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FMR1 repeats and ovarian function: comparing number of CGG repeats and antral follicle count
P-94 Tuesday, October 26, 2010 PREGNANCY CHANCES WITH IN VITRO FERTILIZATION (IVF) BASED ON FMR1-GENOTYPE AND AUTOIMMUNITY (AI). N. Gleicher, I. Lee, A. Weghofer, D. H. Barad. Center for Human Reproduction & Foundation for Reproductive Medicine, New York, NY; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT; Department of Obstetrics and Gynecology, Vienna University School of Medicine, Vienna, Innere Stadt, Austria; Department of Epidemiology and Social Medicine; Department of Obstetrics, Gynegology and Women’s Health, Albert Einstein College of Medicine, Bronx, NY. OBJECTIVE: FMR1 genotype and AI status can affect ovarian reserve (OR), as evaluated by anti-Mu¨llerian hormone (AMH).1, 2 OR affects pregnancy chances, whether spontaneous or via IVF. Pregnancy chances with IVF may, therefore, be associated with FMR1 genotypes and/or autoimmune status. DESIGN: Cohort study. MATERIALS AND METHODS: Normal CGG counts for ovarian function are 26-34. This defines normal (norm), heterozygous (het) and homozygous (hom) genotypes. 3 (Het can in addition be het-norm/low or het-norm/ high). An arbitrarily chosen autoimmune profile reflects AI, 2 and was, together with FMR1 status, investigated in 455 consecutive IVF cycles and then in multiple regression analyses statistically associated with IVF pregnancy outcomes, adjusted for age, race, medication dosage and number of oocytes. RESULTS: Pregnancy rate in norm women was significantly higher (38.6%) than in het-norm/low patients (22.2%; p¼0.001), with het-norm/ high being intermediate (31.7%). Adjusted for age, het-norm/low maintained lower pregnancy rates (p¼0.01) but significance was lost with adjustment for race, medication dosage and oocyte numbers. Controlling for all covariates, AI, alone, almost reached significance in predicting pregnancy chance (p¼0.06). CONCLUSION: FMR1 predicts IVF pregnancy chances (norm best, hetnorm/low worst, het-norm/high intermediate). Loss of significance with adjustments for ovarian factors, suggests a direct FMR1 effect on ovarian function. Almost independent significance of AI suggests that its effects only partially are ovarian (possibly via endometrium?). Since het-norm/ low is strongly associated with AI, non-obese polycystic ovarian (PCO) phenotype, 4 such patients may have inferior pregnancy chances with IVF. 1 Fertil Steril 2009;91:1700-6; 2 Fertil Steril 2009;91:1707-11 ; 3Reprod Biomed Online; 2010;doi:10:1026/j.rbmo. 2010.02.020; 4 Gleicher et al., ASRM 2010;. Supported by: Foundation for Reproductive Medicine; intramural CHR fund.
volving chromosomes X and 1, with no apparent macroscopic loss of genetic material from the translocated chromosomes. Subsequent microarray comparative genomic hybridization (NimbleGen CGX-3 array) revealed a cryptic 382-482 kb deletion at Xq27.2 (arr Xq27.2(140,201,306140,583,606)x1). In order to confirm the microarray findings and localize the deletion, fluorescence in situ hybridization (FISH) analysis was performed with a BAC probe (RP11-1082H4) mapping to the deleted region. The deletion was present on the X chromosome that was not involved in the translocation. CONCLUSION: Our patient exhibits a balanced X-autosomal translocation, which has been associated with POI, but appears to be an incidental finding in this patient. This case further narrows the minimal POF1 deletion associated with POI to a 382-482 kb deletion at Xq27.2.
P-96 Tuesday, October 26, 2010 FMR1 REPEATS AND OVARIAN FUNCTION: COMPARING NUMBER OF CGG REPEATS AND ANTRAL FOLLICLE COUNT. T. Spitzer, E. Johnstone, G. Davis, M. I. Cedars, V. Y. Fujimoto. Reproductive Sciences, University of California San Francisco, San Francisco, CA. OBJECTIVE: Premature ovarian insufficiency has been reported in women carrying FMR1 premutations (Streuli 2009) We explored the association between number of FMR1 CGG repeats and antral follicle count (AFC) in infertile women. DESIGN: Retrospective cross-sectional study. MATERIALS AND METHODS: 363 infertile women underwent FMR1 genotyping and ultrasound for AFC. Women with premature ovarian failure were excluded. A linear regression model was used to assess the effect of FMR1 repeat number on age-adjusted AFC. FMR1 repeats were classified as <45 (normal variation), 45-54 (intermediate allele) or 55-199 (premutation). FMR1 repeats were also classified as per prior work by Barad and Gleicher, and in groupings of 5 to explore subtle differences. RESULTS: Only 1 woman carried a premutation, with 57 CGG repeats. 7 women carried intermediate alleles (2%). FMR1 repeat number was not a significant predictor of AFC in an age-adjusted linear regression when the highest number allele or both allele members were included. Age-adjusted AFC did not differ between FMR1 groups by any of the classification systems used. FMR1 allele numbers- classified in groups of 5 Higher allele CGG repeat number
P-95 Tuesday, October 26, 2010 X-AUTOSOMAL TRANSLOCATION — A DISTRACTION OR A CAUSE OF PRIMARY OVARIAN INSUFFICIENCY? W. Vitek, K. Pagidas, G. Gu, J. R. Pepperell, U. Tantravahi, B. Plante. Division of Reproductive Endocrinology & Infertility, Women & Infants Hospital of Rhode Island, The Warren Alpert Medical School of Brown University, Providence, RI; Genetic Associates, Nashville, TN. OBJECTIVE: To characterize the genetic basis of primary ovarian insufficiency (POI) in a patient with a balanced X-autosomal translocation involving one X chromosome and a deletion at Xq27.2 on the other X chromosome. X-autosomal translocations have been associated with POI, possibly due to aberrations in pairing or X inactivation during folliculogenesis. Additionally, the putative genes leading to POI are located at one of two loci on Xq: POF1 (Xq26-q28) or POF2 (Xq13.3-q22), with the minimal POF1 deletion associated with POI narrowed to a 10.5 Mb region at Xq27.2/Xq27.3-q28. DESIGN: Case report. MATERIALS AND METHODS: 23 year-old with oligomenorrhea and primary infertility. She reported menarche at age 13. After discontinuation of oral contraceptive pills at age 22, she experienced oligomenorrhea and infertility. There was no family history of POI. Her physical exam was unremarkable and showed no stigmata of Turner Syndrome. Relevant laboratory data included: day 3 FSH¼61.2 mIU/mL, day 3 estradiol <20 pg/mL and normal FMR1 premutation testing. RESULTS: Standard karyotype testing (GTG band resolution 550) revealed 46,X,t(X;1)(q22.1;q42.1), indicating a balanced translocation in-
FERTILITY & STERILITYÒ
N
Mean Age
Mean AFC
Age-adjusted Mean AFC
<26 26-30 31-35 36-40
9 188 84 45
36.4 35.3 36.8 37.5
11.9 12.4 12.7 12.3
10.9 12.1 12.7 12.9
41-45 46-50 51-55 56+
15 2 4 1
36.9 39 35.3 33
14.3 8.5 9.7 14.2
14.5 10.3 9.7 14.2
P-value compared with 26-30
Difference in AFC from that predicted by age alone
0.61 0.53 0.53
-1.53 -0.31 0.28 0.41
0.24 0.72 0.51 0.78
1.99 -2.30 -2.73 1.91
CONCLUSION: FMR1 gray zone alleles and premutations are rare in infertile women in the Bay Area, with prevalence comparable to the general population (Cronister 2008). FMR repeat number does not correlate with AFC in this population.
P-97 Tuesday, October 26, 2010 PGD OR NATURAL CONCEPTION? WHAT IS RECOMMENDED FOR COUPLES WITH RECURRENT MISCARRIAGES CAUSED BY TRANSLOCATION CHROMOSOMAL ABERRATIONS? S. Awata, A. Tanaka, M. Nagayoshi, M. Sasaki, I. Tanaka. Saint Mother Hospital, Kitakyushu, Fukuoka, Japan. OBJECTIVE: It has been commonly assumed that preimplantation genetic diagnosis (PGD) for translocations in couples with recurrent miscarriages has
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volving chromosomes X and 1, with no apparent macroscopic loss of genetic material from the translocated chromosomes. Subsequent microarray comparative genomic hybridization (NimbleGen CGX-3 array) revealed a cryptic 382-482 kb deletion at Xq27.2 (arr Xq27.2(140,201,306140,583,606)x1). In order to confirm the microarray findings and localize the deletion, fluorescence in situ hybridization (FISH) analysis was performed with a BAC probe (RP11-1082H4) mapping to the deleted region. The deletion was present on the X chromosome that was not involved in the translocation. CONCLUSION: Our patient exhibits a balanced X-autosomal translocation, which has been associated with POI, but appears to be an incidental finding in this patient. This case further narrows the minimal POF1 deletion associated with POI to a 382-482 kb deletion at Xq27.2.
P-96 Tuesday, October 26, 2010 FMR1 REPEATS AND OVARIAN FUNCTION: COMPARING NUMBER OF CGG REPEATS AND ANTRAL FOLLICLE COUNT. T. Spitzer, E. Johnstone, G. Davis, M. I. Cedars, V. Y. Fujimoto. Reproductive Sciences, University of California San Francisco, San Francisco, CA. OBJECTIVE: Premature ovarian insufficiency has been reported in women carrying FMR1 premutations (Streuli 2009) We explored the association between number of FMR1 CGG repeats and antral follicle count (AFC) in infertile women. DESIGN: Retrospective cross-sectional study. MATERIALS AND METHODS: 363 infertile women underwent FMR1 genotyping and ultrasound for AFC. Women with premature ovarian failure were excluded. A linear regression model was used to assess the effect of FMR1 repeat number on age-adjusted AFC. FMR1 repeats were classified as <45 (normal variation), 45-54 (intermediate allele) or 55-199 (premutation). FMR1 repeats were also classified as per prior work by Barad and Gleicher, and in groupings of 5 to explore subtle differences. RESULTS: Only 1 woman carried a premutation, with 57 CGG repeats. 7 women carried intermediate alleles (2%). FMR1 repeat number was not a significant predictor of AFC in an age-adjusted linear regression when the highest number allele or both allele members were included. Age-adjusted AFC did not differ between FMR1 groups by any of the classification systems used. FMR1 allele numbers- classified in groups of 5 Higher allele CGG repeat number
P-95 Tuesday, October 26, 2010 X-AUTOSOMAL TRANSLOCATION — A DISTRACTION OR A CAUSE OF PRIMARY OVARIAN INSUFFICIENCY? W. Vitek, K. Pagidas, G. Gu, J. R. Pepperell, U. Tantravahi, B. Plante. Division of Reproductive Endocrinology & Infertility, Women & Infants Hospital of Rhode Island, The Warren Alpert Medical School of Brown University, Providence, RI; Genetic Associates, Nashville, TN. OBJECTIVE: To characterize the genetic basis of primary ovarian insufficiency (POI) in a patient with a balanced X-autosomal translocation involving one X chromosome and a deletion at Xq27.2 on the other X chromosome. X-autosomal translocations have been associated with POI, possibly due to aberrations in pairing or X inactivation during folliculogenesis. Additionally, the putative genes leading to POI are located at one of two loci on Xq: POF1 (Xq26-q28) or POF2 (Xq13.3-q22), with the minimal POF1 deletion associated with POI narrowed to a 10.5 Mb region at Xq27.2/Xq27.3-q28. DESIGN: Case report. MATERIALS AND METHODS: 23 year-old with oligomenorrhea and primary infertility. She reported menarche at age 13. After discontinuation of oral contraceptive pills at age 22, she experienced oligomenorrhea and infertility. There was no family history of POI. Her physical exam was unremarkable and showed no stigmata of Turner Syndrome. Relevant laboratory data included: day 3 FSH¼61.2 mIU/mL, day 3 estradiol <20 pg/mL and normal FMR1 premutation testing. RESULTS: Standard karyotype testing (GTG band resolution 550) revealed 46,X,t(X;1)(q22.1;q42.1), indicating a balanced translocation in-
FERTILITY & STERILITYÒ
N
Mean Age
Mean AFC
Age-adjusted Mean AFC
<26 26-30 31-35 36-40
9 188 84 45
36.4 35.3 36.8 37.5
11.9 12.4 12.7 12.3
10.9 12.1 12.7 12.9
41-45 46-50 51-55 56+
15 2 4 1
36.9 39 35.3 33
14.3 8.5 9.7 14.2
14.5 10.3 9.7 14.2
P-value compared with 26-30
Difference in AFC from that predicted by age alone
0.61 0.53 0.53
-1.53 -0.31 0.28 0.41
0.24 0.72 0.51 0.78
1.99 -2.30 -2.73 1.91
CONCLUSION: FMR1 gray zone alleles and premutations are rare in infertile women in the Bay Area, with prevalence comparable to the general population (Cronister 2008). FMR repeat number does not correlate with AFC in this population.
P-97 Tuesday, October 26, 2010 PGD OR NATURAL CONCEPTION? WHAT IS RECOMMENDED FOR COUPLES WITH RECURRENT MISCARRIAGES CAUSED BY TRANSLOCATION CHROMOSOMAL ABERRATIONS? S. Awata, A. Tanaka, M. Nagayoshi, M. Sasaki, I. Tanaka. Saint Mother Hospital, Kitakyushu, Fukuoka, Japan. OBJECTIVE: It has been commonly assumed that preimplantation genetic diagnosis (PGD) for translocations in couples with recurrent miscarriages has
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