Unexpected Associations between the Number of FRAXE Repeats in Boys and Evidence of Diabetes in Their Mothers and Maternal Grandmothers.

Jean Golding,Steven Gregory,Marcus E Pembrey,Yasmin Iles-Caven,Rosie Clark,Genette Ellis,Matthew Suderman

doi:10.21926/obm.genet.2104141

Abstract

The FRAXE section of the FMR2 gene, located on the X chromosome, contains varying numbers of trinucleotide repeats; boys with over 200 repeats tend to have mild cognitive impairments, though this is rare. Little is known, however, concerning the phenotypes of individuals with smaller numbers of repeats. Here we answer the research question as to whether the health of ancestors of boys from whom the relevant X chromosome was inherited differed in any way according to the number of FRAXE repeats. Numbers of FRAXE repeats in 5057 boys from the Avon Longitudinal Study of Parents and Children (ALSPAC) were assessed. The distribution was bimodal, with the second smaller distribution starting at 22 repeats. We tested whether possession of 22+ repeats was associated with differences in the health of mothers (who share the X chromosome) and maternal grandmothers (half of whom share it).Female ancestors of boys with >21 repeats compared with <22 showed that maternal grandmothers (MGM) and mothers (M) had an increased risk of diabetes: MGM Type I odds ratio (OR) 2.40 [95%CI: 1.07,5.38]; MGM Type II OR 1.61 [0.96,2.70]; M OR 1.95 [0.96,3.94] using self-reported questionnaire measures. These results were confirmed from maternal medical records which revealed an increased level of diabetes [OR 2.40 (1.16,4.96)] and an increased risk of repeated glycosuria during pregnancy [OR 1.60 (1.08,2.36)]. We tested numbers of FRAXA repeats and showed no such associations, indicating that the findings were not associated with triploid repeats in general. If these findings are replicated elsewhere, there are at least three possible interpretations: (i) maternal diabetes/prediabetes results in an increased number of FRAXE repeats; (ii) women with high numbers of FRAXE repeats are at increased risk of diabetes; or (iii) some common factor, e.g. genomic instability, results in both diabetes and increased repeats.

Highlights

The FRAXE allele of the FMR2 gene is located at q28 on the X chromosome and contains a varying number of CCG trinucleotide repeats
For the associations with diabetes, we have analysed the data using the number of FRAXE trinucleotide repeats as a continuous variable to discern whether the associations shown with the binary variable is likely to be due to a general effect, or whether it applies to being in the higher bimodal levels of repeats only
Comparison of the groups of maternal grandparents whose grandsons had >21 to those with fewer FRAXE repeats (Supplementary Table S1) showed that the grandparents did not differ in regard to the years in which they were born, or their ages when the study mother was born

Summary

Introduction

The FRAXE allele of the FMR2 ( known as the AFF2) gene is located at q28 on the X chromosome and contains a varying number of CCG trinucleotide repeats. The prevalence of the full mutation at FRAXE in males has been estimated at 1 in 23,400 and is even lower for females [4]. This raises the following two questions: (i) why is there a range in the number of repeats; and (ii) do the individuals with relatively high numbers of repeats benefit in some way?. If the son has a relatively high number of repeats (but

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Conclusion