Skip to main content

Cytogenetics

ISCN

Cytogenetics is a language, and the International System for Human Cytogenomic Nomenclature (ISCN) is its grammar. Published and updated periodically (e.g., ISCN 2020), this book defines the mandatory rules for describing any karyotype, from a simple normal male to the most chaotic cancer genome. The goal of ISCN is ensuring that a description like t(9;22)(q34;q11.2) means exactly the same thing to a laboratory scientist in Berlin as it does to one in Boston

The Basic Formula

Every ISCN string follows a strict order: <Total Chromosome Count>,<Sex Chromosomes>,<Abnormalities>[<Number of Cells>]

  • Comma Use: Commas separate the major components. No spaces are typically used within the string
  • Example: 46,XY[20]
    • 46: Total count
    • XY: Sex complement
    • [20]: Number of metaphases scored

Describing Abnormalities

When abnormalities are present, they are listed after the sex chromosomes

Numerical Abnormalities (+ / -)

  • Gain: A plus sign (+) precedes the chromosome number
    • 47,XY,+21[20] (Male with Trisomy 21)
  • Loss: A minus sign (-) precedes the chromosome number
    • 45,XX,-7[20] (Female with Monosomy 7)
  • Sex Chromosomes: Gains/Losses are reflected directly in the sex string, not with +/-
    • 45,X[20] (Turner Syndrome, not “45,XX,-X”)
    • 47,XXY[20] (Klinefelter, not “47,XY,+X”)

Structural Abnormalities (Short Form)

ISCN uses three-letter abbreviations (e.g., del, dup, inv, t) followed by the chromosome(s) in the first parenthesis, and the band(s) in the second parenthesis

  • Translocation (t): t(A;B)(p1;q2)
    • The semicolon ; separates the two chromosomes and the two breakpoints
    • Example: 46,XY,t(9;22)(q34;q11.2)
      • Translocation between Ch 9 and Ch 22. Breakpoints at 9q34 and 22q11.2
  • Deletion (del): del(A)(p1q2) or del(A)(p1)
    • Interstitial: Two bands listed (start and end of the cut). del(5)(q13q33)
    • Terminal: One band listed (the break point; everything distal is gone). del(5)(q31)
  • Inversion (inv): inv(A)(p1q2)
    • Pericentric: One break in p, one in q. inv(16)(p13q22)
    • Paracentric: Both breaks in the same arm. inv(3)(q21q26)
  • Derivative (der): Used for unbalanced translocations where one partner is lost or the structure is complex
    • der(22)t(9;22): An abnormal Chromosome 22 resulting from a translocation with Ch 9. (The normal 9 is present, the derivative 9 is absent, the normal 22 is present, the derivative 22 is present)

Breakpoint Nomenclature (p & q)

  • p: Short arm (Petite)
  • q: Long arm
  • cen: Centromere
  • ter: Terminal (end of the chromosome). pter or qter
  • Format: (Chromosome)(Arm Band. Sub-band)
    • Correct: 9q34.1
    • Incorrect: 9Q34.1 (Case sensitive)

Mosaicism & Clones

When multiple cell lines are present, they are listed sequentially, separated by a slash (/)

  • Order: The largest clone is usually listed first, followed by smaller clones. However, generally, the Normal line is listed last in constitutional cases to emphasize the abnormality, while in oncology, the stemline is listed first
  • Example (Mosaic Down): 47,XX,+21[15]/46,XX[5]
    • 15 cells have Trisomy 21
    • 5 cells are Normal
  • Example (Clonal Evolution): 46,XY,t(9;22)(q34;q11.2)[10]/47,XY,t(9;22)(q34;q11.2),+8[10]
    • First clone: Ph+ only
    • Second clone: Ph+ AND Trisomy 8 (Evolution)

Uncertainty (The Question Mark)

Cytogenetics is visual, and sometimes the resolution isn’t perfect. ISCN provides a mechanism for doubt

  • Question Mark (?): Placed before the item that is uncertain
    • del(5)(q?): I know it’s a deletion of 5q, but I can’t identify the exact breakpoint band
    • ?del(5)(q31): I suspect there is a deletion at q31, but I’m not 100% sure
  • Add (add): Additional material of unknown origin
    • 46,XX,add(19)(p13): There is extra junk on 19p13, but I don’t know where it came from (banding doesn’t match anything)

ISCN for FISH (ish)

FISH results have their own specific nomenclature, starting with nuc ish (Nuclear Interphase FISH) or ish (Metaphase FISH)

  • Format: nuc ish (Probe x Copy Number)
  • Example (Normal): nuc ish (D21S65x2)[200]
    • Interphase cells show 2 signals for the Chromosome 21 probe (Normal)
  • Example (Deletion): nuc ish (ATMx1)[100/200]
    • The ATM probe (11q) shows only 1 signal (Deletion) in 100 out of 200 cells
  • Example (Fusion): nuc ish (BCR,ABL1)x3(BCR con ABL1x2)[200]
    • Standard dual-fusion probe notation indicating a t(9;22) fusion

Key Formatting Rules Checklist

  1. No spaces (usually)
  2. Use ; to separate chromosomes/bands in translocations
  3. Use . to separate band from sub-band (q11.2)
  4. Total count includes sex chromosomes
  5. Clone size [n] is mandatory
  6. List order in karyogram: Numerical (1-22), then Sex (X, Y)
  7. List order in ISCN string for abnormalities: Numerical order of the affected chromosome
    • Correct: 46,XY,del(5)(q13),t(9;22)(q34;q11.2) (5 comes before 9)
    • Exceptions: Sex chromosome abnormalities usually come first (e.g., 47,XY,+X,t(9;22))