The Principles of Clinical Cytogenetics - Extra Materials - Springer

224 Cynthia Powell
Fig. 5. Balanced reciprocal translocation between the short arms of chromosomes X and 3: 46,X,t(X;3)(p11.3;p21.2).
Brackets indicate regions involved in translocation on the derivative chromosomes. The patient was a 30-yearold
clinically normal, fertile female who had a daughter with an unbalanced translocation consisting of a normal
X, the derivative X, and two normal chromosomes 3 (partial monosomy Xp and partial trisomy 3p).
Earlier studies relied on replication-timing studies to investigate inactivation in X;autosome
translocations. The translocated autosomal material can become delayed in its replication timing,
and this has been used to examine the extent of spread of X inactivation in such cases. It has
recently been demonstrated that late replication is a poor correlate of the spread of gene silencing
(169). The spreading of late replication is often incomplete and might skip some autosomal bands
and affect others (170). This suggests that autosomal chromatin does not transmit or maintain the
inactivation signal as efficiently as the X chromosome (169). Sharp et al. (169) reported a family
with both a balanced and unbalanced (X;10) translocation segregating. A female with the unbalanced
form was phenotypically normal except for secondary amenorrhea. Although the derivative
X chromosome was late-replicating, the late-replicating region extended only to the X;autosome
boundary and did not appear to spread into the translocated segment of 10q. However, transcriptional
analysis showed that the translocated segment of 10q was mostly inactive, consistent with
the phenotype of the patient. There have been several other reports of patients with X;autosome translocations
with mild phenotypes in which no spreading of late replication into the attached autosome
was observed (171,172). This suggests that silencing of autosomal genes by X inactivation can
occur without apparent delay in the replication timing of the surrounding chromatin. The use of
replication-timing studies to evaluate the extent of spread of inactivation in X;autosome translocations
can be misleading (169) and should not be used to make predictions of phenotype. In a study
of five cases with X;autosome translocations, there appears to be some correlation between the
pattern of gene silencing and clinical phenotype (173). However, use of such techniques for prognostic
purposes on a clinical basis awaits further studies. Cytogenetic features such as depletion of
histone acetylation and H3 lysine 4 dimethylation provide more reliable indicators of the extent of
spread of X inactivation than replication-timing studies (173).
Prenatal detection of an unbalanced X;autosome translocation presents a difficult counseling problem
(see Chapter 20). Although there have been reports of affected females having only secondary