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Screening for mutations in the cystic fibrosis transmembrane regulator gene in an infertility clinic
Screening for mutations in the cystic fibrosis transmembrane regulator gene in an infertility clinic In 2001, the American College of Obstetricians and Gynecologists recommended screening for cystic fibrosis mutations in all Caucasian couples who were planning pregnancy or seeking prenatal care. Since 2001 we have offered cystic fibrosis screening to all Caucasian infertility patients. Only 2% of our patients have elected to have mutation screening for cystic fibrosis. (Fertil Steril 2007;88:1687–8. 2007 by American Society for Reproductive Medicine.)
With an incidence of 1 in 2500 to 3500 live births, cystic fibrosis (CF) is the most common life-shortening autosomal recessive disease among populations of Northern European descent (1). The genetic cause of CF is a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which results in thick mucous secretions in many systems of the body. Thus far, more than 1200 mutations in the CFTR gene have been identified, although a single mutation, DF508, accounts for approximately 70% of the mutations in European white patients (2). Although CF has a variable presentation, the majority of those affected with CF suffer from pulmonary disease, gastrointestinal and nutritional abnormalities, and male infertility. With advances made in treating the disease, the median age of survival is approximately 37 years of age (3, 4). The estimated lifetime direct cost of treatment for CF was over $1 million in 2001 (5). Because of the high morbidity and mortality common among those affected with CF, the National Institutes of Health issued a consensus statement in April 1997 recommending that CF carrier screening be offered to adults with a family history of CF, partners of individuals with CF, couples planning a pregnancy, and couples seeking prenatal testing (1). Later, in October 2001 the American College of Obstetricians and Gynecologists (ACOG), in support of recommendations from the American College of Medical Genetics, advised that CF screening be offered to individuals with a family history of CF, reproductive partners of individuals with CF, or couples in whom one or both partners were Ashkenazi Jewish or white and were planning a pregnancy or seeking prenatal care, and that the test be made available to all patients as desired (1). From October 2001 to October 2006, a total of 1028 couples were evaluated for primary or secondary infertility in
Received December 22, 2006; revised and accepted January 11, 2007. Reprint requests: Keith A. Hansen, M.D., Department of Obstetrics and Gynecology, Sanford School of Medicine of the University of South Dakota, 1400 West 22nd Street, Sioux Falls, SD 57105 (FAX: 605-357-1528; E-mail: [email protected]).
0015-0282/07/$32.00 doi:10.1016/j.fertnstert.2007.01.065
our program: 1006 couples were Caucasian, 3 Native American, 7 Asian Indian, 2 African American, 2 Japanese, 2 Egyptian, and 6 Hispanic. The couples all denied having a first-degree or second-degree relative with CF. Following the initial consultation, the patients were offered formal genetic counseling with a genetic counselor. During this nondirective counseling session, a genetic counselor reviewed the patient’s risk of being a CF carrier based on population statistics and family history. The couples were also informed of the residual risk if the mutation testing came back negative for mutations. The counselor would then discuss the screening process and the options of sequential or simultaneous screening for the couple. Twenty-two (2%) of the Caucasian couples had sequential screening for CFTR gene mutations. All of the non-Caucasian patients were made aware of the availability of CFTR gene mutation screening, and none of these couples desired screening. Of the 22 couples sequentially screened, four began by testing the male and 18 by testing the female partner. The four couples where the male was screened had a history of male factor infertility and wanted to screen before deciding on a method of infertility treatment. In the couples where the female was screened, there was a wide variety of diagnoses including male factor infertility. Only one couple out of the 22, had a positive screen for a mutation in the CFTR gene. This couple had male factor infertility, and the male was discovered to be a heterozygote for the R117C mutation. His condition was ultimately diagnosed by cytogenetics as Klinefelter syndrome. The broad purpose of a screening test is to determine which individuals in a population have a condition but are unaware that they have it. For preconception genetic screening, this means detecting individuals who are carriers of mutant alleles that could increase their risk of having a child with a serious genetic illness. For a screening test to be effective, it must be implemented by the population of interest. There are a number of reasons why a screening test may be underused, including cost, lack of benefit from early detection of the condition, high false-positive and false-
Fertility and Sterility Vol. 88, No. 6, December 2007 Copyright ª2007 American Society for Reproductive Medicine, Published by Elsevier Inc.
1687
TABLE 1 Cystic fibrosis mutations tested in genzyme panel. DF311 DF508 DI507 394delTT 406-1G>A 405 þ 1G>A 405 þ 3A>C 444delA 457TAT>G 574delA 621 þ 1G>T 663delT 712-1G>T 711 þ 1G>T 711 þ 5G>A 1078delT 1288insTA 1677delTA 1717-1G>A 1812-1G>A 1898 þ 1G>A 1898 þ 5G>T 1949del84 2043delG 2055del9>A
2105del13ins5 2108delA 2143delT 2183delAA>G 2184delA 2184insA 2307insA 2789 þ 5G>A 2869insG 3120G>A 3120 þ 1G>A 3171delC 3199del6 3659delC 3667del4 3791delC 3849 þ 10kbC>T 3876delA 3905insT 4016insT 935delA 936delTA A455E R347P R709X
R553X R560T R75X R764X S1196X S1251N S1255X S549R S364P S549N A559T C524X CFTR dele2,3 (21kb) D1152H E60X E92X G178R G330X G480C G542X G551D G85E K710X L206W M1101K
N1303K P574H Q1238X Q359K/T360K Q552X Q493X Q890X R1066C R1158X R1162X R117C R117H R334W R347H R352Q T338I V520F W1089X W1204X W1282X Y1092X Y122X
Slostad. Cystic fibrosis screening in infertility. Fertil Steril 2007.
negative rates, low predictive value, or harmful or painful administration. In preconception CF screening programs, the purpose is to determine which parents are heterozygous for the most common mutations in the CFTR gene and at higher risk of having a child with this disease. This screening method does not completely eliminate the over 1200 described mutations in the CFTR gene, but only those of highest frequency in the patient’s population (Table 1). Hence, a patient with a negative screen still has a residual risk of carrying a less frequent or unknown mutation. The couple seeking treatment for infertility offers a unique opportunity to discuss preconception CF screening. When both partners are heterozygous for CF, they can be counseled about donor sperm, donor eggs, donor embryos, preimplantation diagnosis, or prenatal diagnosis. Nonetheless, when screening for CF was made optional in this study, only 2% of patients elected to proceed. The majority of patients who refused to participate noted that the cost of the test ($260) was a major impediment to them. In our opinion, improvements in governmental and insurance reimbursement for genetic services, including screening tests, will result in a significant increase in use of these tests. 1688
Slostad et al.
Correspondence
Jennifer Slostad, B.S.a Quinn P. Stein, M.S., C.G.C.b,c Jason D. Flanagan, M.S.b,c Keith A. Hansen, M.D.b,c a Sanford School of Medicine, Sioux Falls; b Sanford Health/Ob/Gyn Ltd., Sioux Falls; and c Sanford Research/USD, Department of Obstetrics/Gynecology, Sanford School of Medicine at University of South Dakota, and Sioux Valley Hospitals and Health Systems, Sioux Falls, South Dakota
REFERENCES 1. Implementing prenatal screening for cystic fibrosis in routine obstetric practice. Am J Obstet Gynecol 2005;192:527–34. 2. Palomaki GE, Haddow JE, Bradley LA, FitzSimmons SC. Updated assessment of cystic fibrosis mutation frequencies in non-Hispanic Caucasians. Genet Med 2002;4:90–4. 3. Gregg AR, Simpson JL. Genetic screening for cystic fibrosis. Obstet Gynecol Clin North Am 2002;29:329–40. 4. Cystic Fibrosis Foundation. Patient Registry: Annual Data Report 2004. Available at: http://www.cff.org/ID¼4573/TYPE¼2676/2004%20Patient %20Registry%20Report.pdf 5. Prenatal cystic fibrosis screening in Mexican Americans: an economic analysis. Am J Obstet Gynecol 2003;189:769–74.
Vol. 88, No. 6, December 2007
With an incidence of 1 in 2500 to 3500 live births, cystic fibrosis (CF) is the most common life-shortening autosomal recessive disease among populations of Northern European descent (1). The genetic cause of CF is a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which results in thick mucous secretions in many systems of the body. Thus far, more than 1200 mutations in the CFTR gene have been identified, although a single mutation, DF508, accounts for approximately 70% of the mutations in European white patients (2). Although CF has a variable presentation, the majority of those affected with CF suffer from pulmonary disease, gastrointestinal and nutritional abnormalities, and male infertility. With advances made in treating the disease, the median age of survival is approximately 37 years of age (3, 4). The estimated lifetime direct cost of treatment for CF was over $1 million in 2001 (5). Because of the high morbidity and mortality common among those affected with CF, the National Institutes of Health issued a consensus statement in April 1997 recommending that CF carrier screening be offered to adults with a family history of CF, partners of individuals with CF, couples planning a pregnancy, and couples seeking prenatal testing (1). Later, in October 2001 the American College of Obstetricians and Gynecologists (ACOG), in support of recommendations from the American College of Medical Genetics, advised that CF screening be offered to individuals with a family history of CF, reproductive partners of individuals with CF, or couples in whom one or both partners were Ashkenazi Jewish or white and were planning a pregnancy or seeking prenatal care, and that the test be made available to all patients as desired (1). From October 2001 to October 2006, a total of 1028 couples were evaluated for primary or secondary infertility in
Received December 22, 2006; revised and accepted January 11, 2007. Reprint requests: Keith A. Hansen, M.D., Department of Obstetrics and Gynecology, Sanford School of Medicine of the University of South Dakota, 1400 West 22nd Street, Sioux Falls, SD 57105 (FAX: 605-357-1528; E-mail: [email protected]).
0015-0282/07/$32.00 doi:10.1016/j.fertnstert.2007.01.065
our program: 1006 couples were Caucasian, 3 Native American, 7 Asian Indian, 2 African American, 2 Japanese, 2 Egyptian, and 6 Hispanic. The couples all denied having a first-degree or second-degree relative with CF. Following the initial consultation, the patients were offered formal genetic counseling with a genetic counselor. During this nondirective counseling session, a genetic counselor reviewed the patient’s risk of being a CF carrier based on population statistics and family history. The couples were also informed of the residual risk if the mutation testing came back negative for mutations. The counselor would then discuss the screening process and the options of sequential or simultaneous screening for the couple. Twenty-two (2%) of the Caucasian couples had sequential screening for CFTR gene mutations. All of the non-Caucasian patients were made aware of the availability of CFTR gene mutation screening, and none of these couples desired screening. Of the 22 couples sequentially screened, four began by testing the male and 18 by testing the female partner. The four couples where the male was screened had a history of male factor infertility and wanted to screen before deciding on a method of infertility treatment. In the couples where the female was screened, there was a wide variety of diagnoses including male factor infertility. Only one couple out of the 22, had a positive screen for a mutation in the CFTR gene. This couple had male factor infertility, and the male was discovered to be a heterozygote for the R117C mutation. His condition was ultimately diagnosed by cytogenetics as Klinefelter syndrome. The broad purpose of a screening test is to determine which individuals in a population have a condition but are unaware that they have it. For preconception genetic screening, this means detecting individuals who are carriers of mutant alleles that could increase their risk of having a child with a serious genetic illness. For a screening test to be effective, it must be implemented by the population of interest. There are a number of reasons why a screening test may be underused, including cost, lack of benefit from early detection of the condition, high false-positive and false-
Fertility and Sterility Vol. 88, No. 6, December 2007 Copyright ª2007 American Society for Reproductive Medicine, Published by Elsevier Inc.
1687
TABLE 1 Cystic fibrosis mutations tested in genzyme panel. DF311 DF508 DI507 394delTT 406-1G>A 405 þ 1G>A 405 þ 3A>C 444delA 457TAT>G 574delA 621 þ 1G>T 663delT 712-1G>T 711 þ 1G>T 711 þ 5G>A 1078delT 1288insTA 1677delTA 1717-1G>A 1812-1G>A 1898 þ 1G>A 1898 þ 5G>T 1949del84 2043delG 2055del9>A
2105del13ins5 2108delA 2143delT 2183delAA>G 2184delA 2184insA 2307insA 2789 þ 5G>A 2869insG 3120G>A 3120 þ 1G>A 3171delC 3199del6 3659delC 3667del4 3791delC 3849 þ 10kbC>T 3876delA 3905insT 4016insT 935delA 936delTA A455E R347P R709X
R553X R560T R75X R764X S1196X S1251N S1255X S549R S364P S549N A559T C524X CFTR dele2,3 (21kb) D1152H E60X E92X G178R G330X G480C G542X G551D G85E K710X L206W M1101K
N1303K P574H Q1238X Q359K/T360K Q552X Q493X Q890X R1066C R1158X R1162X R117C R117H R334W R347H R352Q T338I V520F W1089X W1204X W1282X Y1092X Y122X
Slostad. Cystic fibrosis screening in infertility. Fertil Steril 2007.
negative rates, low predictive value, or harmful or painful administration. In preconception CF screening programs, the purpose is to determine which parents are heterozygous for the most common mutations in the CFTR gene and at higher risk of having a child with this disease. This screening method does not completely eliminate the over 1200 described mutations in the CFTR gene, but only those of highest frequency in the patient’s population (Table 1). Hence, a patient with a negative screen still has a residual risk of carrying a less frequent or unknown mutation. The couple seeking treatment for infertility offers a unique opportunity to discuss preconception CF screening. When both partners are heterozygous for CF, they can be counseled about donor sperm, donor eggs, donor embryos, preimplantation diagnosis, or prenatal diagnosis. Nonetheless, when screening for CF was made optional in this study, only 2% of patients elected to proceed. The majority of patients who refused to participate noted that the cost of the test ($260) was a major impediment to them. In our opinion, improvements in governmental and insurance reimbursement for genetic services, including screening tests, will result in a significant increase in use of these tests. 1688
Slostad et al.
Correspondence
Jennifer Slostad, B.S.a Quinn P. Stein, M.S., C.G.C.b,c Jason D. Flanagan, M.S.b,c Keith A. Hansen, M.D.b,c a Sanford School of Medicine, Sioux Falls; b Sanford Health/Ob/Gyn Ltd., Sioux Falls; and c Sanford Research/USD, Department of Obstetrics/Gynecology, Sanford School of Medicine at University of South Dakota, and Sioux Valley Hospitals and Health Systems, Sioux Falls, South Dakota
REFERENCES 1. Implementing prenatal screening for cystic fibrosis in routine obstetric practice. Am J Obstet Gynecol 2005;192:527–34. 2. Palomaki GE, Haddow JE, Bradley LA, FitzSimmons SC. Updated assessment of cystic fibrosis mutation frequencies in non-Hispanic Caucasians. Genet Med 2002;4:90–4. 3. Gregg AR, Simpson JL. Genetic screening for cystic fibrosis. Obstet Gynecol Clin North Am 2002;29:329–40. 4. Cystic Fibrosis Foundation. Patient Registry: Annual Data Report 2004. Available at: http://www.cff.org/ID¼4573/TYPE¼2676/2004%20Patient %20Registry%20Report.pdf 5. Prenatal cystic fibrosis screening in Mexican Americans: an economic analysis. Am J Obstet Gynecol 2003;189:769–74.
Vol. 88, No. 6, December 2007