Chromosomal Disorders – Aneuploidy, Euploidy and Chromosomal Aberrations

Chromosomal Disorders


Chromosome abnormalities (alterations that are large enough to be seen under the microscope) are responsible for a significant number of diseases, occurring with a frequency of 1/150 live births. These are leading cause of mental retardation as well as miscarriage (spontaneous abortion).

Chromosomal abnormalities are seen in 50% of first-trimester pregnancy loss. Chromosomal abnormalities are observed in 20% of second-trimester pregnancy loss.

Human Chromosomes

Human cells contain 46 chromosomes, 22 pairs of autosomes (numbered 1 to 22), and two sex chromosomes (XX is female, XY is male). The haploid number of chromosomes is 23, also termed n.

Diploid is 2n, or 46 chromosomes. In mitosis, the DNA is replicated, leading to a 4n state, and then cell division creates two daughter cells containing a 2n content of the DNA.

During meiosis and gamete formation, two meiotic divisions take place. The cell first replicates its DNA, creating a 4n content of the DNA. In meiosis I, the cell divides such that each daughter cell obtains a 2n content of the DNA, but as opposed to mitosis, at the 2n stage the cell contains exact duplicates of each chromosome except for regions where crossing over between homologous chromosomes has occurred.

In meiosis II, the cell splits again, creating n content of the DNA in the germ cells. Crossing over of genetic material between homologous chromosomes occurs during pachytene sub-stage of meiosis I.

Abnormalities of Chromosome Number

Abnormalities of chromosome number can be of following two types:

  1. Euploid refers to cells with a multiple of 23 chromosomes (23 is haploid, 46 is diploid, 69 is triploid, and 92 is tetraploid). Triploidy and tetraploidy are incompatible with human life.
  2. Aneuploid refers to conditions when the total chromosome number is not a multiple of 23. Aneuploidy involves primarily monosomies (one copy of one chromosome) or trisomies (three copies of one chromosome).

Severity of such conditions are different in different cases. For example:

  1. Autosomal monosomies are always lethal.
  2. Autosomal trisomies are often lethal with only a few exceptions (see Table 1).
  3. Sex chromosome aneuploidies are better tolerated.

The cause of aneuploidy is nondisjunction or failure of separation of chromosomes during gamete formation. Nondisjunction is unequal chromosome sorting during meiosis I or II, in which the “wrong” number of chromosomes is distributed to the daughter cells (one too many, or one too few). If the appropriate chromosomal markers are available, one can determine whether a nondisjunction event occurred in meiosis I or II.

Abnormalities of Chromosome Structure

  1. Inversions: two breaks in a single chromosome and an inversion of genetic material between the breaks.
  2. Duplications: part of a chromosome is duplicated and inserted into the same chromosome.
  3. Insertions: a section of one chromosome is inserted into another chromosome, and there does not have to be a loss of genetic material.
  4. Isochromosomes: an abnormal centromere division can lead to chromosomes in which entire arms are swapped between homologous chromosomes, such that an isochromosome can contain two p arms or two q arms derived from the two copies of a particular chromosome.
  5. Reciprocal translocations: occur when there are breaks in two different chromosomes and the material between the breaks is mutually exchanged.
  6. Robertsonian translocations: occur between acrocentric chromosomes (13, 14, 15, 21, 22) in which the short arms (satellites) are lost and the long arms are fused between the two chromosomes.

Microdeletion Syndromes

Microdeletion syndromes have a consistent but complex phenotype associated with a small (less than five megabases) chromosomal deletion. FISH (fluorescent in situ hybridization) is often necessary to detect such microdeletions. Common examples include Langer–Giedion syndrome, retinoblastoma, etc.