Development and Validation of a Mathematical Model to Predict the Complexity of FMR1 Allele Combinations

Rodrigues, Bárbara; Vale-Fernandes, Emídio; Maia, Nuno; Santos, Flávia Carvalho; Marques, Isabel; Santos, Rosário; Nogueira, António J.A.; Jorge, Paula

doi:10.3389/fgene.2020.557147

Cited by 3 publications

(13 citation statements)

References 22 publications

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“…1b). To compare PM samples behavior with that of the previously published using the same mathematical model, samples from that publication were used as a reference (Rodrigues et al 2020). A distribution into four quadrants, separated by an allelic score of 150 was obtained in all sets, similarly to that obtained in the reference set, revealing the same distinct behaviors (Fig.…”

Section: Mathematical Model Validationmentioning

confidence: 87%

“…The reference set, composed by one hundred and thirty-one female samples with normal (n = 127) and intermediate genotypes (n = 4), was previously described and characterized in Rodrigues et al (Rodrigues et al 2020) (the summary of the results can be found in Supplementary Table 1).…”

Section: Reference Setmentioning

confidence: 99%

“…In FMR1 normal-sized alleles (5 to 44 CGGs), the repetitive region is usually interrupted by one or more AGGs, typically occurring at every 9th or 10th CGG (Tabolacci et al 2022). Expanded alleles, namely premutated, are predominantly composed by pure CGGs; loss of AGG interruption(s) has been linked to the instability of the repetitive region and the increased risk of expansion (Napierala et al 2005 (Rodrigues et al 2020). Herein, in order to evaluate the association between the combination of normal and premutated allelic scores with the ovulatory dysfunction underlying FXPOI, re ected in the age at amenorrhea, the mathematical model was applied in FMR1 premutation carriers, validating its use in samples with distinct genotypic characteristics.…”

Section: Introductionmentioning

confidence: 99%

“…2014a (United States of America, n = 498, designated by set 3 ). In total, 577 results were retrieved and the allelic score, which re ects the FMR1 CGG/AGG substructure, was calculated separately for each allele, using mathematical model described in Rodrigues et al (Rodrigues et al 2020). The age at amenorrheade ned by at least 4 months of secondary amenorrhea and follicle-stimulating hormone (FSH) menopausal levels (Allen et al 2018) -was been recorded only in samples from set 2 (mean age 38.7 ± 8.5 years, range 18-56).…”

Section: Introductionmentioning

confidence: 99%

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

Rodrigues

Sousa

Yrigollen

et al. 2023

Preprint

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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.

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Section: Mathematical Model Validationmentioning

confidence: 87%

Section: Reference Setmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Rodrigues

Sousa

Yrigollen

et al. 2023

Preprint

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“…each woman, we calculated the FMR1 allelic complexity score developed by Rodrigues et al(Rodrigues et al, 2020), which integrates the AGG interspersion number and pattern but also the total repeat length, to reflect the polymorphic CGG/AGG substructure of the 5 0 UTR of FMR1. We were not able to calculate the allele score for 8 patients in the POI group and 4 in the pregnant women group because the graphs were not available.…”

mentioning

confidence: 99%

Stratification of the risk of ovarian dysfunction by studying the complexity of intermediate and premutation alleles of the FMR1 gene

Quilichini,

Perol,

Cuisset

et al. 2023

American J of Med Genetics Pt A

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FMR1 premutation female carriers are at risk of developing premature/primary ovarian insufficiency (POI) with an incomplete penetrance. In this study, we determined the CGG repeat size among 1095 women with diminished ovarian reserve (DOR) / POI and characterized the CGG/AGG substructure in 44 women carrying an abnormal FMR1 repeat expansion number, compared to a group of 25 pregnant women carrying an abnormal FMR1 CGG repeat size. Allelic complexity scores of the FMR1 gene were calculated and compared between the two groups. In the DOR/POI cohort, 2.1% of women presented with an intermediate repeat size and 1.9% with a premutation. Our results suggest that the risk of POI is highest in the mid‐range of CGG repeats. We observed that the allelic score is significantly higher in POI women compared to the pregnant women group (p‐value = 0.02). We suggest that a high allelic score due to more than 2 AGG interspersions in the context of an intermediate number of repetitions could favor POI. Larger studies are still needed to evaluate the relevance of this new tool for the determination of the individual risk of developing POI in women with abnormal number of CGG repeats.

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

Rodrigues,

Sousa,

Yrigollen

et al. 2024

Reprod Biol Endocrinol

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Background Premutations in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene, defined as between 55 and 200 CGGs, have been implicated in fragile X-associated primary ovarian insufficiency (FXPOI). Only 20% of female premutation carriers develop early ovulatory dysfunction, the reason for this incomplete penetrance is unknown. This study validated the mathematical model in premutation alleles, after assigning each allele a score representing allelic complexity. Subsequently, allelic scores were used to investigate the impact of allele complexity on age at amenorrhea for 58 premutation cases (116 alleles) previously published. Methods The allelic score was determined using a formula previously described by our group. The impact of each allelic score on age at amenorrhea was analyzed using Pearson’s test and a contour plot generated to visualize the effect. Results Correlation of allelic score revealed two distinct complexity behaviors in premutation alleles. No significant correlation was observed between the allelic score of premutation alleles and age at amenorrhea. The same lack of significant correlation was observed regarding normal-sized alleles, despite a nearly significant trend. Conclusions Our results suggest that the use of allelic scores combination have the potential to explain female infertility, namely the development of FXPOI, or ovarian dysfunction, despite the lack of correlation with age at amenorrhea. Such a finding is of great clinical significance for early identification of females at risk of ovulatory dysfunction, enhancement of fertility preservation techniques, and increasing the probability for a successful pregnancy in females with premutations. Additional investigation is necessary to validate this hypothesis.

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Development and Validation of a Mathematical Model to Predict the Complexity of FMR1 Allele Combinations

Cited by 3 publications

References 22 publications

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

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

Stratification of the risk of ovarian dysfunction by studying the complexity of intermediate and premutation alleles of the FMR1 gene

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

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