We report a nonsense mutation in FMR1
in a patient with classic fragile X syndrome and his carrier mother with mild intellectual impairment. The fragile X syndrome can be considered semi-dominant, with manifestations of a full mutation in female carriers, depending on the proportion of active versus inactive X chromosomes carrying the mutation. Earlier studies have shown that phenotypical normal females have a skewed X inactivation pattern in favour of the inactive X carrying the mutation.8
As the X inactivation in the mother showed an equal distribution, some degree of intellectual impairment would be expected. However, this study was performed in blood and therefore is an approximation, as we do not know the pattern in brain.
Surprisingly, few point mutations have been found in the FMR1
gene. Two of these are truncating mutations in the N-terminal half of the gene and supposedly lead to nonsense-mediated decay of the mRNA. These two mutations caused classical fragile X syndrome.5
Another patient had a missense mutation in one of the KH domains and had a more severe phenotype.4
This could be due to a gain-of-function effect; however, in this family X-linked glycogenosis was also present, which might have contributed to the phenotype. The observed low frequency of point mutations in FMR1
might be because FMR1
is not routinely screened for point mutations, but is only investigated for the common CGG expansion; another reason could be that point mutations in this gene give atypical or even lethal phenotypes. More than 1100 patients have been screened for point mutations in FMR1
;3, 9, 10, 11, 12, 13, 14, 15
however, only one missense mutation of questionable pathogeneity was identified.3
The individuals investigated in these studies represent a very heterogenous group of patients with developmental delay, indicating that FMR1
mutations are not a common cause for mental impairment. To our knowledge, a mutational screening of FMR1
has not been performed in a large cohort of patients with typical fragile X syndrome negative for repeat expansion. Therefore, the frequency of point mutations in FMR1
in classical fragile X syndrome is unknown. The patient presented in this study shows a typical fragile X phenotype, and his mother shows a phenotype comparable to a female with a full mutation. We therefore suggest that in patients with clinical fragile X syndrome and no CGG expansion expanded molecular diagnosis should be considered, including western blot analysis and DNA sequencing.