The Principles of Clinical Cytogenetics - Extra Materials - Springer

222 Cynthia Powell
STRUCTURAL ABNORMALITIES OF THE X CHROMOSOME
In addition to the isochromosome Xq commonly found in patients with Turner syndrome, the X
chromosome can be involved in translocations, both balanced and unbalanced, and can also have
deletions and duplications (see Chapter 9).
Structural abnormalities of the X in males are generally associated with more severe phenotypic
manifestations than in females. This is partly explained by preferential inactivation of the structurally
abnormal X in cases of duplications or deletions or in unbalanced X;autosome translocations in
females. In cases of balanced X;autosome translocations, there is usually preferential inactivation of
the normal X chromosome. Theories explaining this are discussed in the following paragraphs. Highresolution
chromosome analysis should be performed on females manifesting X-linked disorders to
look for a structural X abnormality.
The molecular X inactivation pattern seems to correlate with phenotype in women with structural
abnormalities of the X. Completely nonrandom X inactivation of the abnormal X is generally associated
with a normal phenotype, whereas those with skewed or random inactivation patterns usually have
nonspecific mental retardation and/or congenital abnormalities. The X inactivation status of women
with structurally abnormal X chromosomes and an abnormal phenotype should be assayed as part of a
routine clinical work-up. The phenotype could be correlated with differences in X inactivation ratios
(145). There have been very few reports on the use of prenatal X inactivation studies in amniotic fluid
or CVS (146) (see Chapter 12). Studies comparing prenatal and postnatal analysis of X inactivation and
their correlation with phenotypic and developmental outcomes are needed before these could be used to
give prognostic information in female fetuses with X-chromosome abnormalities.
X;Autosome Translocations
Balanced Translocations
In females, balanced X-autosome translocations can be divided into four phenotypic categories:
normal phenotype with or without history of recurrent miscarriage, gonadal dysfunction with primary
amenorrhea or premature ovarian failure (POF), a known X-linked disorder, or congenital
abnormalities and/or developmental delay (147). The reasons for the variable phenotypes are complex
and not fully understood, making genetic counseling in cases of prenatal detection of these
translocations very difficult.
Translocations involving the X chromosome and an autosome often lead to primary or secondary
ovarian failure and sometimes Turner syndrome-like features if the translocation occurs within the
critical region of Xq13-q26 (148–150). There are several different hypotheses concerning the cause of
gonadal dysfunction in these cases, including disruption of POF-related genes (149,151), a position
effect resulting from local alteration of chromatin caused by the translocation (148,150), and incomplete
pairing of X chromosomes at pachytene (152). In cases in which the translocated X chromosome
is the inactive X, inactivation will spread from the translocated X segment to the attached autosomal
material, where it will inactivate genes. The other X-chromosome segment will remain active. There is
incorrect dosage of both autosomal and X-linked genes in these cells, with functional autosomal monosomy
for the derived (X)t(X;aut) chromosome that contained the X inactivation center, and functional
X chromosome disomy for the portion of the X chromosome translocated onto the active (autosomal)
reciprocal translocation product (153). There is strong selection against such cells. In general, the normal
X is preferentially inactivated in approximately 75% of such patients (153,154). When the translocation
disrupts a gene located on the X chromosome, a female with such a translocation could manifest
a disease condition (155,156). Any mutated genes on the translocated X chromosome will be fully
expressed, as they would be in a male (3). Several X-linked genes have been mapped in this way.
A “critical region” determining normal ovarian function has been hypothesized at Xq13-Xq26
(150,157). The majority of females with balanced translocations with breakpoints in this region usually
have POF (secondary amenorrhea associated with elevated gonadotropin levels before the age of