Mg. Butler et al., MOLECULAR-GENETIC ANALYSIS OF MENTALLY-RETARDED MALES WITH FEATURES OF THE FRAGILE-X SYNDROME, JIDR. Journal of intellectual disability research, 39, 1995, pp. 544-553
The fragile-X [fra(X)] or Martin-Bell syndrome is the most common fami
lial cause of mental retardation and is characterized by the presence
of an Xq27.3 chromosome fragile site. Unstable DNA sequences represent
ing large increases in the number of CGG trinucleotide DNA base repeat
s of the FMR-1 gene are located at the fragile site and responsible fo
r the fra(X) syndrome. In order to identify whether cytogenetically no
rmal yet mentally retarded males without a known cause of their retard
ation had expansion of the CGG repeat segment of the FMR-1 gene, molec
ular genetic studies using Southern hybridization were performed with
two DNA probes (fxa241 and Ox1.9) following digestion of genomic DNA f
rom each patient with restriction enzymes Pst1 and EcoR1/Eag1, respect
ively. DNA studies were performed on 20 (12.3%) out of 162 (122 white
and 40 black people) cytogenetically normal mentally retarded males wi
thout a known cause of their retardation, but with high anthropometric
discriminant values and/or clinical checklist scores identified previ
ously and consistent with the fra(X) syndrome. None of the 20 males sh
owed expansion of the CGG repeat of the FMR-1 gene detectable with the
two probes used in this study. While heterogeneous single base pair s
ubstitutions, or small deletions or insertions in the FMR-1 gene could
exist in our patients, aberrations in other X-linked mental retardati
on genes, not identified to date but whose gene product can produce a
phenotype similar to fra(X), either independently or in conjunction wi
th the recently identified FMR-1 protein, should be considered and are
under investigation. Our study supports the idea that major FMR-1 gen
e expansion detectable with Southern hybridization is rare in cytogene
tically normal mentally retarded males, including those with physical
and behavioural features seen in the fra(X) syndrome.