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Molecular and Clinical Characterization of Y Chromosome Microdeletions in Infertile Men: A 10-Year Experience in Italy

Department of Histology, Microbiology and Medical Biotechnologies (A.F., B.A., E.S., C.C., R.S., A.G., C.F.), Centre for Male Gamete Cryopreservation, University of Padova, 35121 Padova, Italy; and Department of Medical Pathophysiology (A.L.), University of Rome "La Sapienza," 00100 Rome, Italy

Address all correspondence and requests for reprints to: Professor Carlo Foresta, University of Padova, Department of Histology, Microbiology and Medical Biotechnologies, Centre for Male Gamete Cryopreservation, Via Gabelli, 63, 35121 Padova, Italy. E-mail: carlo.foresta{at}unipd.it.

Context: An explosive growth in Y chromosome long arm (Yq) microdeletion testing demand for male infertility occurred in the past few years. However, despite the progresses in the biology of this chromosome, a number of molecular and clinical concerns are not supported by definitive data.

Objective: The objective was to provide information on the type and prevalence of microdeletions in infertile males, indication for testing, genotype-phenotype correlation, sperm aneuploidies, and genetic counseling.

Design and Setting: We performed a prospective study from January 1996 to December 2005 in an academic clinic.

Patients: We studied 3073 consecutive infertile men, of which 625 were affected by nonobstructive azoospermia and 1372 were affected by severe oligozoospermia. Ninety-nine patients with microdeletions are described here.

Main Outcome Measures: Yq microdeletions, seminal analysis, reproductive hormones, testicular cytology/histology, and sperm sex chromosomes aneuploidies were used as outcome measures.

Results: The prevalence of microdeletions was 3.2% in unselected infertile men, 8.3% in men with nonobstructive azoospermia, and 5.5% in men with severe oligozoospermia. Only 2 of 99 deletions were found in men with more than 2 million sperm/ml. No clinical data are useful to identify a priori patients with higher risk of Yq microdeletions. Most deletions are of the AZFc-b2/b4 subtype and are associated with variable spermatogenic phenotype, with sperm present in 72% of the cases. Complete AZFa and AZFb (P5/Proximal P1) deletions are associated with Sertoli cell-only syndrome and alterations in spermatocyte maturation, respectively, whereas partial deletions in these regions are associated with milder phenotype and frequent presence of sperm. Men with AZFc-b2/b4 deletions produce a higher percentage of sperm with nullisomy for the sex chromosomes and XY-disomy.

Conclusions: This extensive clinical research expands the knowledge on genotype-phenotype relationships and confirms that the identification of Yq microdeletions has significant diagnostic and prognostic value, adding useful information for genetic counseling in these patients.

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