Chromosomal Abnormalities, Nondisjunction, and Karyotypes

Chromosomal abnormalities are changes in the number or structure of chromosomes, nondisjunction is the failure of chromosomes to separate properly during cell division, and a karyotype is an organized picture of all the chromosomes of a cell, used to detect such changes. In brief: a normal human karyotype has 46 chromosomes, written 46,XX for a female and 46,XY for a male. Down syndrome (trisomy 21) is written 47,XX,+21 or 47,XY,+21. Most embryos with an abnormal chromosome number do not survive to birth, and the chance of nondisjunction in the egg increases with the age of the mother.

Chromosome analysis is used in prenatal screening, cancer diagnosis and the investigation of infertility. This guide explains how nondisjunction happens in meiosis I and II, the main syndromes caused by changes in chromosome number, structural changes, how a karyotype is prepared and read, works through a karyotype interpretation and a risk-by-age example, and corrects common mistakes.

What is nondisjunction?

Nondisjunction means “not coming apart”. It happens when homologous chromosomes (in meiosis I) or sister chromatids (in meiosis II or mitosis) fail to separate and both go to the same daughter cell. The other daughter cell gets none.

• In meiosis I: a pair of homologs stays together. Of the four gametes, two have an extra chromosome (n + 1), and two lack that chromosome (n − 1).
• In meiosis II: sister chromatids fail to separate. Of the four gametes, one has an extra chromosome (n + 1), one lacks it (n − 1), and two are normal (n).

If an abnormal gamete is fertilized by a normal one, the zygote is trisomic (2n + 1, three copies of one chromosome) or monosomic (2n − 1, a single copy). A change in the number of single chromosomes is called aneuploidy. Having whole extra sets of chromosomes (3n, 4n) is called polyploidy, which is common in plants and is usually lethal in humans. Most nondisjunction events occur in maternal meiosis I. Because human eggs begin meiosis before birth and are held in prophase I for decades, the risk increases with maternal age. Nondisjunction in mitosis, after fertilization, causes mosaicism, in which the body contains cells with different chromosome numbers.

Which syndromes result from abnormal chromosome numbers?

Many embryos with an abnormal number of chromosomes are lost in early pregnancy: chromosome abnormalities are found in about half of early miscarriages. Only a few aneuploidies are compatible with live birth, mostly those involving small chromosomes carrying few genes, and the sex chromosomes.

• Down syndrome (trisomy 21): affects about 1 in 700 births. Features include intellectual disability of variable degree, characteristic facial features, and an increased risk of heart defects and other health conditions. Many people with Down syndrome live into their 60s.
• Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13): severe, and most affected babies die within the first year.
• Turner syndrome (45,X): a female with one X chromosome. Short stature and infertility are common, and intelligence is generally normal.
• Klinefelter syndrome (47,XXY): a male with an extra X. Tall stature, reduced fertility, and sometimes learning difficulties.
• Triple X (47,XXX) and XYY (47,XYY): often mild or without noticeable features.

No known live birth has a monosomy of an autosome (a chromosome other than X or Y), as it is not compatible with development. Having an extra X in females does not usually cause severe problems because of X-inactivation, which silences all but one X in each cell.

Common aneuploidies

What are structural abnormalities?

These are changes in the structure of chromosomes, caused by breakage and wrong rejoining.

• Deletion: a piece is lost. In cri-du-chat syndrome (5p−), the short arm of chromosome 5 is missing.
• Duplication: a section is repeated.
• Inversion: a segment is turned around. Carriers are usually healthy, but they may have fertility problems or children with imbalances.
• Translocation: a piece moves to another chromosome. In a reciprocal translocation, two chromosomes exchange pieces. In a Robertsonian translocation, two acrocentric chromosomes (such as 14 and 21) join. A carrier with a 14;21 translocation has 45 chromosomes and is healthy, but may produce gametes that lead to Down syndrome. About 3 to 4 percent of Down syndrome cases are due to translocation, which can be inherited.
• The “Philadelphia chromosome”, a translocation between chromosomes 9 and 22 in blood cells, causes chronic myeloid leukemia, and it is an example of a somatic abnormality.

What is a karyotype and how is it made?

A karyotype shows the complete chromosome set of an individual, arranged in pairs by size and shape. The procedure is:

1. Cells (white blood cells, amniotic fluid cells or a tissue sample) are grown in culture and stimulated to divide.
2. A chemical (colchicine) is added to stop the cells at metaphase, when the chromosomes are most condensed and visible.
3. The cells are swollen with a low-concentration salt solution, fixed and dropped onto slides, so that the chromosomes spread out.
4. The chromosomes are stained to show a pattern of light and dark bands (G-banding), which is specific for each chromosome and allows structural changes to be detected.
5. A photograph is taken, and the chromosomes are cut out digitally and arranged in pairs, numbered 1 to 22 in order of decreasing size, and the sex chromosomes (X and Y) are placed last.

Modern techniques supplement the karyotype: fluorescent in situ hybridization (FISH), which uses fluorescent probes for specific chromosomes or genes, and chromosomal microarray and sequencing, which detect smaller changes than can be seen under a microscope.

How are abnormalities detected before birth?

• Screening tests (give a risk estimate, not a diagnosis): ultrasound measurement of fluid at the back of the fetal neck (nuchal translucency) at 11 to 14 weeks, maternal blood tests for certain hormones and proteins, and non-invasive prenatal testing (NIPT), which analyzes fragments of fetal DNA in the mother’s blood from about 10 weeks. NIPT detects trisomy 21 in more than 99 percent of cases, with a low false-positive rate, but a positive result needs confirmation.
• Diagnostic tests: chorionic villus sampling (CVS, from 10 to 13 weeks, a sample of placental tissue) and amniocentesis (from about 15 to 16 weeks, a sample of amniotic fluid taken with a needle). They give a definite chromosome analysis, but carry a small risk of miscarriage (roughly 0.1 to 0.3 percent according to recent estimates).

The results raise personal and ethical decisions. Genetic counselors help families to understand the options.

Worked example: reading karyotypes and age risk

Reading a karyotype

Interpret three karyotypes.

1. 46,XY: 46 chromosomes, including X and Y: a normal male.
2. 47,XX,+21: 47 chromosomes, XX (female), plus an extra chromosome 21: a female with Down syndrome (trisomy 21).
3. 45,X: only 45 chromosomes with a single X: Turner syndrome.

The number of autosomes in a trisomy 21 karyotype is 22 × 2 + 1 = 45, plus two sex chromosomes = 47. In a gamete from nondisjunction in meiosis I of the mother, the egg would have 24 chromosomes (22 autosomes + 1 extra chromosome 21 + X), and the sperm 23, so the zygote has 47.

Age and risk

Approximate risks of having a baby with Down syndrome by maternal age are given below (values from commonly cited studies; different sources vary).

From age 25 to age 40, the risk rises by a factor of 1 250 ÷ 100 = 12.5. Even at age 40, 99 percent of babies do not have Down syndrome, and since there are more births to younger women, more than half of all babies with Down syndrome are born to mothers under 35. This is why screening is offered to all pregnant women. The percentages are 1 divided by the denominator times 100, e.g. 100 ÷ 350 = 0.29.

How were these abnormalities discovered?

The correct human chromosome number of 46 was established by Joe Hin Tjio and Albert Levan in 1956. In 1959, Jérôme Lejeune and colleagues showed that Down syndrome is caused by an extra chromosome 21, and in the same year Charles Ford found 45,X in Turner syndrome and Patricia Jacobs and John Strong found 47,XXY in Klinefelter syndrome. Calvin Bridges showed nondisjunction in fruit flies in 1913 to 1916, which provided the first proof of the chromosome theory of heredity. Banding techniques in the early 1970s made it possible to identify each chromosome and structural changes.

Which mistakes are common?

Mistake 1: Describing a trisomy as an extra pair of chromosomes

It is a single extra chromosome. In Down syndrome, there are 47 chromosomes in total: 22 pairs, three copies of chromosome 21 and two sex chromosomes.

Mistake 2: Confusing nondisjunction with a mutation of a gene

Nondisjunction changes the number of chromosomes, but the genes themselves are normal.

Mistake 3: Believing that only older mothers have babies with chromosome abnormalities

The risk is higher with age, but most affected babies are born to younger women, because they have more births overall.

Mistake 4: Treating a screening result as a diagnosis

Screening estimates risk. Only a diagnostic test, such as a karyotype from CVS or amniocentesis, confirms a diagnosis.