Expanded CGG repeats in the fragile X syndrome

The heritable unstable sequences explain two
unusual characteristics of the fraX syndrome;
(i) the transition from a premutation (about
60–200 CGG repeats) without clinical manifestation
into a full mutation (more than 200 CGG
repeats) during transmission through the
germline, and (ii) differences in the FRAXA
locus within a given family.
Fragile X syndrome is heritable as an X-linked
dominant trait. The risk of transmission and
clinical manifestation varies according to the
type of mutation (premutation or full mutation),
the gender of the patient and of the parent
carrying an expanded trinucleotide repeat, and
the relationship within the family. Males with
the full mutation are mentally retarded and do
not reproduce. Heterozygous females for the
full mutation have a risk of variable mental retardation
of 50%. They transmit the full mutation
to 50% of their offspring. A premutation
present in amale (“normal male transmitter”) is
transmitted to all daughters and none of the
sons. Female carriers of the premutation or full
mutation have a 50% risk of transmitting the
mutant allele. The actual risk of manifest fragile
X syndrome depends on the number of CGG repeats
and varies between 10% (60–69 repeats)
and 50% (more than 100 repeats) for sons (Gene
Clinics at http: www.geneclinics.org).
The number of CGG repeats is variable within a
family. In the pedigree shown (1), individuals II-
3 and III-1 have more than 200 repeats and have
fragile X syndrome. Individuals I-2, I-3, II-1, and
III-3 are carriers of the premutation with 79–82
repeats. The normal number of CGG repeats is 6
to about 50, the premutation is defined by
about 55 to 100, and the full disease-causing
mutation by more than 200 repeats (2).
The different numbers of CGG repeats can be
demonstrated in Southern blots as DNA fragments
of different sizes (3). The normal gene is
represented by a small DNA fragment (S). A premutation
leads to slightly enlarged fragments.
The full mutation is characterized by large fragments
(L). With this procedure, a reliable diagnosis
of the genotype is possible. (Photograph of
a Southern blot: HindIII digestion and hybridization
with probe Ox1.1; P. Steinbach, Ulm).