Activation Ratio Correlates with IQ in Female Carriers of the FMR1 Premutation

Abstract

Carriers of the FMR1 premutation (PM) allele are at risk of one or more clinical conditions referred to as FX premutation-associated conditions (FXPAC). Since the FMR1 gene is on the X chromosome, the activation ratio (AR) may impact the risk, age of onset, progression, and severity of these conditions. The aim of this study was to evaluate the reliability of AR measured using different approaches and to investigate potential correlations with clinical outcomes. Molecular and clinical assessments were obtained for 30 PM female participants, and AR was assessed using both Southern blot analysis (AR-Sb) and methylation PCR (AR-mPCR). Higher ARs were associated with lower FMR1 transcript levels for any given repeat length. The higher AR-Sb was significantly associated with performance, verbal, and full-scale IQ scores, confirming previous reports. However, the AR-mPCR was not significantly associated (p > 0.05) with these measures. Similarly, the odds of depression and the number of medical conditions were correlated with higher AR-Sb but not correlated with a higher AR-mPCR. This study suggests that AR-Sb may be a more reliable measure of the AR in female carriers of PM alleles. However, further studies are warranted in a larger sample size to fully evaluate the methylation status in these participants and how it may affect the clinical phenotype.

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation

“…Additionally, several studies have suggested that lower AR values could be linked to cognitive and behavioral challenges in female PM carriers [ 97 , 106 , 107 , 108 , 109 , 110 ], potentially affecting the risk, severity, and age of onset of FXPAC. Despite numerous studies investigating the role and impact of the AR in PM carriers, there are discrepancies among their findings that may be partially attributable to technical variability, as previously reported [ 86 , 111 , 112 , 113 , 114 ], or to differences in the methods employed to calculate the AR (as discussed in Protic et al, this special issue [ 115 ]). At the International Premutation Conference, novel data were presented demonstrating a noteworthy correlation between clinical measures and the AR.…”