S. Dahoun-Hadorn and C. Williamson
The pathology of the human chromosomes (the " substance " of heredity) is the subject of cytogenetics, in which the chromosomes are examined and a karyotype established, at the resolution level of the optical microscope.
Cytogenetic analysis is performed by pairing our forty-six human chromosomes in a well-defined order based on characteristic bands inherent to each chromosome. This analysis is undertaken on a cell undergoing mitosis (metaphase).
A karyotype may be established on any cell line capable of division (mitosis), but readily accessible lineages are generally used i.e.: lymphocytes extracted from whole blood, or, in case of postnatal diagnosis, fibroblasts grown from skin biopsies. For prenatal purposes, trophoblast-derived cell lines (choriocentesis), amniocytes (amniocentesis) or lymphocytes from fetal blood (cordocentesis) are studied. Cell lines grown from curettage material (abortion) may also be used. Sperm and oocyte karyotypes may also be established on the basis of cross-fertilization techniques recently developed.
The cells obtained are processed in the following manner:
A human male has 44 autosomes and 2 gonosomes (XY).
A human female has 44 autosomes and 2 gonosomes (XX).
In normal chromosome structure the centromere or central core is flanked by two " arms ": the short arm (p) and the long arm (q). The basic structure is the same for all chromosomes, with the exception that the acrocentric chromosomes have little or no short arm. The 23 pairs differ in the length of the arms, and each shows unique banding pattern.
Numerical aberrations, which can affect either the autosomes or the gonosomes (sex chromosomes), involve the loss or gain of a part of or an entire chromosome. This gives rise in the latter case to a trisomy (a chromosome of which three copies are present) or in the former to a monosomy (a single copy).
Structural aberrations affect a portion of one or several chromosomes; these can be of several types, and imply in general that a break has taken place and given rise to one of the following rearrangements:
Clinical characteristics of unbalanced chromosomal aberrations
Missing or excessive autosomal material (e.g. trisomies) gives rise to two or more of the following, and causes clinically-recognizable syndromes:
Although the number and importance of symptoms is variable even within a group of patients with the same anomaly, a certain pattern generally exists, producing a characteristic phenotype which usually permits clinical diagnosis. Mental retardation is the common denominator. Monosomies of entire autosomes are incompatible with life, but partial monosomies due to small or even large deletions can affect all chromosomes, generally producing severe clinical syndromes.
Clinical characteristics of balanced autosomal rearrangements
In this case, the normal quantity of chromosomal material is preserved, but in disorganized fashion either due to an exchange between two chromosomes (translocation), with no net loss or gain of genetic material, or due to a centromere fusion. Whatever the structural defect, there is rarely a major clinical abnormality, but reproductive problems may arise; in women spontaneous abortion is most often seen, whereas in men spermatogenesis may be impaired, resulting in primary sterility.
Clinical characteristics of gonosomal abnormalities
The clinical implications are different from autosomic abnormalities: growth retardation is less frequent (with the exception of X monosomy or Turner’s syndrome), and in some sex chromosomal disorders, growth may even be accelerated. Dysmorphism is more subtle, and internal malformations and mental retardation are infrequent. Borderline intelligence is however not unusual in XXY and XXX syndromes, and 45,X women have a higher incidence of internal (heart and renal) malformations than women with other disorders.
X chromosome monosomy is the only example of a monosomy compatible with life but even conceptuses with this defect are for the most part " eliminated " as spontaneous abortions.
Most important are fertility problems secondary to gonadal dysgenesis, which is an almost constant feature in large X chromosome structural defects. In X monosomy, however, the presence of two cell lines (a mosaicism) may lead to fertility, especially if the normal cell line predominates. Reproduction may also remain possible if the affected gonosomal segment is sufficiently small.
When is a karyotype indicated?
Prenatal diagnosis is sometimes offered to reduce the anxiety of parents of a child with a congenital defect, whether of chromosomal origin or not; this is not, however, based on medical need.
When at least two of the following abnormalities are present:
It is well to bear in mind that a single chromosome carries several thousand genes, and that monogenic disorders, or even those involving several genes cannot be determined by cytogenetic techniques alone, the purpose or which is to detect major aberrations, involving chromosome number or structure.
Nonetheless, karyotyping remains the essential tool for analysis of some forms of reproductive difficulties, in prenatal screening, and in the diagnosis of a number of relatively frequent clinical syndromes.
Edited by Aldo Campana,