The Principles of Clinical Cytogenetics - Extra Materials - Springer

Fragile X 499
Table 4
Characteristics of the Cloned Folate-Sensitive Fragile Sites a
Copy number
Symbol Location Disease Normal Premutation Full mutation
FRAXA Xq27.3 Fragile X syndrome 6–54 61–200 230 to > 1000
FRAXE Xq28 Fragile XE syndrome 6–25 ?50–200 200 to > 800
FRAXF Xq28 None 6–29 ? 300 to 1000
FRA16A 16p13.1 None 16–50 ?50–200 ?1000–2000
FRA11B 11q23.3 Offspring predisposed
to Jacobsen syndrome
11 85–100 100–1000
a Source: Adapted from reference 32.
and increasing severity, is known as anticipation. All the disorders are either X-linked or autosomal
dominant except Friedreich ataxia, which is autosomal recessive.
The CGG trinucleotide repeats (included in Class 1) are located at folate-sensitive fragile sites
(31) and their characteristics are summarized in Table 4. Based on the trinucleotide repeat size in
FRAXA and FRAXE, an individual can be classified as normal, premutation, or full mutation. An
individual with a normal repeat size is characterized by stability of the repeat length and normal
intelligence, whereas an individual with a premutation repeat size shows instability of the repeat
length from generation to generation, but normal intelligence. In contrast, full mutation individuals
have massive repeat sizes differing in lengths (“mosaic”) in a pattern that is often conserved across
tissues, resulting in fragile X syndrome. The values of these repeat lengths for fraX are listed in
Table 4.
Instability of the CGG Repeat
Through observational studies of families with the fragile X syndrome, several factors involved in
CGG repeat instability have been proposed, including sex of the transmitting parent, size and structure
of the CGG repeat, and other yet-to-be-identified factors. With the resolution of the Sherman
paradox, it is now known that a premutation-sized repeat has the propensity to expand when passed
through a female germline, and the size of the resulting expansion is positively correlated with the
maternal repeat size (33–37). In contrast, when passed through a male germline, the premutation does
not dramatically change in repeat size and often contracts or remains the same (36–38).
In addition to the sex of the transmitting parent, the size and structure of the CGG repeat have been
implicated in playing a role in instability. Sequencing of the CGG repeat revealed that the repeat
is not pure and is interspersed with one to three AGGs (adenine–guanine–guanine sequences) every
9–10 CGGs in the general population. Among families with the fragile X syndrome, premutationsized
repeats usually have one AGG at the proximal most end of the repeat, or none at all (39–41).
Transmission studies of families with premutation- or intermediate-sized repeats demonstrate that
these are unstable if more than 34 repeats at the 3' end of the repeat structure are uninterrupted by an
AGG (36,39,41). To date, all known expansions have occurred at the 3' end of the repeat. This polarity
of expansion further demonstrates the importance of the 3' end of the repeat in the expansion
process. Although the role of the AGG interruption has only been minimally defined by experimental
studies (42), these observational and population studies suggest that the AGG sequence acts as an
anchor during DNA replication to prevent expansions or deletions that are the result of slips or
misalignments of the repeat sequence during replication (43–45).
Despite the identification of these factors, it is clear that other yet-to-be identified factors are
involved in the expansion process. These unknown factors could include both cis- and trans-acting
factors. Two cis-acting factors proposed in the literature are chromosomal background (44) and the