The Principles of Clinical Cytogenetics - Extra Materials - Springer

496 Dana Crawford and Patricia Howard-Peebles
Table 1
Methods for Inducing Folate-Sensitive Fragile Sites
Number Method Additive a
1 Thymidine and folic acid deprivation b —
2 Inhibiting folate metabolism Aminopterin
Methotrexate
Trimethoprin
3 Inhibiting thymidylate synthetase Fluorodeoxyuridine (FUdR)
Fluorodeoxycytidine (FCdR)
4 Excess thymidine 300–600 mg/L
5 Combination of nos. 3 and 4 c FUdR + thymidine (300–600 mg/L)
a All additives applied for last 24 hours of culturing time.
b Requires serum supplements of 5%, pH 7.3, and sterility of cultures.
c See also reference 6.
numerous reports appeared in the literature (11). Based on this early work, a clinically nonspecific
X-linked MR disorder was delineated and called Renpenning’s syndrome, Martin-Bell syndrome, or
nonspecific X-linked MR. In 1959, Lubs described the first family with cytogenetic expression of the
“marker X” (which became the fragile X), and the heterogeneity of this nonspecific X-linked MR
disorder became apparent (12). Numerous disorders have been delineated from this original subgroup
of MR males and, in a continuing effort, a total of at least 124 X-linked disorders involving
MR have been described (13,14). The fraX subgroup was unique because there was a diagnostic
laboratory test; the name Martin–Bell syndrome was attached when this family, first described in
1943, was shown to be positive for fraX (15). However, the popular name for this disorder became
fragile X syndrome.
Inheritance of fraX
It became apparent soon after the cytogenetic test became available that the inheritance and penetrance
of fragile X syndrome was unlike that of any previously described X-linked disorder, although
it came closest to an X-linked dominant with reduced penetrance. It was determined that some males
who inherited the fraX were clinically normal, but passed the disorder to their normal daughters and
frequently had affected grandchildren. The term “transmitting male” (TM) was coined to describe
such unaffected carrier males. These TMs were thought to be the missing 20% of affected males
described by Sherman et al. from 206 fraX families (16,17). Their observation, that the mothers of
TMs are much less likely to have affected offspring than are the TMs unaffected daughters, became
known as the Sherman paradox. Other unusual features of fragile X syndrome are that TMs have
fewer mentally retarded daughters than do unaffected carrier females, affected females occur more frequently
(about one of three) than in other X-linked disorders, and affected females have more affected
offspring that do unaffected carrier females.
Cytogenetic Expression of fraX
The fraX site is located in band Xq27.3, one of six fragile sites located on the X chromosome (see
Table 2). It can be visualized in both solid stained and banded preparations (see Figure 1). However,
banded preparations are required because other fragile sites and lesions can mimic fraX (5,18,19).
Three other fragile sites have been found in bands Xq27–28: FRAXD (20), FRAXE (21), and FRAXF
(22). The latter two sites (see Table 2) cannot be cytogenetically distinguished from fraXGDF. The standard
ISCN nomenclature (see Chapter 3) to cytogenetically designate fraX is 46,Y,fra(X)(q27.3) for
an affected male and 46,X,fra(X)(q27.3) for an expressing female (23).