The Principles of Clinical Cytogenetics - Extra Materials - Springer

504 Dana Crawford and Patricia Howard-Peebles
Reyniers et al. (122) showed that full mutation or mosaic full/premutation males only produce
premutation sperm and, therefore, premutation daughters, because repeat expansion occurs only in
females (33). Testicular selection against full mutation sperm is unlikely since male Fmr1 knockout
mice show fertility (123). These data support a model of expansion only in somatic cells and protection
of the premutation in the germline cells. However, Malter et al. showed, in full mutation fetuses,
that only full mutation alleles (in the unmethylated state) were found in oöcytes from intact ovaries or
in immature testes from 13-week fetuses, but that both full and premutation alleles were found in the
germ cells of a 17-week male fetus (124). They hypothesize that the full mutation contracts in the
fetal testes, with subsequent selection for the premutation sperm. In females, the expansion could
occur during maternal oögenesis or very early in embryogenesis, prior to general methylation. The
answer requires analysis of oöcytes from premutation females.
CURRENT GENETIC ASPECTS OF FRAGILE X SYNDROME
Prevalence of Full Mutations and Premutations
Using the cytogenetic technique developed in the late 1970s described above (2), Webb et al.
(125) and Turner et al. (126) tested school-aged children with mental retardation from Coventry,
England, and Sydney, Australia, respectively, for the fraX. In both studies, the investigators assumed
that all males affected with the fragile X syndrome are mentally retarded and would be found among
programs, schools, or institutions for children with special needs. Under this assumption, both groups
tested the target population for fraX and extrapolated their findings to the general population, giving
an estimate of 1 in 1000 males and 1 in 2610 males, respectively. Similarly designed studies in Sweden
(127) and Finland (128) supported these estimates of the prevalence of the fragile X syndrome among
males and firmly established the syndrome as the second most common cause of mental retardation.
As previously discussed, the cytogenetic test employed by these early prevalence studies proved
to be inaccurate, missing 6–10% of affected males and at least 30% of the females (100,129). The
cytogenetic test also produced false positives, which is discussed in further detail below. Once FMR1
was cloned in 1991, more accurate and sensitive techniques became available for diagnosis. Using
the new DNA-based technology, the Coventry and Sydney groups revisited their original study populations
and revised the prevalence of the full mutation as 1 in 4167 and 1 in 4348 males, respectively
(130). Since then, several large, population-based studies have established that the prevalence of the
full mutation is probably between 1 in 6000 to 1 in 4000 males of northern European descent (131).
Although fraX has been identified in individuals with cytogenetic abnormalities such as XXY, XXX,
XYY, and +21, as well as in those with other genetic disorders such as neurofibromatosis, these cases
are likely coincidental as a result of the frequencies of both disorders in human populations. Despite
the downward revision of prevalence, the fragile X syndrome remains the second most frequent
known cause of mental impairment, surpassed only by Down syndrome.
Estimates for the prevalence of the full mutation among other racial/ethnic groups as well as
females are generally lacking. To date, only two population-based studies in African-derived populations
have been performed, and they suggest that the frequency of the full mutation is at least equal,
if not higher, compared with European-derived populations (131). For females, no population-based
studies have been performed to date. Based on the fact that the gene responsible for the fragile X
syndrome is on the X chromosome and the fact that only females can transmit the disease-causing
mutation to their offspring, the prevalence of the full mutation among females is expected to equal
the prevalence estimated for males. However, because of X-activation and possibly other factors,
only 30–50% of females with the full mutation are mentally retarded (IQ 70.