11.2 Deviating chromosome number or structure

• Introduction
• Origin of the deviating number of chromosomes
• Origin of the deviating chromosome structure
  • Deletion
  • Duplication
  • Inversion
  • Insertion
  • Isochromosome formation
  • Reciprocal translocation
  • Robertsonian translocation
• Polyploidy
• Mosaic

Introduction

Congenital abnormalities can be caused by an anomaly in the number or structure of the chromosomes. Disorders in the gametogenesis, that is, in the first and second meiotic divisions in the formation of oocytes and sperm cells, lead to such defects.

Chromosomal mutations can be made visible with staining methods (banding techniques). Following the staining the chromosomes are analyzed using a 1000x enlargement. With this one can recognize the chromosomes as striped cords and display them in a karyogram, after they have been ordered according to their size and the positions of the centromeres. Various groups of similar chromosomes are created in this way.
Today, small aberrations are examined using a molecular cytogenetic (FISH) approach. Among other things, the FISH (fluorescence-in-situ-hybridizing) method makes possible the targeted identification of partial aneuploidies such as deletions, duplications and unbalanced translocations (see below) that cannot be resolved with a light microscope. A comprehensive array of DNA probes and techniques are today available from which one can choose for utilization, depending on the diagnostic problem being worked on. With the FISH method chromosomal alterations can be analyzed down to a size of ca. 5 million nucleotides.
Smaller defects lie below the resolution limit of this approach - today they are analyzed using DNA analysis techniques.

Origin of the deviating number of chromosomes

Fig. 5
Origin of trisomy/monosomy of the sex chromosomes due to a non-disjunction in meiosis 1 (orange). Germ cells are formed thereby that lead, at the time of fertilization, to a number of chromosomes other than 46.

During spermato/oogenesis gametes with additional but also with missing chromosomes can be formed. Since meiosis takes place in two steps, the disorders can occur in the disjunctions of the first or of the second meiotic divisions.

Fig. 6
If a disorder occurs in the meiosis 2 disjunction (orange), germ cells will be formed that again have too few or too many chromosomes.

In Figs. 5 and 6 disorders of the maturation divisions of the germ cells are shown. Thereby monosomies and trisomies can form. Trisomies of the sex chromosomes (XXX, XXY or XYY) occur relatively frequently and can be lived with, whereas monosomies are generally lethal, those with Turner's syndrome forming the single exception.

Among the trisomies of the autosomes, trisomy 21 (Down syndrome) is the most well known. The occurrence of trisomy 21, as well as many other chromosomal aberrations caused by non-disjunctions, is highly correlated with the age of the mother. The probability of bearing a child with trisomy 21 increases exponentially with age. If a young mother apparently gives birth to a child bearing a trisomy 21, however, a differential diagnosis of an inherited chromosomal aberration must by all means be considered (compare robertsonian translocation).

The two further, most frequent types of trisomy after trisomy 21 encountered in living newborns are trisomy 13 (Patau's syndrome) and trisomy 18 (Edwards's syndrome).