Maternal FMR1 alleles expansion in newborns during transmission: a prospective cohort study.

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: Offspring would have a higher risk of developing FXS due to maternal FMR1 alleles expansions during transmission. This is the first prospective cohort study in Pakistan for finding FMR1 allelic status of pregnant women and their newborn offspring in follow-up. The robust offspring risk for FXS estimated in this study may be valuable information for genetic counseling of women carriers for FMR1 expanded alleles. The family history and miscarriage were detected as effective indicators for FXS carrier screening in Pakistani women.

Fragile X premutation carrier screening in Pakistani preconception women in primary care consultation.

PURPOSE: Women of reproductive age who carry fragile X premutation (PM) alleles have 56 to 200 CGG repeats in the 5'-untranslated region of FMR1 gene are at increased risk for producing children with intellectual disabilities (ID) or autism spectrum disorders (ASD) due to expansion of PM alleles to full mutation alleles (> 200 repeats) during maternal transmission. METHODS: In present study fragile X PM carrier screening was performed in total 808 women who were consulting primary health care centers for preconception care in Khyber Pakhtunkhwa region of Pakistan between April, 2018 and December, 2020. Polymerase chain reaction (PCR) was performed for detection of PM carrier women and the CGG repeats number was confirmed by Southern blotting and capillary electrophoresis. RESULTS: The prevalence rate for PM carriers among preconception women was found to be 0.7% that was contributed by 0.5% women in risk group (RG1) with family history of ID and 0.2% in risk group 2 (RG2) with family history of ASD. PM carrier women had at least one affected child or sibling. In addition, the preconception women with FMR1 PM alleles were found to be at increased risk for primary ovary insufficiency (RG1: P = 0.0265, RG2: P = 0.0389), postpartum depression (RG1: P = 0.0240, RG2: P = 0.0501) and neuropsychiatric disorders (RG1: P = 0.0389, RG2: P = 0.0432). CONCLUSIONS: Current study provides first evidence of fragile X PM carrier screening in Pakistani preconception women in primary care consultation. Findings of current study may help to improve preconception care and to reduce burden of fragile X associated disorders in our population.