Utilizing FMR1 gene mutations as predictors of treatment success in human in vitro fertilization.

Mutations of the fragile X mental retardation 1 (FMR1) gene are associated with distinct ovarian aging patterns.To confirm in human in vitro fertilization (IVF) that FMR1 affects outcomes, and to determine whether this reflects differences in ovarian aging between FMR1 mutations, egg/embryo quality or an effect on implantation.IVF outcomes were investigated in a private infertility center in reference to patients' FMR1 mutations based on a normal range of CGG(n = 26-34) and sub-genotypes high (CGG(n>34)) and low (CGG(<26)). The study included 3 distinct sections and study populations: (i) A generalized mixed-effects model of morphology (777 embryos, 168 IVF cycles, 125 infertile women at all ages) investigated whether embryo quality is associated with FMR1; (ii) 1041 embryos in 149 IVF cycles in presumed fertile women assessed whether the FMR1 gene is associated with aneuploidy; (iii) 352 infertile patients (< age 38; in 1st IVF cycles) and 179 donor-recipient cycles, assessed whether the FMR1 gene affects IVF pregnancy chances via oocyte/embryo quality or non-oocyte maternal factors.Standardized IVF protocols.Morphologic embryo quality, ploidy and pregnancy rates.(i) Embryo morphology was reduced in presence of a low FMR1 allele (P = 0.032). In absence of a low allele, the odds ratio (OR) of chance of good (vs. fair/poor) embryos was 1.637. (ii) FMR1 was not associated with aneuploidy, though aneuploidy increased with female age. (iii) Recipient pregnancy rates were neither associated with donor age or donor FMR1. In absence of a low FMR1 allele, OR of clinical pregnancy (vs. chemical or no pregnancy) was 2.244 in middle-aged infertility patients.A low FMR1 allele (CGG(<26)) is associated with significantly poorer morphologic embryo quality and pregnancy chance. As women age, low FMR1 alleles affect IVF pregnancy chances by reducing egg/embryo quality by mechanisms other than embryo aneuploidy

Characteristics in section (ii) of women undergoing IVF for non-fertility related indications.

<p>Characteristics in section (ii) of women undergoing IVF for non-fertility related indications.</p

Donor egg recipients and infertility patients using autologous oocytes included in section (iii).

<p>Donor egg recipients and infertility patients using autologous oocytes included in section (iii).</p

The distribution of morphologic embryo quality for each <i>FMR1</i> sub-genotype.

<p>*Morphologic embryo quality in sub-genotypes with a <i>low</i> allele present was significantly reduced in comparison to those without a <i>low</i> allele (P = 0.032). OR of chance of good vs. fair/poor embryos in absence of a <i>low</i> allele was 1.637.</p

Characteristics of infertile patients in section (i).

<p>Characteristics of infertile patients in section (i).</p

The distribution of embryo ploidy based on patients <i>FMR1</i> sub-genotype.

<p><i>FMR1</i> mutations were not statistically associated with embryo ploidy, though the high aneuploidy rate in biallelic <i>low</i>, <i>hom-low/low</i> women is quite remarkable. Lack of significance may in here-reported findings, therefore, be consequence of small patient numbers. Also of interest is the very low aneuploidy rate in women with one <i>low</i> and one <i>high</i> allele, presenting with only approximately half the aneuploidy rate of even <i>norm</i> women. While these findings, dues to small patient numbers, also need to be viewed with caution, they could suggest a compensatory benefit from a <i>high</i> allele on negative effects of a <i>low</i> allele.</p

The distribution of clinical pregnancies based on <i>FMR1</i> sub-genotype of Clinical pregnancy rates in A oocyte donors and B middle-aged infertility patients.

<p>Oocyte recipient pregnancy rates were not associated with donor <i>FMR1</i>. Using a logistic regression model in middle-aged infertility patients, OR of clinical pregnancy vs. chemical or no pregnancy was 2.244 in absence of a <i>low FMR1</i> allele vs. presence of <i>low</i> alleles (P = 0.0015), suggesting 1.244-times odds of clinical IVF pregnancy in absence of a <i>low FMR1</i> allele.</p