The Principles of Clinical Cytogenetics - Extra Materials - Springer

Sex Chromosomes and Sex Chromosome Abnormalities 209
Pseudoautosomal Regions
The distal region of the short arms of the X and Y chromosomes contain highly similar DNA
sequences. During normal meiosis in the male, an XY bivalent is formed and crossing-over occurs
between these regions. Because this resembles the crossing-over that occurs between autosomes,
these regions have been termed pseudoautosomal or PAR1 (see Fig. 1). There is also a region of
homology (PAR2) at the distal ends of Xq and Yq, which has been observed to associate during male
meiosis, with proven recombination events (14) (see also Chapter 2).
The Y Chromosome
The Y chromosome is made up of several different regions. These include the pseudoautosomal
regions at the distal short and long arm, PAR1 and PAR2, the heterochromatic region on the long
arm, and the recently sequenced male-specific region of the Y (MSY) located between PAR1 and
PAR2, with 78 protein-coding genes that encode 27 distinct proteins (see Fig. 1). Twelve of the MSY
genes are ubiquitously expressed in many organs throughout the body, whereas 11 MSY genes are
expressed predominantly in the testes (15).
The testis-determining factor (TDF) that leads to differentiation of the indifferent gonads into
testes is located on the short arm of the Y chromosome. TDF was mapped by molecular analysis of
sex-reversed patients (chromosomally female but phenotypically male and vice versa), and the gene
SRY (sex-determining region Y) was identified in 1990 (16). It is located on the short arm of the Y at
band p11.3 in the MSY region (see Fig. 1). Deletions and mutations in this gene have been found in
some 46,XY females (see below).
The Y chromosome has a highly variable heterochromatic region on its long arm. The length of this
region is usually constant from one generation to the next. A gene controlling spermatogenesis, termed
the azoospermia factor (AZF) was first proposed by Tiepolo and Zuffardi in 1976 and mapped to the
distal part of the euchromatic Yq11 region (Yq11.23) (17) (see Fig. 1). In studies of men with
azoospermia or severe oligospermia, deletions in different intervals of Yq11 have been found and
three nonoverlapping regions or azoospermia factors (AZFa, AZFb, and AZFc from proximal to
distal Yq) have been defined as spermatogenesis loci (18) (see Chapter 11).
A locus for susceptibility to gonadoblastoma (GBY) has been proposed on the Y chromosome
based on the high incidence of gonadoblastoma in females with 45,X/46,XY mosaicism or XY
gonadal dysgenesis (19). Deletion mapping has localized this putative gene to a region near the centromere,
but it has raised the possibility of multiple GBY loci dispersed on the Y chromosome (20,21).
One of the most likely candidate genes in this region is TSPY, which is expressed in gonadoblastoma
tissues (22).
NUMERICAL ABNORMALITIES OF THE SEX CHROMOSOMES
Introduction
Numerical abnormalities of the sex chromosomes are one of the most common types of chromosomal
aneuploidy, with a frequency of 1 in 500 live births. This might be the result of the fact that
abnormalities of sex chromosomes have less severe clinical abnormalities and are more compatible
with life as compared to autosomal disorders. Reasons for this include inactivation of all additional X
chromosomes and the small number of genes on the Y chromosome.
Sex chromosome abnormalities are more commonly diagnosed prenatally than autosomal aneuploidies,
and genetic counseling for these conditions is often more complex and challenging than that
for an autosomal abnormality. In the past, many individuals with sex chromosome abnormalities
would have gone through life undetected, as they do not have physical or developmental problems
that would have warranted a chromosome study (23). Women undergoing amniocentesis and chorionic
villus sampling (see Chapter 12) should be informed about the possibility of detecting a sex