Hum. Reprod. Advance Access originally published online on January 29, 2004
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Human Reproduction, Vol. 19, No. 3, 540-546,
March 2004
© 2004 European Society of Human Reproduction and Embryology
Improved detection of cystic fibrosis mutations in infertility patients with DNA sequence analysis
1 Department of Urology, University of California San Francisco, 1600 Divisadero Street, Box 1695, San Francisco, CA 94143-1695, 2 Genetic Risk Assessment Program, California Pacific Medical Center, 3700 California St G330, San Francisco, CA 94118, and 3 Ambry Genetics Corporation, 2060 Placentia Avenue, Suite A5, Costa Mesa, CA 92627, USA
4 To whom correspondence should be addressed at: Department of Urology, University of California, San Francisco, 1600 Divisadero Street, RmA633, San Francisco, CA 94143-1695, USA. e-mail: pturek{at}urol.ucsf.edu
BACKGROUND: Accurate determination of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is critical for genetic counselling and treatment of obstructive azoospermia. Of concern is that detection rates with routine CFTR mutation panels vary widely depending on patient ancestry; and such panels have limited value for azoospermic patients, who are more likely to carry rare mutations. An alternative approach offers comprehensive, CFTR mutation analysis by a DNA sequence method. We investigated whether this method could improve CFTR detection rates in men with obstructive azoospermia in a prospective study of men with obstructive azoospermia and their partners who were referred for genetic counselling and testing at one of two institutions. METHODS: Sixteen patients with congenital absence of the vas deferens (CAVD, n = 14) or idiopathic obstructive azoospermia (n = 2) were studied. DNA from all patients was analysed for mutations by the DNA sequence method. In addition to this method, six men underwent CFTR analysis by a common 25 or 31 mutation panel coupled with poly T analysis. In 10 subjects, common mutation panel findings were inferred from DNA sequence method results. RESULTS: Overall, 12/16 (75%) azoospermic patients had one or more CFTR mutations and/or 5T alleles, including 12 mutations in 10 patients (two compound heterozygotes) and seven 5T alleles in six patients (one homozygote). The sequence method detected all mutations and three variants of unknown significance. By comparison, the common mutation panels detected only 3/12 mutations (25%) and 0/3 variants. CONCLUSION: The DNA sequence method detects more CFTR mutations than common mutation panels. Given the serious, clinical consequences of transmitting such mutations, this study underscores the importance of accurate, CFTR mutation detection in men with obstructive azoospermia and their partners.
Key words: azoospermia/congenital absence of the vas deferens/cystic fibrosis/genetic testing/male infertility
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