FMR1 allelic complexity in premutation carriers provides no evidence for a correlation with age at amenorrhea

Abstract

Abstract The purpose of this study was to assess FMR1 gene allelic complexity in female premutation carriers using a previously validated mathematical model and correlate with age at amenorrhea. FMR1 CGG and AGG number and pattern results were obtained from distinct publications, however, age at amenorrhea was available in only one of these studies. Approximately 4.7% were alleles with no AGGs, with the 30 CGG allele being the most frequent among the normal-sized alleles (39.1%). Ninety-seven different AGG interspersion patterns were identified, and despite the presence of two AGG interruptions in vast majority, the most common patterns varied between (CGG)10AGG(CGG)9AGG(CGG)9 and (CGG)9AGG(CGG)9AGG(CGG)9. Interestingly, the two most common patterns in set 2, (CGG)11AGG(CGG)10AGG(CGG)7, and (CGG)10AGG(CGG)10AGG(CGG)7 are absent from samples from other studies. No statistically significant difference in the allelic scores of the premutated alleles was observed between samples from the different publications. Correlation of the allelic score of each allele revealed two distinct complexity behaviors. In a covariance analysis, there was an inverse relationship between logarithmic models resulting from these samples and those of the reference set previously published by our group. This result supports a more robust model including observations from larger cohorts, showing that the mathematical model can be used in premutated samples. The use of the allelic scores combinations, despite the absence of correlation with age at amenorrhea, has the potential to positively impact several parameters that drive female infertility, namely Fragile X-associated Primary Ovarian Insufficiency (FXPOI) development, ovarian dysfunction and hormonal levels.