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Absence of de novo Y-chromosome microdeletions in male children conceived through intracytoplasmic sperm injection

Absence of de novo Y-chromosome microdeletions in male children conceived through intracytoplasmic sperm injection
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  Absence of de novo Y-chromosome microdeletionsin male children conceived through intracytoplasmicsperm injection Molecular screening for Y-chromosome microdeletions in 96 Spanish male children conceived throughintracytoplasmic sperm injection (ICSI) was conducted. No microdeletions were detected; these resultssupport the notion that de novo Y-chromosome alterations are rare and unrelated to the ICSI technique itself.(Fertil Steril   2004;82:1679–80. ©2004 by American Society for Reproductive Medicine.)Since the first observation of microscopic deletions of the long arm of Y chromosome in subfertile men,considerable interest has been shown in identifying Y-linked genes involved in male gametogenesis and infertility(1).Forthisreason,anintensemolecularanalysisofsubfertilementofindYqalterationshasbeenperformed.These investigations have led to the identification of different chromosomal regions containing independent loci relatedto male gametogenesis and azoospermia (azoospermia factors, or AZFs). Specifically, at least three nonoverlappingregions of Yq (called AZFa, AZFb, and AZFc) have been firmly related to male infertility (2). Consequently, moleculardiagnosisofY-chromosomemicrodeletionsisnowavailableandroutinelyindicatedinsubfertilepatientswith low sperm concentrations (  5  10 6  /mL). In addition, Yq screening is also indicated in all individuals whoare candidates for intracytoplasmic sperm injection (ICSI) techniques (3). The ICSI technique has been widely used in reproductive medicine since 1991. However, concerns about thesafety and genetic consequences of this reproductive method have been expressed (4). Several research groups are investigating the genetic consequences of ICSI. Previous reports have detected a slight increase of chromosomalaberrations, mainly in the sexual chromosomes, in children born after ICSI. In addition, at least two independentresearch groups have investigated the rate of Y-chromosome microdeletions in male children conceived throughICSI (4, 5). Kent-First et al. (4) analyzed the incidence of Y-chromosome microdeletions in 35 male children born after ICSI. Interestingly, they found two infants with Y chromosome microdeletions undetected in the peripheral bloodoftheirrespectivefathers.Theysuggestedthatthesemicrodeletionscouldbeinheritedfrominfertilefathers’mosaicfor intact Y and microdeleted Y chromosomes. Finally, the group claimed that mosaicism might be a factor inmale-related infertility and that somatic cell lineages might be not always by a direct reflection of the germ celllineage (4). Tochecktheseobservations,Crametal.(5)carriedoutaY-chromosomeanalysisofinfertilemenandtheirmale children conceived through ICSI. Using a larger sample size of male children conceived through ICSI (n  99),they did not observe de novo deletions at any time (5). The research group led by David Cram concluded that these events are rare after ICSI in men with both idiopathic seminiferous tubule failure and other common male factorindications. They believed it was necessary to collect more data to reach a final conclusion regarding the incidenceof apparent de novo Y-chromosome microdeletions in children conceived through ICSI (5). To add new and independent data to these controversial results, we conducted a molecular screening of Ychromosome microdeletions in 96 male children of Spanish men, conceived through ICSI. Here we present newdata regarding the integrity of the Y chromosome in these 96 male children.The referral center for this research was the Unidad de Reproducción at Gutenberg Centre (Málaga, Spain). Atotal of 96 children conceived through ICSI were recruited. This sample size represents all male children conceivedthrough ICSI born in our center between 1996 and 2000 whose parents consented to participate in the research. Wehave divided these subjects into two groups, according to seminal analyses of their fathers. Group A consisted of 46 male children of men with severe oligospermia (  5  10 6  /mL) or nonobstructive azoospermia. In the fathersof group A, the prevalence of Y-chromosome microdeletions was 2 of 39 (5.1%). Group B consisted of 50 malechildren of men with moderate oligospermia, normal seminal analysis, obstructive azoospermia, or cryptorchidism.No Y-chromosome microdeletions were detected in fathers of group B. Written informed consent was obtainedfrom all patients included in the present study. Deoxyribonucleic acid banking and genetic tests included in thisstudy complied with the international regulations regarding collection, treatment, storage and use of genetic data(International Bioethics Committee, UNESCO SHS-503/2001/CIB-8/3). Received March 16, 2004;revised and accepted June22, 2004.Supported by theMinisterio de Ciencia yTecnología (FIT-010000-2003-70, FIT-010000-2003-89, and PTQ-2002-0206).Reprint requests: AgustínRuiz, M.D., Ph.D.,Departamento de GenómicaEstructural, Neocodex,Edificio Acrópolis Módulos110-111, Crta. Nacional IV,Km 536, Seville 41020,Spain (FAX: 34-955-047325;E-mail: CORRESPONDENCE FERTILITY AND STERILITY  VOL. 82, NO. 6, DECEMBER 2004 Copyright ©2004 American Society for Reproductive MedicinePublished by Elsevier Inc.Printed on acid-free paper in U.S.A. 0015-0282/04/$30.00doi:10.1016/j.fertnstert.2004.06.039 1679  Y-chromosome microdeletion screening was performed accordingto a real-time polymerase chain reaction–based protocol previouslyreported by us (1). This method is fast and reliable and permits the scanning of DNA from one patient per hour, minimizing the risk of cross-contamination and false-positive and false-negative results (1). Using this new technology, we were unable to detect any Y chromo-some microdeletions in our cohort of male children conceived throughICSI. This result supports the notion that de novo Y-chromosomemicrodeletions are rare and unrelated to the ICSI technique itself. Ourdata are in accordance with the work previously published by Cram etal. (5). Moreover, our sample size of ICSI-conceived male children of  men with sperm counts  5  10 6  /mL (n  46) is the largest reportedto date. In fact, Cram et al. (5) only reported the results in 27 ICSI- conceived male children of men with severe oligospermia or azoosper-mia phenotype, whereas Kent-First et al. (4) reported the results in 35 ICSI-conceived male children.By considering the results obtained together, it seems evident thatthe rate of de novo or mosaic-related Y chromosome microdeletions inchildren conceived through ICSI must be low. However, further stud-ies are needed to determine whether there really is a differential risk between the ICSI-conceived male children of severe oligozoospermic/ azoospermic patients and those of healthy male patients regarding Ychromosome integrity or other specific genetic alterations.  Acknowledgments:  The authors thank the patients for participation in thisstudy, and Carmen Segura, Inmaculada Calcedo, Inmaculada Medina, Al-berto Flores, José Félix García-España, and Juan José Sanchez for patientand sample management. Belén Buch, M.S. a José Jorge Galán, M.S. b Miguel Lara, M.S. a Luis Miguel Real, Ph.D. b Manuel Martínez-Moya, M.D. a Agustín Ruiz, M.D., Ph.D. b Unidad de Reproducción, a Centro Gutenberg, Málaga, Spain;and Departamento de Genómica Estructural, b  Neocodex,Seville, Spain References 1. Buch B, Galan JJ, Lara M, Ruiz R, Segura C, Real LM, et al.Scanning of Y-chromosome azoospermia factors loci using real-timepolymerase chain reaction and melting curve analysis. Fertil Steril2003;80:907–13.2. Vogt PH, Edelmann A, Kirsch S, Henegariu O, Hirschmann P,Kiesewetter F, et al. Human Y chromosome azoospermia factors(AZF) mapped to different subregions in Yq11. Hum Mol Genet1996;5:933–43.3. Simoni M, Kamischke A, Nieschlag E. Current status of the moleculardiagnosis of Y-chromosomal microdeletions in the work-up of maleinfertility. Initiative for international quality control. Hum Reprod 1998;13:1764–8.4. Kent-First MG, Kol S, Muallem A, Ofir R, Manor D, Blazer S, et al. Theincidence and possible relevance of Y-linked microdeletions in babiesborn after intracytoplasmic sperm injection and their infertile fathers.Mol Hum Reprod 1996;2:943–50.5. Cram DS, Ma K, Bhasin S, Arias J, Pandjaitan M, Chu B, et al. Ychromosome analysis of infertile men and their sons conceivedthrough intracytoplasmic sperm injection: vertical transmission of deletions and rarity of de novo deletions. Fertil Steril 2000;74:909–15. 1680  Buch et al.  Correspondence Vol. 82, No. 6, December 2004
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