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Array Comparative Genomic Hybridization Profiling Analysis Reveals Deoxyribonucleic Acid Copy Number Variations Associated with Premature Ovarian Failure

Department of Endocrinology (C.D., N.B., B.D., P.B., S.C.-M.), Saint-Antoine Hospital, Centre de Référence des Maladies, Endocriniennes Rares de la Croissance, Assistance Publique-Hôpitaux de Paris, ER9 University Pierre et Marie Curie, 75005 Paris, France; Department of Cytogenetics (A.A.), Robert Debré Hospital, 75019 Paris, France; Department of Genetics and Embryology (M.-F.P.), Armand Trousseau Hospital, 75012 Paris, France; Department of Embryology and Cytogenetics (G.T.), Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 935, and Department of Obstetrics and Gynecology (R.F.), Antoine Béclère Hospital, INSERM U782, University Paris 11, 92140 Clamart, France; Department of Reproductive Endocrinology (D.D.), Jeanne de Flandre Hospital, 59000 Lille, France; Department of Reproductive Medicine and Gynecology (B.F.), University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; and Department of Endocrinology (N.R.-C.), Haut Lévèque Hospital, 33604 Bordeaux, France

Address all correspondence and requests for reprints to: Sophie Christin-Maitre, M.D., Ph.D., Reproductive Endocrine Unit, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France. E-mail: sophie.christin-maitre{at}sat.aphp.fr.

Introduction: Premature ovarian failure (POF) is defined by amenorrhea of at least 4- to 6-month duration, occurring before 40 yr of age, with two FSH levels in the postmenopausal range. Its etiology remains unknown in more than 80% of cases. Standard karyotypes, having a resolution of 5–10 Mb, have identified critical chromosomal regions, mainly located on the long arm of the X chromosome. Array comparative genomic hybridization (a-CGH) analysis is able to detect submicroscopic chromosomal rearrangements with a higher genomic resolution. We searched for copy number variations (CNVs), using a-CGH analysis with a resolution of approximately 0.7 Mb, in a cohort of patients with POF.

Patients and Methods: We prospectively included 99 women. Our study included a conventional karyotype and DNA microarrays comprising 4500 bacterial artificial chromosome clones spread on the entire genome.

Results: Thirty-one CNVs have been observed, three on the X chromosome and 28 on autosomal chromosomes. Data have been compared to control populations obtained from the Database of Genomic Variants (http://projects.tcag.ca/variation). Eight statistically significantly different CNVs have been identified in chromosomal regions 1p21.1, 5p14.3, 5q13.2, 6p25.3, 14q32.33, 16p11.2, 17q12, and Xq28.

Conclusion: We report the first study of CNV analysis in a large cohort of Caucasian POF patients. In the eight statistically significant CNVs we report, we found five genes involved in reproduction, thus representing potential candidate genes in POF. The current study along with emerging information regarding CNVs, as well as data on their potential association with human diseases, emphasizes the importance of assessing CNVs in cohorts of POF women.