- Email: [email protected]
Cystic fibrosis screening implementation at the University of Michigan
SMFM Abstracts S49 141
142
CYSTIC FIBROSIS SCREENING IMPLEMENTATION AT THE UNIVERSITY OF MICHIGAN KATHLEEN HANLON-LUNDBERG1, SAMUEL BAUER2, RAJANI AATRE-KESHAVAMURTHY2, 1 University of Michigan, Obstetrics & Gynecology, Ann Arbor, Michigan, 2 University of Michigan, Obstetrics and Gynecology, Ann Arbor, Michigan OBJECTIVE: Obstetric patients and providers were educated regarding cystic fibrosis carrier screening (CFCS) based on ACOG/ACMG guidelines. We evaluated uptake of CFCS, impact on obstetric management including incidence of amniocentesis and pregnancy termination, and estimated cost of program implementation. STUDY DESIGN: This prospective cohort study includes pregnant patients and those planning pregnancy who elected CFCS between 3/1/2002 - 2/28/2004. Laboratory records identified cases. Electronic medical records provided correlative demographic and pregnancy outcome data. Ethnicity is selfreported. RESULTS: 1370 patients or couples presented for CFCS (5% preconception, 95% prenatal). 1334 couples without family history of CF were further evaluated. 1215 patients, 47 partners, and 72 couples underwent CFCS. 64/ 1287 patients were CFCS positive: 4 of their partners were positive, 46 were negative, 14 were not tested. 0/47 partners were positive. No amniocenteses were performed due to CFCS. 1135 (85.1%) patients undergoing CFCS were Caucasian, representing 67.7% (5027/7425) of our delivering population. Approximately 22.6% (1135/ 5027) of Caucasian couples chose CFCS. CF carrier rate was 1:19 Caucasians. 10.9% of those screened for CF were from ethnic groups not at high risk. A total of 1376 persons with negative family history had periconceptional CFCS. At $444 per test, laboratory costs equal $610,944. We estimate $3500 direct cost of education and supplies. Cost for the first two years of CFCS: $614,444. Insurance has been paying for most CFCS. CONCLUSION: Cost and benefit of carrier screening for genetic disease is impacted by incidence of carrier status in those choosing to be screened and management decisions of those who screen positive. In our first two years of liberalized CFCS, a minority of ‘‘at risk’’ patients were screened who would not have been offered testing prior to this program. None who screened positive had prenatal diagnosis or pregnancy termination for this indication.
143
CHIMERIC TWINS WITH THE SAME MATERNAL AND DIFFERENT PATERNAL GENETIC CONTRIBUTIONS VIVIENNE SOUTER1, MELISSA PARISI2, DALE NYHOLT3, RAJ KAPUR4, IAN GLASS5, KENT OPHEIM6, GRANT MONTGOMERY3, 1Banner Good Samaritan Hospital, Department of Obstetrics and Gynecology, Phoenix, Arizona, 2 University of Washington, Genetics, Seattle, Washington, 3Queensland Institute of Medical Research, Genetic Epidemiology Laboratory, Brisbane, Queensland, Australia, 4University of Washington, Pathology, Seattle, Washington, 5Seattle Childrens Hospital and Regional Medical Center, Medical Genetics, Seattle, Washington, 6Seattle Childrens Hospital and Regional Medical Center, Department of Laboratories, Seattle, Washington OBJECTIVE: The objective was to investigate a set of twins, one a true hermaphrodite (TH) with ambiguous external genitalia and one a phenotypically normal male. STUDY DESIGN: Each twin was investigated by: histological examination of bilateral gonadal biopsies; karyotyping of peripheral blood lymphocytes and skin fibroblasts; FISH probes for the X and Y chromosomes on touch imprints from gonadal biopsies; and analyzing multiple DNA markers in DNA from blood and skin fibroblasts. RESULTS: Histological examination of bilateral gonadal biopsies showed normal testicular tissue in in the phenotypically normal male twin. In the twin who was a true hermaphrodite the biopsy from the left gonad showed predominantly testicular tissue and that from the right gonad showed predominantly ovarian differentiation. Karyotyping results are shown in Table 1. In DNA from blood the twins were concordant for all DNA markers evaluated. In DNA samples from skin fibroblasts the twins were discordant for 4 of the 10 markers excluding the possibility of monozygosity. Analysis of a further 95 DNA markers showed that the twins shared the same alleles from the mother for all autosomal markers evaluated and for markers on the X chromosome. However, the twins did not share all alleles from the father. CONCLUSION: Molecular genetic studies of these 46,XX/46,XY twins determined them to have a shared maternal genetic contribution and two paternal genetic contributions. The case highlights the existence of twinning events outside of the traditional classification of twins and the need for more research into the etiology and mechanisms of twinning.
144
Table 1
Peripheral lymphocytes Skin fibroblasts Touch imprints from right gonad Touch imprints from left gonad
Twin with Ambiguous Genitalia
Phenotypically Normal Male
46,XX[60%]/46,XY[40%] 46,XX[95%]/46,XY[5%] XX[42%]/XY[57%]/X[1%]
46,XX[57%]/46,XY[43%] 46,XX[45%]/46,XY[55%] XX[8%]/XY[77%]/X[15%]
XX[35%]/XY[55%]/X[10%]
XX[31%]/XY[59%]/X[9%]
INHERITED THROMBOPHILIAS AND SEVERE PREGNANCY COMPLICATIONS: A STRUCTURED REVIEW TIFFANEE LENZI1, KRISTIE KEETON1, MARK CHAMES1, SCOTT RANSOM2, ELLEN MOZURKEWICH1, 1University of Michigan, Obstetrics & Gynecology, Ann Arbor, Michigan, 2University of Michigan, Obstetrics, Gynecology, Health Management and Policy, Ann Arbor, Michigan OBJECTIVE: To evaluate the association between inherited thrombophilias and severe pregnancy complications. STUDY DESIGN: We searched Medline and PubMed from the year 1966 to July 2004 with key words ‘‘thrombophilia’’ and ‘‘pregnancy’’ and all subheadings. Case-control studies that reported pregnancy complications of severe preeclampsia (PE), abruption, intrauterine growth restriction (IUGR) and intrauterine fetal demise (IUFD) were selected. Exposures of interest were the inherited thrombophilias: Factor V Leiden mutation (FVL), the prothrombin gene mutation G20210A (PT), homozygosity for the methylenetetrahydrofolate reductase mutation (MTHFR) and protein S deficiency. Pooled odds ratio and 95% confidence intervals were generated using a fixed effects model with RevMan software. RESULTS: 99 articles were extracted, of which 52 with 12,495 participants met inclusion criteria. The FVL mutation was significantly associated with severe PE, abruption, IUGR and IUFD. The PT mutation was significantly associated with abruption, IUGR and IUFD. Deficiency of protein S was significantly associated with severe PE, IUGR and IUFD. Homozygosity for MTHFR was not significantly associated with any pregnancy complication. (Table I). CONCLUSION: The inherited thrombophilias FVL, PT mutation and protein S deficiency are associated with severe pregnancy complications. Pooled odds ratios with 95% CI FVL Severe PE Abruption IUGR IUFD
2.90 2.80 1.98 3.38
PT (2.12,3.96) (1.89,4.13) (1.39,2.63) (2.20,5.19)
1.94 8.14 2.32 2.27
MTHFR (0.98,3.85) (3.90,17.0) (1.47,3.65) (1.28,4.02)
1.21 1.07 1.23 1.34
Protein S deficiency
(0.92,1.60) 3.08 (0.37,3.14) 2.11 (0.93,1.62) 3.07 (0.99,1.81) 20.43
(1.09,8.68) (0.47,9.34) (1.05,8.97) (3.77,111)
DOCUMENTATION OF GENOTYPIC AND ALLELIC FREQUENCY VARIATIONS IN TNF RECEPTOR 1 LOCI BETWEEN ETHNIC GROUPS RAMKUMAR MENON1, DIGNA ROSA VELEZ2, SCOTT WILLIAMS3, STEPHEN FORTUNATO4, 1Perinatal Research Center, Nashville, Tennessee, 2Vanderbilt University, Department of Molecular Physiology and Biophysics, Nashville, Tennessee, 3Vanderbilt University, Medicine, Nashville, Tennessee, 4The Perinatal Research Center, Maternl-Fetal Medicine, Nashville, Tennessee OBJECTIVE: We have reported an imbalance in the concentration of TNF and its soluble TNF receptors (sTNFRs -which neutralize TNF function) in response to an infectious stimulus in African Americans (AA) compared to Caucasians (C). The ligand-soluble receptor function is more balanced in C than in AA. This imbalance in AA can translate into overwhelming TNF bioactivity, which may explain the higher rate of prematurity among AA. We hypothesize that genetic polymorphisms in TNF and TNF receptor genes contribute to this disparity. Herein we examine the genotypic and allelic frequency variations in TNF Receptor 1 Loci in the DNA samples from maternal blood and (MB) and cord blood (CB). STUDY DESIGN: In our study, women with delivery at term (controls- term) and women with spontaneous preterm delivery (cases-PTD; below 36 weeks of gestation) were recruited. Genotyping was done using Taqman assays for SNPs in the TNFR1ngene (C17692T, A15228G, A4204G, C-7294G, chromosomal location 6,317,783). Tests for allelic and genotypic were performed using TFPGA and RxC statistical software, respectively. RESULTS: A total of 682 DNA samples were collected (cases in brackets) (MB (n = 339; AA = 113[17], C = 226[39]) and CB (n = 343; AA = 116[17], C = 227[37]). For sites A15228G, A4204G, and 6,317,783 the two ethnic groups differed for all allelic and genotypic comparisons (Total sample, Term and PTD for CB and MB). At C17692T C and AA differed except for the PTD comparisons. There were no differences at significant ethnic differences for C-7294G. CONCLUSION: In this case-control study, significant differences in the genotypic and allelic frequencies were observed in many of SNPs studied on TNFR1 gene. Preliminary analysis comparing cases and controls within an ethnic group suggest that there may be both allelic and genotypic association with PTD at site -7294 in C populations. This difference in the genotypic and allelic frequencies may explain the phenotypic variation (in the concentration of sTNFRs) observed in our earlier reported studies.
142
CYSTIC FIBROSIS SCREENING IMPLEMENTATION AT THE UNIVERSITY OF MICHIGAN KATHLEEN HANLON-LUNDBERG1, SAMUEL BAUER2, RAJANI AATRE-KESHAVAMURTHY2, 1 University of Michigan, Obstetrics & Gynecology, Ann Arbor, Michigan, 2 University of Michigan, Obstetrics and Gynecology, Ann Arbor, Michigan OBJECTIVE: Obstetric patients and providers were educated regarding cystic fibrosis carrier screening (CFCS) based on ACOG/ACMG guidelines. We evaluated uptake of CFCS, impact on obstetric management including incidence of amniocentesis and pregnancy termination, and estimated cost of program implementation. STUDY DESIGN: This prospective cohort study includes pregnant patients and those planning pregnancy who elected CFCS between 3/1/2002 - 2/28/2004. Laboratory records identified cases. Electronic medical records provided correlative demographic and pregnancy outcome data. Ethnicity is selfreported. RESULTS: 1370 patients or couples presented for CFCS (5% preconception, 95% prenatal). 1334 couples without family history of CF were further evaluated. 1215 patients, 47 partners, and 72 couples underwent CFCS. 64/ 1287 patients were CFCS positive: 4 of their partners were positive, 46 were negative, 14 were not tested. 0/47 partners were positive. No amniocenteses were performed due to CFCS. 1135 (85.1%) patients undergoing CFCS were Caucasian, representing 67.7% (5027/7425) of our delivering population. Approximately 22.6% (1135/ 5027) of Caucasian couples chose CFCS. CF carrier rate was 1:19 Caucasians. 10.9% of those screened for CF were from ethnic groups not at high risk. A total of 1376 persons with negative family history had periconceptional CFCS. At $444 per test, laboratory costs equal $610,944. We estimate $3500 direct cost of education and supplies. Cost for the first two years of CFCS: $614,444. Insurance has been paying for most CFCS. CONCLUSION: Cost and benefit of carrier screening for genetic disease is impacted by incidence of carrier status in those choosing to be screened and management decisions of those who screen positive. In our first two years of liberalized CFCS, a minority of ‘‘at risk’’ patients were screened who would not have been offered testing prior to this program. None who screened positive had prenatal diagnosis or pregnancy termination for this indication.
143
CHIMERIC TWINS WITH THE SAME MATERNAL AND DIFFERENT PATERNAL GENETIC CONTRIBUTIONS VIVIENNE SOUTER1, MELISSA PARISI2, DALE NYHOLT3, RAJ KAPUR4, IAN GLASS5, KENT OPHEIM6, GRANT MONTGOMERY3, 1Banner Good Samaritan Hospital, Department of Obstetrics and Gynecology, Phoenix, Arizona, 2 University of Washington, Genetics, Seattle, Washington, 3Queensland Institute of Medical Research, Genetic Epidemiology Laboratory, Brisbane, Queensland, Australia, 4University of Washington, Pathology, Seattle, Washington, 5Seattle Childrens Hospital and Regional Medical Center, Medical Genetics, Seattle, Washington, 6Seattle Childrens Hospital and Regional Medical Center, Department of Laboratories, Seattle, Washington OBJECTIVE: The objective was to investigate a set of twins, one a true hermaphrodite (TH) with ambiguous external genitalia and one a phenotypically normal male. STUDY DESIGN: Each twin was investigated by: histological examination of bilateral gonadal biopsies; karyotyping of peripheral blood lymphocytes and skin fibroblasts; FISH probes for the X and Y chromosomes on touch imprints from gonadal biopsies; and analyzing multiple DNA markers in DNA from blood and skin fibroblasts. RESULTS: Histological examination of bilateral gonadal biopsies showed normal testicular tissue in in the phenotypically normal male twin. In the twin who was a true hermaphrodite the biopsy from the left gonad showed predominantly testicular tissue and that from the right gonad showed predominantly ovarian differentiation. Karyotyping results are shown in Table 1. In DNA from blood the twins were concordant for all DNA markers evaluated. In DNA samples from skin fibroblasts the twins were discordant for 4 of the 10 markers excluding the possibility of monozygosity. Analysis of a further 95 DNA markers showed that the twins shared the same alleles from the mother for all autosomal markers evaluated and for markers on the X chromosome. However, the twins did not share all alleles from the father. CONCLUSION: Molecular genetic studies of these 46,XX/46,XY twins determined them to have a shared maternal genetic contribution and two paternal genetic contributions. The case highlights the existence of twinning events outside of the traditional classification of twins and the need for more research into the etiology and mechanisms of twinning.
144
Table 1
Peripheral lymphocytes Skin fibroblasts Touch imprints from right gonad Touch imprints from left gonad
Twin with Ambiguous Genitalia
Phenotypically Normal Male
46,XX[60%]/46,XY[40%] 46,XX[95%]/46,XY[5%] XX[42%]/XY[57%]/X[1%]
46,XX[57%]/46,XY[43%] 46,XX[45%]/46,XY[55%] XX[8%]/XY[77%]/X[15%]
XX[35%]/XY[55%]/X[10%]
XX[31%]/XY[59%]/X[9%]
INHERITED THROMBOPHILIAS AND SEVERE PREGNANCY COMPLICATIONS: A STRUCTURED REVIEW TIFFANEE LENZI1, KRISTIE KEETON1, MARK CHAMES1, SCOTT RANSOM2, ELLEN MOZURKEWICH1, 1University of Michigan, Obstetrics & Gynecology, Ann Arbor, Michigan, 2University of Michigan, Obstetrics, Gynecology, Health Management and Policy, Ann Arbor, Michigan OBJECTIVE: To evaluate the association between inherited thrombophilias and severe pregnancy complications. STUDY DESIGN: We searched Medline and PubMed from the year 1966 to July 2004 with key words ‘‘thrombophilia’’ and ‘‘pregnancy’’ and all subheadings. Case-control studies that reported pregnancy complications of severe preeclampsia (PE), abruption, intrauterine growth restriction (IUGR) and intrauterine fetal demise (IUFD) were selected. Exposures of interest were the inherited thrombophilias: Factor V Leiden mutation (FVL), the prothrombin gene mutation G20210A (PT), homozygosity for the methylenetetrahydrofolate reductase mutation (MTHFR) and protein S deficiency. Pooled odds ratio and 95% confidence intervals were generated using a fixed effects model with RevMan software. RESULTS: 99 articles were extracted, of which 52 with 12,495 participants met inclusion criteria. The FVL mutation was significantly associated with severe PE, abruption, IUGR and IUFD. The PT mutation was significantly associated with abruption, IUGR and IUFD. Deficiency of protein S was significantly associated with severe PE, IUGR and IUFD. Homozygosity for MTHFR was not significantly associated with any pregnancy complication. (Table I). CONCLUSION: The inherited thrombophilias FVL, PT mutation and protein S deficiency are associated with severe pregnancy complications. Pooled odds ratios with 95% CI FVL Severe PE Abruption IUGR IUFD
2.90 2.80 1.98 3.38
PT (2.12,3.96) (1.89,4.13) (1.39,2.63) (2.20,5.19)
1.94 8.14 2.32 2.27
MTHFR (0.98,3.85) (3.90,17.0) (1.47,3.65) (1.28,4.02)
1.21 1.07 1.23 1.34
Protein S deficiency
(0.92,1.60) 3.08 (0.37,3.14) 2.11 (0.93,1.62) 3.07 (0.99,1.81) 20.43
(1.09,8.68) (0.47,9.34) (1.05,8.97) (3.77,111)
DOCUMENTATION OF GENOTYPIC AND ALLELIC FREQUENCY VARIATIONS IN TNF RECEPTOR 1 LOCI BETWEEN ETHNIC GROUPS RAMKUMAR MENON1, DIGNA ROSA VELEZ2, SCOTT WILLIAMS3, STEPHEN FORTUNATO4, 1Perinatal Research Center, Nashville, Tennessee, 2Vanderbilt University, Department of Molecular Physiology and Biophysics, Nashville, Tennessee, 3Vanderbilt University, Medicine, Nashville, Tennessee, 4The Perinatal Research Center, Maternl-Fetal Medicine, Nashville, Tennessee OBJECTIVE: We have reported an imbalance in the concentration of TNF and its soluble TNF receptors (sTNFRs -which neutralize TNF function) in response to an infectious stimulus in African Americans (AA) compared to Caucasians (C). The ligand-soluble receptor function is more balanced in C than in AA. This imbalance in AA can translate into overwhelming TNF bioactivity, which may explain the higher rate of prematurity among AA. We hypothesize that genetic polymorphisms in TNF and TNF receptor genes contribute to this disparity. Herein we examine the genotypic and allelic frequency variations in TNF Receptor 1 Loci in the DNA samples from maternal blood and (MB) and cord blood (CB). STUDY DESIGN: In our study, women with delivery at term (controls- term) and women with spontaneous preterm delivery (cases-PTD; below 36 weeks of gestation) were recruited. Genotyping was done using Taqman assays for SNPs in the TNFR1ngene (C17692T, A15228G, A4204G, C-7294G, chromosomal location 6,317,783). Tests for allelic and genotypic were performed using TFPGA and RxC statistical software, respectively. RESULTS: A total of 682 DNA samples were collected (cases in brackets) (MB (n = 339; AA = 113[17], C = 226[39]) and CB (n = 343; AA = 116[17], C = 227[37]). For sites A15228G, A4204G, and 6,317,783 the two ethnic groups differed for all allelic and genotypic comparisons (Total sample, Term and PTD for CB and MB). At C17692T C and AA differed except for the PTD comparisons. There were no differences at significant ethnic differences for C-7294G. CONCLUSION: In this case-control study, significant differences in the genotypic and allelic frequencies were observed in many of SNPs studied on TNFR1 gene. Preliminary analysis comparing cases and controls within an ethnic group suggest that there may be both allelic and genotypic association with PTD at site -7294 in C populations. This difference in the genotypic and allelic frequencies may explain the phenotypic variation (in the concentration of sTNFRs) observed in our earlier reported studies.