for

  • Incidental Constitutional Defect in Cancer
    • Scenario: A 60-year-old male getting a bone marrow biopsy for anemia is found to have 47,XXY (Klinefelter)
    • Implication: This is constitutional (germline), not the cause of his anemia, but it explains why he never had children. It must be reported
  • Incidental Tumor Defect in Constitutional
    • Scenario: A prenatal amniocentesis for “Advanced Maternal Age” shows a deletion of 13q14 (RB1 gene)
    • Implication: The fetus has a high risk of Retinoblastoma (eye cancer)
  • Benign Polymorphisms
    • 1qh+, 9qh+, 16qh+, Yqh+, inv(9).
    • Implication: None.: Do not confuse the clinician. These are often described in the comments (“Note: A pericentric inversion of chromosome 9 was observed, which is a known normal variant”) rather than the main diagnosis line

Summary Table: Context Matters

Abnormality If found in Newborn Blood (Constitutional) If found in Bone Marrow (Acquired)
Trisomy 21 Down Syndrome Likely transient leukemia (TMD) or AML
Deletion 5q Cri-du-Chat Syndrome (Severe ID) MDS 5q- Syndrome (Anemia, Good Prognosis)
Trisomy 8 Mosaic Warkany Syndrome MDS or AML (Intermediate Risk)
Monosomy 7 Likely technical artifact (or very rare MDS predisposition) High Risk MDS/AML
inv(9) Normal Variant Normal Variant (Not a clone)