NeuroGenetics Curriculum·intermediate·25 min

Human Chromosome Nomenclature (ISCN)

Master the International System for Human Cytogenomic Nomenclature — the universal language for describing karyotypes, structural rearrangements, and array-based copy number findings.

Tags: Basic Genetics · Neurogenetics

Learning Objectives

  1. 1.Describe chromosome morphology and the principles of G-banding at clinical resolution
  2. 2.Interpret standard karyotype notation according to ISCN guidelines
  3. 3.Write ISCN nomenclature for common structural chromosomal abnormalities
  4. 4.Distinguish between constitutional and mosaic chromosomal findings
  5. 5.Interpret cytogenomic microarray nomenclature for copy number variants

01Chromosome Morphology and G-Banding

Human somatic cells contain 46 chromosomes — 22 pairs of autosomes and one pair of sex chromosomes. Each chromosome has a characteristic size, centromere position, and banding pattern that allows unambiguous identification. G-banding (Giemsa staining after trypsin treatment) is the standard technique for cytogenetic analysis and produces the distinctive alternating light and dark band pattern used for karyotyping.

Key Points

  • Centromere position divides chromosomes into short arm (p, from French 'petit') and long arm (q)
  • Chromosome morphology by centromere position: metacentric (centromere central), submetacentric (centromere off-center), acrocentric (centromere near tip; chromosomes 13, 14, 15, 21, 22)
  • G-dark bands (AT-rich, gene-poor, late-replicating); G-light bands (GC-rich, gene-dense, early-replicating)
  • Standard clinical karyotype resolution: 400–550 bands; high-resolution banding: 550–850 bands; detects rearrangements ≥5–10 Mb

02ISCN Karyotype Notation: The Basics

The International System for Human Cytogenomic Nomenclature (ISCN) provides a standardized framework for describing chromosomal findings. A complete karyotype description contains three mandatory components: the total chromosome number, the sex chromosome complement, and any abnormality or variant observed.

Key Points

  • Normal male: 46,XY — Normal female: 46,XX
  • Format: [total chromosome number],[sex chromosomes],[abnormalities]
  • Band nomenclature: chromosome number + arm (p/q) + region + band + sub-band (e.g., 7q11.23 = chromosome 7, long arm, region 1, band 1, sub-band 23)
  • Chromosome arms are divided from centromere outward: region 1, band 1 immediately flanks the centromere; band numbers increase toward the telomere

03Numerical and Structural Abnormalities

ISCN provides specific symbols and notation rules for all classes of chromosomal abnormalities. Numerical abnormalities (aneuploidy) change the total copy number of one or more chromosomes. Structural abnormalities rearrange chromosomal material without necessarily changing total chromosome count.

Key Points

  • Trisomy: extra chromosome indicated by '+': 47,XY,+21 = male trisomy 21 (Down syndrome)
  • Monosomy: missing chromosome indicated by '−': 45,X = Turner syndrome
  • Deletion: del(chromosome)(band range) — e.g., del(7)(q11.23q11.23) or del(7)(q11.23) for interstitial deletion
  • Duplication: dup; Inversion: inv; Translocation: t (balanced reciprocal) or der (derivative chromosome); Ring chromosome: r

04Mosaicism and Special Notations

Mosaicism — the presence of two or more chromosomally distinct cell populations in an individual — arises from a post-zygotic mutation. Mosaic findings require careful interpretation as clinical severity often correlates with the proportion of abnormal cells and the tissues affected.

Key Points

  • Mosaic notation: cell line 1[cell count]/cell line 2[cell count] — e.g., 45,X[12]/46,XX[18] = mosaic Turner syndrome
  • The cell count in brackets follows ISCN guidelines: minimum 20 metaphases analyzed for routine constitutional studies
  • Isodicentric chromosomes: idic — a single chromosome with two centromeres derived from one chromosome
  • Marker chromosomes: mar — small, structurally abnormal chromosome of uncertain origin; require FISH or array for characterization

05Array Cytogenomics: ISCN Notation for CNVs

Chromosomal microarray (CMA) and whole-genome sequencing generate copy number variant (CNV) data that must be described in standardized notation. ISCN 2020 introduced a comprehensive framework for reporting array findings using genome build coordinates alongside classic cytogenetic band nomenclature.

Key Points

  • Array ISCN format: arr[genome build] chromosomal band(start_coordinate_end_coordinate)×copy number
  • Example — 22q11.2 deletion: arr[GRCh38] 22q11.21(18,912,231_21,465,672)×1 (single copy = deletion in a diploid genome)
  • Duplication notation: ×3 for a single extra copy (3 total) in a diploid individual
  • Copy-neutral LOH (loss of heterozygosity = ROH or regions of homozygosity): hmz — indicates loss/absence of heterozygosity without copy number change; important for recessive disease and imprinting disorders

Quiz Questions

1. A child with intellectual disability and cardiac defects has a karyotype reported as 46,XX,del(22)(q11.2q11.2). This notation describes:

  1. A.A duplication of the 22q11.2 region on the long arm
  2. B.An interstitial deletion at band q11.2 on chromosome 22✓
  3. C.A balanced translocation between chromosome 22 and another
  4. D.A ring chromosome 22 with loss of both telomeres

The notation del(22)(q11.2q11.2) describes an interstitial deletion on the long arm (q) of chromosome 22 at band q11.2. This is the 22q11.2 deletion syndrome (DiGeorge/velocardiofacial syndrome), one of the most common microdeletion syndromes. The 'del' symbol indicates a deletion, and the band coordinates in parentheses specify the deleted segment. The total chromosome count remains 46 because only a small interstitial segment is lost.

2. A microarray report reads: arr[GRCh38] 16p11.2(29,592,751_30,190,029)x3. How should this result be interpreted?

  1. A.A deletion of approximately 600 kb at 16p11.2, leaving one copy
  2. B.A duplication of approximately 600 kb at 16p11.2, giving three copies✓
  3. C.Copy-neutral loss of heterozygosity spanning the 16p11.2 region
  4. D.A balanced inversion within the 16p11.2 region of chromosome 16

In array ISCN notation, x3 indicates three copies of the specified region in a diploid individual, meaning a duplication (normal diploid copy number is 2). The size is approximately 30,190,029 minus 29,592,751 = ~597 kb. The 16p11.2 duplication is associated with neurodevelopmental phenotypes including autism, schizophrenia risk, and underweight/microcephaly, contrasting with the reciprocal deletion which is associated with autism and obesity.

3. Chromosomes 13, 14, 15, 21, and 22 are classified as acrocentric. Which structural feature makes them susceptible to Robertsonian translocations?

  1. A.They have unusually large telomeric regions that promote end-to-end chromosome fusion events
  2. B.Their centromeres are near the tip, with short arms carrying only redundant rDNA repeats✓
  3. C.They contain constitutive fragile sites that are prone to breakage during meiotic division
  4. D.They are the smallest human chromosomes and cluster together at the nucleolar organizer

Acrocentric chromosomes have centromeres positioned near the tip, creating very short arms (p arms) that contain primarily ribosomal RNA gene repeats (rDNA) and satellite DNA. Robertsonian translocations occur when two acrocentric chromosomes fuse at or near the centromere, with loss of the short arms. Because the short arms carry only redundant rDNA sequences, their loss is tolerated. The most common Robertsonian translocation is rob(13;14), and rob(14;21) is clinically significant as a cause of familial Down syndrome.

4. A newborn with ambiguous genitalia has a karyotype result of 46,XX/46,XY[15/15]. This mosaic finding most likely arose from:

  1. A.Non-disjunction during maternal meiosis I producing two distinct sex lines
  2. B.Chimerism — fusion of two separately fertilized zygotes during early development✓
  3. C.X-chromosome inactivation skewing in a 46,XX individual causing mosaicism
  4. D.A Y chromosome microdeletion causing partial loss of sex-determining genes

A 46,XX/46,XY mosaic karyotype with two distinct sex chromosome complements is most consistent with chimerism rather than standard mosaicism. True chimerism arises from fusion of two separately fertilized zygotes (or absorption of a twin) during early development, producing an individual with two genetically distinct cell lines. This is different from mosaicism, which arises from a post-zygotic mutation in a single zygote. The distinction has implications for gonadal development and management.

5. A cytogenetics laboratory sends a G-banded karyotype report. A resident asks about the genomic properties underlying dark versus light chromosome bands. Which statement correctly describes these bands?

  1. A.Dark bands are GC-rich, gene-dense, and early-replicating; light bands are AT-rich and gene-poor
  2. B.Dark bands are AT-rich, gene-poor, and late-replicating; light bands are GC-rich and gene-dense✓
  3. C.Both dark and light bands have identical gene density, nucleotide composition, and replication timing
  4. D.Dark bands contain only non-coding repetitive DNA; all protein-coding genes reside in light bands

G-dark (Giemsa-positive) bands are AT-rich, relatively gene-poor, and replicate late in S-phase. G-light (Giemsa-negative) bands are GC-rich, gene-dense, and replicate early. This distinction has clinical relevance: deletions in gene-dense light bands are more likely to cause multi-gene contiguous gene syndromes, and the banding pattern helps cytogeneticists identify structural abnormalities by revealing disruptions in the expected alternating pattern.