Chromosomal Abnormalities

Short version. Numerical abnormalities (aneuploidies and polyploidies) are gains or losses of whole chromosomes. The viable autosomal trisomies in liveborns are 21 (Down), 18 (Edwards), and 13 (Patau); the common sex-chromosome aneuploidies are 45,X (Turner), 47,XXY (Klinefelter), 47,XYY, and 47,XXX. Structural rearrangements include reciprocal and Robertsonian translocations, inversions, deletions, duplications, isochromosomes, and ring chromosomes. Submicroscopic copy-number variants — the 22q11.2 deletion, 7q11.23 deletion (Williams-Beuren), 15q11-q13 deletions (Prader-Willi / Angelman) and many others — were brought into systematic view by chromosomal microarray. Constitutional abnormalities are present in every cell; somatic abnormalities, such as the t(9;22) Philadelphia chromosome of chronic myeloid leukaemia, are acquired in particular tissues. Detection is now layered: karyotype for whole-chromosome and large rearrangements, FISH for targeted regions, microarray for copy-number variation, NIPT for prenatal screening of common trisomies, sequencing for everything else.

Numerical abnormalities

A numerical abnormality is a gain or loss of one or more whole chromosomes. Aneuploidy is a deviation by one chromosome (trisomy = three copies; monosomy = one copy); polyploidy is a complete extra set (triploidy = 3n = 69 chromosomes; tetraploidy = 4n = 92). Most autosomal monosomies and most polyploidies are incompatible with development beyond very early gestation; the survivable autosomal trisomies in humans are 21, 18, and 13.

Most aneuploidies originate at maternal meiosis I. Hassold and Hunt (2001) reviewed the evidence: a combination of poor recombination on certain chromosomes (especially chromosome 21), the long arrest of human oocytes in prophase I from foetal life until ovulation, and progressive loss of meiotic cohesion with maternal age combine to produce the steep age dependence of trisomy. The mechanistic detail is described in cell cycle, mitosis and meiosis; the syndromes themselves are catalogued below.

Down syndrome (trisomy 21)

Trisomy 21 is the most common viable autosomal aneuploidy in liveborn infants, with an overall live-birth prevalence of approximately one in 700. It is the first chromosomal disease ever described: Lejeune, Gautier and Turpin (1959) reported an extra small chromosome (later identified as chromosome 21) in nine children with Down syndrome, founding human cytogenetics as a discipline. The phenotype includes characteristic facial features, intellectual disability, congenital heart defects in around 40-50% of cases (especially atrioventricular septal defects), and a higher than population background risk of childhood leukaemia. Approximately 95% of cases are free trisomy 21 (47,XX,+21 or 47,XY,+21); approximately 4% are due to a Robertsonian translocation (commonly der(14;21)) producing functional trisomy 21; approximately 1% are mosaic.

Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13)

Trisomies 18 and 13 are individually rarer than trisomy 21 (live-birth prevalence approximately one in 5,000 and one in 10,000 respectively) and have considerably higher early-life mortality. Trisomy 18 (Edwards) is associated with severe intrauterine growth restriction, congenital heart defects, characteristic clenched hands, and rocker-bottom feet. Trisomy 13 (Patau) is associated with holoprosencephaly, severe midline defects, polydactyly, and a similarly poor early prognosis. Both are detectable prenatally by NIPT or karyotype on a chorionic villus or amniotic fluid sample.

Sex-chromosome aneuploidies

The common sex-chromosome aneuploidies are individually rare but collectively common. Turner syndrome (45,X), monosomy X, is associated with short stature, primary ovarian insufficiency, congenital heart defects (notably bicuspid aortic valve and aortic coarctation), and characteristic physical features. The great majority of 45,X conceptions miscarry; the survival of others appears to depend on partial mosaicism. Klinefelter syndrome (47,XXY), the most common sex-chromosome aneuploidy in males, is associated with hypogonadism, infertility, gynaecomastia, and a varied behavioural and cognitive phenotype. 47,XYY and 47,XXX are individually similar in frequency but typically present with milder, more variable phenotypes; many cases are never identified.

Sex-chromosome aneuploidies illustrate dosage compensation: the X-inactivation system mosaically silences one X chromosome in each somatic cell of XX individuals and silences supernumerary Xs in cases like 47,XXY and 47,XXX. The Y chromosome is gene-poor outside the pseudoautosomal regions, which is why polysomy of Y is more tolerable than autosomal polysomy.

Structural rearrangements

Structural rearrangements involve the breakage and rejoining of chromosomes in a non-physiological pattern. The categories are:

Reciprocal translocation: an exchange of segments between two non-homologous chromosomes. A balanced reciprocal translocation has no net loss or gain of material; the carrier is typically phenotypically normal but is at risk of producing unbalanced gametes due to the geometry of segregation at meiosis from the resulting quadrivalent.
Robertsonian translocation: a fusion of two acrocentric chromosomes (chromosomes 13, 14, 15, 21, 22) at or near their centromeres, producing a single derivative chromosome and effectively eliminating the satellited short arms. Robertsonian translocations occur in approximately one in 1,000 individuals; the most common is der(13;14). Carriers are typically phenotypically normal but are at risk of producing unbalanced gametes leading to trisomy or monosomy of the involved acrocentric, and account for approximately 4% of Down syndrome.
Inversion: a segment of a chromosome reverses orientation. Pericentric inversions include the centromere; paracentric inversions do not. Inversion carriers are at risk of producing unbalanced gametes when crossover occurs within the inverted region during meiosis.
Deletion: loss of a chromosomal segment. Terminal deletions remove the end of a chromosome (e.g. 5p deletion in cri-du-chat syndrome); interstitial deletions remove an internal segment.
Duplication: gain of an extra copy of a chromosomal segment.
Isochromosome: a chromosome with two identical arms, formed by transverse rather than longitudinal centromere division. The isochromosome of the long arm of X (i(X)(q10)) is one cause of Turner syndrome.
Ring chromosome: a chromosome that has lost both telomeres and joined end-to-end, often with associated terminal deletions.
Insertion: a segment is moved from one chromosome to another non-homologous chromosome.
Marker chromosome: a small extra chromosome of unknown origin, usually identified only after molecular characterisation.

The distinction between balanced rearrangements (no net gain or loss of material; carrier typically phenotypically normal but reproductively at risk) and unbalanced rearrangements (net gain or loss; phenotype usually present in the carrier) is central to genetic counselling teaching.

The Philadelphia chromosome: a somatic, oncogenic translocation

Constitutional chromosomal abnormalities are present in every cell of the body and are inherited or arise in the germline. Somatic chromosomal abnormalities arise in particular tissues at particular life stages and are not transmitted to offspring. The first somatic chromosomal abnormality with a known disease association was the Philadelphia chromosome, described by Nowell and Hungerford (1960) as a small marker chromosome found consistently in cells from chronic myeloid leukaemia. The Philadelphia chromosome was later shown to be the derivative chromosome 22 from a reciprocal translocation t(9;22)(q34;q11), in which the BCR gene on chromosome 22 is fused to the ABL1 gene on chromosome 9. The resulting BCR-ABL1 fusion encodes a constitutively active tyrosine kinase that drives the leukaemia. BCR-ABL1 was the target of the first selective targeted cancer therapy (imatinib), which transformed the prognosis of the disease and remains a textbook example of cancer biology and drug development.

Many other recurrent translocations are characteristic of particular cancers: t(15;17) in acute promyelocytic leukaemia, t(8;14) in Burkitt lymphoma, t(14;18) in follicular lymphoma. Cytogenetics remains a foundation of haematological cancer classification.

Microdeletion and microduplication syndromes

Many recurrent submicroscopic copy-number variants — segmental gains and losses of a few hundred kilobases to a few megabases — produce reproducible syndromes. They typically arise by non-allelic homologous recombination between flanking low-copy repeats (segmental duplications), so the same regions tend to recur as deletions and reciprocal duplications. Examples taught as canonical:

22q11.2 deletion syndrome (DiGeorge / velocardiofacial): a 1.5-3 megabase deletion at 22q11.2; one of the most common recurrent microdeletions, with conotruncal cardiac defects, palatal abnormalities, immune deficiency, and a variable cognitive and psychiatric phenotype.
7q11.23 deletion (Williams-Beuren syndrome): a ~1.5 megabase deletion including ELN, with supravalvular aortic stenosis, characteristic facial features, intellectual disability, and a sociable personality profile.
15q11-q13 deletion (Prader-Willi and Angelman syndromes): deletion of the same region produces different syndromes depending on the parental origin of the deletion, owing to genomic imprinting at the locus. Paternal deletion causes Prader-Willi; maternal deletion causes Angelman. The mechanism is the textbook example of imprinting and is covered further in imprinting and uniparental disomy in pedigrees.
17p11.2 deletion (Smith-Magenis) and the reciprocal 17p11.2 duplication (Potocki-Lupski).
16p11.2 deletion / duplication: a recurrent ~600 kilobase region with reciprocal phenotypes, both associated with neurodevelopmental impact.
1p36 deletion syndrome: one of the most common terminal microdeletion syndromes, with intellectual disability, seizures, and characteristic facial features.

The systematic association of recurrent copy-number variants with developmental phenotypes was established by Cooper and colleagues (2011), who built a "morbidity map" comparing CNV frequencies in 15,767 cases with developmental delay against population controls; this paper remains the reference for the disease association of recurrent CNVs. Both the named syndromes and the rarer rearrangements are catalogued in resources such as DECIPHER and OMIM.

Detection: a layered toolkit

The cytogenetic toolkit covers a wide resolution range. Each test answers a different question, and the modern workflow uses several together rather than choosing one.

Karyotype (G-banding): the survey-of-record for whole-chromosome aneuploidies and large (~5-10 megabase) structural rearrangements. The only routine test that can characterise a balanced reciprocal or Robertsonian translocation in detail.
Fluorescence in situ hybridisation (FISH): for targeted detection of a known region. Locus-specific probes for, say, the 22q11.2 deletion or the t(9;22) translocation. Painting probes for translocation analysis. Suitable when the question is specific.
Chromosomal microarray (aCGH; SNP array): copy-number variation across the whole genome at sub-megabase resolution. The recommended first-tier test in much of constitutional cytogenetics for unexplained intellectual disability, congenital anomalies, or autism. Cannot detect balanced rearrangements or low-level mosaicism.
Whole-genome sequencing: increasingly substitutes for microarray; also detects balanced rearrangements (by paired-end and split-read signals) and base-level changes. Long-read sequencing further improves resolution of complex structural variation.
Non-invasive prenatal testing (NIPT): short-read sequencing or array genotyping of cell-free DNA in maternal plasma, which is partly of placental (and therefore foetal) origin. NIPT screens for the common autosomal trisomies (21, 18, 13) and sex-chromosome aneuploidies, with high sensitivity and specificity in the high-risk population. Bianchi et al. (2014) demonstrated improved positive predictive value of cell-free DNA testing over standard biochemical screening in a general-risk obstetric cohort, and NIPT is now widely offered as a first-tier prenatal screen in high-income systems.

Whatever the test, results are reported in ISCN nomenclature (current edition ISCN 2024) so that findings are interpretable across laboratories. The way ISCN-format findings integrate with NSGC pedigree notation is covered in ISCN pedigree symbols; for educational visualisation of named bands and example rearrangements, see the karyogram viewer.

Constitutional vs somatic; copy-number variation in the constitutional context

Constitutional abnormalities are present in every cell from conception (or in mosaic form, present in a substantial proportion of cells from very early development); they are the typical concern of constitutional cytogenetics, prenatal testing, and reproductive counselling. Somatic abnormalities, by contrast, are acquired in particular tissues during life — the acquired translocations of haematological cancers, the chromosome instability of solid tumours — and are the concern of cancer cytogenetics. The same techniques (karyotype, FISH, microarray, sequencing) are used in both, but the questions differ.

Copy-number variation in the constitutional context spans a continuum: from the rare, recurrent microdeletion and microduplication syndromes described above, through rare CNVs of unknown significance, through common CNVs (>1% allele frequency) that are the substrate of population-level variation. Most common CNVs have no detectable phenotypic effect; some contribute to risk for complex traits in the same way as common single-nucleotide variation does. The integration of CNV data with single-nucleotide variation, structural variation, and family-history data is one of the key analytical layers in modern human genetics.

Pedigree implications

Chromosomal abnormalities have characteristic pedigree signatures. A balanced translocation may segregate silently through several generations, then produce affected offspring through unbalanced gametes; the recurrence-risk pattern depends on the geometry of the rearrangement. Robertsonian translocations are associated with recurrent miscarriage and a characteristic risk of trisomic offspring. Imprinted-region deletions show parent-of-origin dependent inheritance: paternal versus maternal transmission of the same molecular lesion produces different syndromes. Educational pedigree drawing tools that record the karyotype against pedigree nodes — for example, the karyotype-aware pedigree workflow described in ISCN pedigree symbols, and the imprinting-aware workflow in imprinting and UPD pedigrees — are designed to make these patterns visible to learners.

References

Lejeune J, Gautier M, Turpin R. Etude des chromosomes somatiques de neuf enfants mongoliens. Comptes rendus hebdomadaires des seances de l'Academie des sciences 1959;248:1721.
Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science 1960;132:1497.
Hassold T, Hunt P. To err (meiotically) is human: the genesis of human aneuploidy. Nature Reviews Genetics 2001;2:280.
Cooper GM, Coe BP, Girirajan S et al. A copy number variation morbidity map of developmental delay. Nature Genetics 2011;43:838.
Bianchi DW, Parker RL, Wentworth J et al. DNA sequencing versus standard prenatal aneuploidy screening. New England Journal of Medicine 2014;370:799.
ISCN 2024: An International System for Human Cytogenomic Nomenclature. Karger.
DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans. Wellcome Sanger Institute.
OMIM: Online Mendelian Inheritance in Man. Johns Hopkins University.