Chromosomal Disorders

Chromosomal disorders form a category of genetic disorder that is fundamentally distinct, in its underlying cause, from the single-gene Mendelian disorders discussed in the previous section (§4.15): rather than arising from a mutation occurring within just one particular gene, a chromosomal disorder instead arises from an abnormality affecting the overall NUMBER, or alternatively the physical STRUCTURE, of one or more WHOLE chromosomes, typically as a direct consequence of an error occurring during the process of meiotic cell division while gametes are being formed. By far the single most common underlying cause of a chromosomal-NUMBER disorder is a meiotic error called non-disjunction — the failure of the two members of a given pair of homologous chromosomes (or, in a comparable error occurring during mitosis rather than meiosis, the failure of a pair of sister chromatids) to separate properly and cleanly from one another at the anaphase stage of cell division, so that ONE of the two resulting daughter cells mistakenly receives an EXTRA, additional copy of that particular chromosome, while the OTHER daughter cell correspondingly receives NO copy of that chromosome at all. When a gamete carrying such an abnormal chromosome number, produced through non-disjunction, subsequently fuses with an entirely normal gamete at the moment of fertilisation, the resulting zygote ends up with either one chromosome MORE, or one chromosome FEWER, than the normal diploid chromosome number characteristic of that species.

This particular kind of numerical change, affecting the number of just one or two INDIVIDUAL chromosomes rather than an entire complete SET of chromosomes, is technically termed aneuploidy, and is conventionally written using the notation 2n+1 to denote trisomy (one single extra chromosome present beyond the normal diploid complement) or 2n−1 to denote monosomy (one single chromosome missing from the normal diploid complement); this important category is quite distinct from polyploidy, in which an organism instead gains one or more ENTIRE additional complete SETS of chromosomes all at once (conventionally written 3n, 4n, and so forth) — a condition that, while relatively common and often entirely well-tolerated in many plant species, is essentially incompatible with survival in human beings.

Down's syndrome, the single most commonly encountered autosomal aneuploidy that remains compatible with live birth and ongoing survival in humans, is caused specifically by trisomy affecting chromosome 21 — that is, the presence of three copies, rather than the normal two copies, of this particular chromosome, giving the overall karyotype 47,XX (in an affected female) or 47,XY (in an affected male), with an extra copy present of the smallest of all the human autosomes. This condition usually arises from an instance of non-disjunction specifically affecting chromosome 21 occurring during meiosis in the mother (with the underlying risk of such non-disjunction events rising demonstrably with increasing maternal age), and an individual affected by Down's syndrome typically shows a characteristic and recognisable combination of physical and developmental features, including a noticeably short stature, a comparatively small and rounded head, a mouth that is habitually held partially open together with a furrowed or somewhat protruding tongue, broad and comparatively short fingers often accompanied by a single characteristic crease running across the palm, and, in the great majority of affected individuals, some degree of mental retardation of varying severity. …