Interpretation of Test Results

Because FMR1 appears to be the only disease-causing gene for FXS, test specificity is 100%. Using both Southern blot analysis and PCR specific for FMR1, test sensitivity for repeat expansion can be estimated to be nearly 99%, as only rare point mutations, small deletions/insertions remote from the repeat segment, or gene inversions would be missed. However, these nonrepeat expansion molecular alterations may be underascertained in FMR1 since gene regions downstream of the repeat segment in exon 1 are rarely investigated, even if repeat expansion is not present. As detected by testing, the presence of cellular mosaicism, in either repeats or methylation, presents potential problems for prediction of FXS severity. Essentially all patients with mutations resulting in reduction of FMRP are impaired,but expression of variable amounts of FMRP may allow some individuals to function at a higher level than expected. These individuals may occasionally have intelligence quotients that are not in the MR range. Prognostication of severity based on testing of a young child should be b c predicated with great caution during genetic counseling, because no long-term study exists following the development of individuals with methylation mosaicism.

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