Further refinement in defining the effect of heterozygous-abnormal CGG counts on the FMR1 (fragile X) gene: definition of a distinct subgroup of PCOS patients, based on norma/low genotype

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OBJECTIVE: We report elsewhere that normal and heterozygous (het) or homozygous (hom) abnormal counts on the FMR1 gene reflect distinct ovarian aging curves. Het abnormal can, however, be normal/low or normal/high, which may affect ovarian reserve (OR) differently.DESIGN: Cohort study.MATERIALS AND METHODS: Triple CGG counts on FMR1 gene were investigated in 339 consecutive women. A normal count was 26-32 and FMR1 was considered normal (norm) with both alleles in normal range, het if 1, and hom if both alleles were abnormal. Het could be low/normal (het-1) or high/normal (het-2). Whether OR, reflected by anti-Müllerian hormone (AMH) and oocytes yield (phenotype), differs depending on FMR1 genotype, was investigated in 4 groups (norm, het-1, het-2, hom) for groups as a whole, and stratified for age < 35 and ≥ 35 years. Mean ranks between groups were compared with Kruskal-Wallis or Mann Whitney tests.RESULTS: Among participants in all 4 groups was no difference in AMH (p=0.24) and oocytes (p= 0.054). Age-stratified, women < 35 years demonstrated, however, significant difference between norm and het-2 and hom and het-1 AMH (Z = -2.22, p = 0.027) and oocytes (Z = -3.194, p = 0001), not noted above age 35. Het-1 genotype at young age expresses the highest AMH, decreasing rapidly in the early 30s. Het-2, in contrast, presents already at young age with 2nd lowest AMH after hom.CONCLUSIONS: Refinement in CGG count analysis of het abnormal women demonstrates distinct differences in ovarian aging patterns between het-1 and het-2 genotypes. Based on initially very high AMH in het-1 and observed habitués, the het-1 genotype appears to represent (normal weight) women with non-typical PCOS, who at young age unusually rapidly lose OR. OBJECTIVE: We report elsewhere that normal and heterozygous (het) or homozygous (hom) abnormal counts on the FMR1 gene reflect distinct ovarian aging curves. Het abnormal can, however, be normal/low or normal/high, which may affect ovarian reserve (OR) differently. DESIGN: Cohort study. MATERIALS AND METHODS: Triple CGG counts on FMR1 gene were investigated in 339 consecutive women. A normal count was 26-32 and FMR1 was considered normal (norm) with both alleles in normal range, het if 1, and hom if both alleles were abnormal. Het could be low/normal (het-1) or high/normal (het-2). Whether OR, reflected by anti-Müllerian hormone (AMH) and oocytes yield (phenotype), differs depending on FMR1 genotype, was investigated in 4 groups (norm, het-1, het-2, hom) for groups as a whole, and stratified for age < 35 and ≥ 35 years. Mean ranks between groups were compared with Kruskal-Wallis or Mann Whitney tests. RESULTS: Among participants in all 4 groups was no difference in AMH (p=0.24) and oocytes (p= 0.054). Age-stratified, women < 35 years demonstrated, however, significant difference between norm and het-2 and hom and het-1 AMH (Z = -2.22, p = 0.027) and oocytes (Z = -3.194, p = 0001), not noted above age 35. Het-1 genotype at young age expresses the highest AMH, decreasing rapidly in the early 30s. Het-2, in contrast, presents already at young age with 2nd lowest AMH after hom. CONCLUSIONS: Refinement in CGG count analysis of het abnormal women demonstrates distinct differences in ovarian aging patterns between het-1 and het-2 genotypes. Based on initially very high AMH in het-1 and observed habitués, the het-1 genotype appears to represent (normal weight) women with non-typical PCOS, who at young age unusually rapidly lose OR.