Sex Chromosomes and Sex Chromosome Abnormalities

Department of Genetics, Kaiser Permanente, San Jose Medical Center, San Jose, CA 95123, USA

Keywords

• Sex chromosome • Sex chromosome abnormalities • X-inactivation • Mosaicism • X-linked mental retardation

The X and Y chromosomes are the two sex chromosomes in humans. Females have two X chromosomes, whereas males have one X and one Y chromosome. It is believed that the X was named by earlier researchers as unknown and the Y was named alphabetically after X. Compared with the 22 pairs of autosomes in humans, the pair of the sex chromosomes is unique in many aspects.

• The X chromosome is much larger and more gene-rich than the Y chromosome. The X chromosome is 2.6 times the size of the Y chromosome, containing 155.27 Mb or 5% of the total genome of 3.10 billion base pairs (bp), whereas the Y chromosome contains 59.37 Mb or 1.9% of the total genome. There are 1965 genes in an X chromosome compared with 421 genes in the Y chromosome. The gene density in the X chromosome is 17.8-fold higher than the Y chromosome, 1 gene per 7901 bp in X versus 1 gene per 141,029 bp in Y (Table 1).¹

• Unlike the X chromosome, the main function of the Y chromosome is in male sexual development. The presence of the Y chromosome, specifically the gene SRY (sex-determining region Y) or TDF (testis-determining factor) located at Yp11.3, determines a male gender, whereas the absence of the SRY gene results in a female phenotype. However, many other genes located on the X chromosome and autosomes are also involved in sex determination and development. The other Y-specific genes also play a role in spermatogenesis.

• Pairing and recombination between the X and the Y chromosomes during male meiosis only occurs between homologous segments located on both ends of the X and the Y chromosomes, the so-called pseudoautosomal regions (PAR). The ends of the Xp/Yp, or PAR1 region, are 2.64 Mb in size with 24 genes and transcripts, and the ends of the Xq/Yq, or PAR2 region, are 330 kb in size with 8 genes and transcripts (Fig. 1).¹ The genes in the PAR regions act like genes in the autosomes and do not follow sex-linked inheritance. The suppression of X-Y recombination through evolution prevents sex-determining genes on the Y chromosome moving to the X chromosome. However, the repairing function for accumulated mutations on the Y chromosome relies on its unusual abundant segmented duplications organized in palindrome structures.^2,³

• The huge difference in size and gene content between the X and the Y chromosomes has created an “inequality” between the two sexes. To compensate, one X chromosome in females is inactivated and forms a Barr body during early embryogenesis. X-inactivation, or lyonization, is regulated by the gene called inactive X (Xi)-specific transcript (XIST) located at the X-inactivation center on the proximal long (q) arm of the X chromosome (Xq13.2) (see Fig. 1). Normally, X-inactivation occurs in a random fashion in female somatic cells and results in somatic mosaicism. X-inactivation may happen nonrandomly or skewed as a mechanism to minimize harm when there are structural abnormalities involving an X chromosome such as deletions, duplications, and translocations. For this reason a female carrier may be phenotypically normal but a male is affected or will not survive even though he has the same X chromosome abnormality. Incomplete skewed X-inactivation is often the basis for various degrees of manifestation of phenotypes in females with X chromosome abnormalities. Genes in the PAR regions are not subject to X-inactivation. Many genes on the X chromosome, most of them on the short (p) arm, escape from inactivation. Dosage imbalance of the genes in PAR regions and genes that escape X-inactivation contribute to the phenotypes in females with an X chromosome anomaly.^4,⁵

• Although mosaicism is not unique in sex chromosome abnormalities, the consequences are not as straightforward as in autosomes. This is particularly true in external genital appearance, which may vary from female ambiguous external genitalia, male of hermaphroditism depending on the type, level, and distribution of the mosaicism. The presence of a cell line with the Y chromosome (SRY locus) in females or the presence of a 45,X cell line in males has the greatest influence on gender appearance and sexual development.

Table 1 X and Y chromosome statistics

	X	Y
Length (bp)	155,270,560	59,373,566
Known protein-coding genes	825	47
Novel protein-coding genes	27	12
Pseudogene	762	318
MicroRNA genes	128	15
Ribosomal RNA genes	22	7
Small nuclear RNA genes	85	17
snoRNA genes	64	3
Miscellaneous RNA genes	52	2
Total genes	1965	421
Single-nucleotide polymorphisms	1,342,023	273,615

Data from Human Genome Build 19, UCSC, Ensembl release 61—Feb 2011. http://may2009.archive.ensembl.org/Homo_sapiens/Location/Chromosome?r=X:1-154913754 and http://may2009.archive.ensembl.org/Homo_sapiens/Location/Chromosome?r=Y. Accessed April 15, 2011.

Fig. 1 X and Y chromosomes.

(Idiograms are from International System for Human Cytogenetic Nomenclature (ISCN) 2009, Data from Nussbaum R, Mclnnes RR, Willard HF. Thompson & Thompson Genetics in Medicine. 6th edition. Saunders: Elsevier; 2004.)

Sex Chromosome Abnormalities

From the point of view of clinical cytogenetics, this article focuses on constitutional sex chromosome abnormalities detected by conventional cytogenetics and fluorescence in situ hybridization (FISH). To simplify, sex chromosome abnormalities are classified into numerical and structural abnormalities, each further divided into the presence or absence of the Y chromosome as well as involvement of both the X and Y chromosomes by genotype (karyotype).

Sex Chromosome Numerical Abnormalities

Klinefelter syndrome (47,XXY) is the most common sex chromosome numerical abnormality in males, occurring in 1 in 1000 males. It is often diagnosed by chromosome analysis following a referral for infertility or gynecomastia. The 47,XYY syndrome is another common abnormality in males, also occurring in 1 in 1000 males. It is often an accidental finding in chromosome analysis or observed in individuals referred to cytogenetics as part of laboratory tests to rule out fragile X syndrome because of behavioral problems. Some rare forms of sex chromosome numerical aberrations in males have been reported, including 48,XXYY, 48,XXXY, 49,XXXXY, and 49,XYYYY. A chromosome number over 50 with 6 or more sex chromosomes has never been reported and is likely lethal. For every extra X chromosome the IQ decreases about 15 to 16 points, with language most affected.⁶ All these patients have global developmental delay in gross motor, fine motor, and speech and language. Males with 48,XXYY have a higher IQ and adapt better in daily living skills compared with 48,XXXY and 49,XXXXY males, but all seem equally problematic with regard to communication and socialization skills.⁷ The intellectual deficiency in males with poly Y, such as 49,XYYYY, is not as proportional as in poly X.⁸ Height seems to be increased with the gain of an extra Y chromosome but decreased with the gain of an extra X chromosome.

Turner syndrome, or 45,X, is one of the most common sex chromosome numerical aberrations in females, occurring in 1 in 5000 females. The great majority of nonmosaic 45,X conceptions do not survive to term. It is still debatable whether all the surviving individuals with a nonmosaic 45,X karyotype found in amniotic fluid or a peripheral blood sample are actually mosaic in other types of tissues. The 47,XXX syndrome is seen in 1 in 5000 females and is often found by accident rather than because of a specific clinical indication. The majority of individuals with 47,XXX are not diagnosed. Although the clinical phenotype is usually mild, recent reviews suggest that many clinical issues need to be addressed.⁹–¹¹ As in males, some rare forms of polysomy for the X chromosome, 48,XXXX¹² and 49,XXXXX^13,¹⁴ will result in severe developmental delay, mental retardation, and behavioral problems.

Mosaicism in sex chromosome abnormalities can present in a variety of combinations and potentially with different degrees of mosaicism in different tissues. This presents a great challenge in the clinical assessment of phenotypes, in particular when found in prenatal samples. Phenotypes are usually milder when there is a normal cell line, male or female, present, such as mosaic Turner syndrome or Klinefelter syndrome.¹⁵ However, gender or sexual development can range from male to female to ambiguous when there is a mixture of cell lines with or without the Y chromosome (Table 2).

Table 2 Sex chromosome numerical abnormalities

Some rare forms of mosaicism have been reported, such as Klinefelter variant with a 46,XX cell line ^20,²¹ or mosaic 45,X/47,XYY or 45,X/46,XY/47,XYY.^22,²³ Mosaicism may be present in as many as 4 or 5 different cell lines.^24,²⁵ Whether the patient has a Turner syndrome phenotype largely depends on the percentage and the distribution of the 45,X cell line, and whether the patient has male external genitalia depends on the presence in the gonads of a Y chromosome containing cell line. Caution should be taken when interpreting a low percentage of X chromosome aneuploidy in advanced aged women, usually referred to cytogenetics with recurrent miscarriages. The most common karyotypes are 45,X/46,XX and 45,X/47,XXX/46,XX. X chromosome aneuploidy is usually under 10%. These women usually do not have a Turner syndrome phenotype, and there is no evidence that the finding is associated with miscarriages.^15,¹⁷–¹⁹ However, if the woman is younger and/or the X chromosome aneuploidy level is higher than expected for her age, careful clinical evaluation is warranted (Table 3).²⁶