Sex chromosome abnormalities may involve aneuploidy, partial deletions or duplications of sex chromosomes, or mosaicism.
(See also Overview of Chromosomal Abnormalities.)
Sex chromosome abnormalities are common and cause syndromes that are associated with a range of congenital and developmental anomalies. The majority are not suspected prenatally but may be incidentally discovered if karyotyping is done for other reasons, such as advanced maternal age. The anomalies are often hard to recognize at birth and may not be diagnosed until puberty.
The effects of X chromosome abnormalities are not as severe as those resulting from analogous autosomal abnormalities. Females with 3 X chromosomes often appear normal physically and mentally and are fertile. In contrast, all known autosomal trisomies (eg, trisomy 13) have clinically significant and, often, devastating effects. Similarly, whereas the absence of 1 X chromosome (monosomy X) causes a specific syndrome in most cases (Turner syndrome [monosomy X]), the absence of an autosome is invariably lethal. It is important to note that people with 1 X chromosome who have mosaicism involving a Y chromosome (ie, some cells with 46,XY) may have a male or female phenotype (1).
Lyon hypothesis (X-inactivation)
By virtue of having 2 X chromosomes, females have 2 loci for every X-linked gene, as compared with a single locus in males. This imbalance would seem to cause a genetic “dosage” problem. However, according to the Lyon hypothesis, 1 of the 2 X chromosomes in each female somatic cell is inactivated genetically early in embryonic life (on or about day 16). In fact, no matter how many X chromosomes are present, all but 1 are inactivated. However, molecular genetic studies have shown that some genes on the inactivated X chromosome (or chromosomes) remain functional, and these few are essential to normal female development. XIST is the gene responsible for inactivating the genes of the X chromosome, producing RNA that triggers inactivation.
Whether the maternal or paternal X is inactivated usually is a random event within each cell at the time of inactivation; that same X then remains inactive in all descendant cells. Thus, all females are essentially mosaic, with some cells having an active maternal X and others having an active paternal X.
Pearls & Pitfalls
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Sometimes, random statistical distribution of inactivation in the relatively small number of cells present at the time of inactivation results in a particular descendant tissue having a preponderance of active maternal or paternal X chromosomes (skewed inactivation). Skewed inactivation may account for the occasional manifestation of minor symptoms in females who are heterozygous for X-linked disorders such as hemophilia and muscular dystrophy (all would presumably be asymptomatic if they had a 50:50 distribution of active X chromosomes). Skewed inactivation also may occur by postinactivation selection.
Reference
1. Guzewicz L, Howell S, Crerand CE, et al: Clinical phenotype and management of individuals with mosaic monosomy X with Y chromosome material stratified by genital phenotype. Am J Med Genet A 185(5):1437-1447, 2021. doi: 10.1002/ajmg.a.62127
