Abstract
Introduction
The CGG repeats in the 5′ untranslated region of the fragile X mental retardation 1 gene (FMR1) gene shows increased instability upon maternal transmission. Maternal FMR1 intermediate (45–54 repeats) and premutation (PM: 55–<200 repeats) alleles usually expand to full mutation (>200 repeats) alleles in offspring and consequently, cause fragile X syndrome (FXS) in them.
Methods
In a prospective cohort study, Pakistani pregnant women in prenatal care were first screened for FMR1 expanded alleles. In the follow-up, pregnancy outcomes in women carrying FMR1 expanded alleles were recorded and their newborn offspring were also screened for FXS.
Results
In a total of 1950 pregnant women, 89 (4.6%) were detected carriers for FMR1 expanded alleles; however, rates of detection of expanded alleles were found significantly high in women with a history of FXS. In addition, miscarriages and birth of affected newborns with FXS were significantly more common in women carrying large size PM alleles and had a history of FXS (P = 0.0494 and P = 0.0494, respectively).
Conclusions
The current study provides the first evidence of screening Pakistani pregnant women for FMR1 expanded alleles in prenatal care. Moreover, the miscarriage was also detected as a clinical predictor for FXS.
Impact
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Offspring would have a higher risk of developing FXS due to maternal FMR1 alleles expansions during transmission.
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This is the first prospective cohort study in Pakistan for finding FMR1 allelic status of pregnant women and their newborn offspring in follow-up.
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The robust offspring risk for FXS estimated in this study may be valuable information for genetic counseling of women carriers for FMR1 expanded alleles.
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The family history and miscarriage were detected as effective indicators for FXS carrier screening in Pakistani women.
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Data availability
All the data used to support the findings of this study are included within the article and are available on request from the corresponding author.
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Acknowledgements
The authors acknowledge all those women who participated in the study.
Funding
This study was financially supported by Higher Education Commission (HEC) under National Research Program for Universities (NRPU) project # 5886.
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Contributions
Clinical data collection, collation, and analysis: R.S., M.Y., H.J., H.T., M.N., N.M., M.J., and S.S. Genetic testing and data analysis: R.S., M.Y., H.T., N.M., I.Z., M.Z., A.A., M.M., N.K., A.H., Z.U.R., and S.S. Manuscript writing and revision: R.S., N.K., Z.U.R., and S.S. Study supervision and coordination: Z.U.R. and S.S. The manuscript has been read and approved by all authors.
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The approval of the present study was obtained from the Research and Ethical Committee and Advanced Studies Research Board (ASRB) of Kohat University of Science and Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan.
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Written informed consent for the publication of the details has been obtained from the participating women, who provided blood samples.
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Shahid, R., Yasin, M., Rehman, Z.U. et al. Maternal FMR1 alleles expansion in newborns during transmission: a prospective cohort study. Pediatr Res 93, 720–724 (2023). https://doi.org/10.1038/s41390-022-02128-2
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DOI: https://doi.org/10.1038/s41390-022-02128-2
