American Journal of Medical Genetics 135A:145–149 (2005) Identification of High Frequency of Y Chromosome Deletions in Patients With Sex Chromosome Mosaicism and Correlation With the Clinical Phenotype and Y-Chromosome Instability Philippos C. Patsalis, 1 * Nicos Skordis, 2 Carolina Sismani, 1 Ludmila Kousoulidou, 1 George Koumbaris, 1 Christina Eftychi, 1 George Stavrides, 1 Antonis Ioulianos, 1 Sophia Kitsiou-Tzeli, 3 Angeliki Galla-Voumvouraki, 4 Zoe Kosmaidou, 5 Charalambos G. Hadjiathanasiou, 4 and Ken McElreavey 6 1 Department of Cytogenetics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus 2 Makarios Hospital, Nicosia, Cyprus 3 Athens University, ‘‘Agia Sofia’’ Children’s Hospital, Athens, Greece 4 Athens University, ‘‘P.& A. Kyriakou’’ Children’s Hospital, Athens, Greece 5 Alexandra Hospital, Athens, Greece 6 Institut Pasteur, Paris, France A mosaic karyotype consisting of a 45,X cell line and a second cell line containing a normal or an abnormal Y chromosome is relatively common and is associated with a wide spectrum of clinical phenotypes. The aim of this study was to investi- gate patients with such a mosaic karyotype for Y chromosome material loss and then study the possible association of the absence of these regions with the phenotype, diagnosis, and Y- chromosome instability. We studied 17 clinically well-characterized mosaic patients whose karyo- type consisted of a 45,X cell line and a second cell line containing a normal or an abnormal Y chro- mosome. The presence of the Y chromosome cen- tromere was verified by fluorescence in situ hybridization (FISH) and was then characterized by 44 Y-chromosome specific-sequence tagged site (STS) markers. This study identifies a high fre- quency of Yq chromosome deletions (47%). The deletions extend from interval 5 to 7 sharing a common deleted interval (6F), which overlaps with the azoospermia factor region (AZF) region. This study finds no association between Y-chro- mosome loci hosting genes other than SRY, and the phenotypic sex, the diagnosis, and the pheno- type of the patients. Furthermore, this study shows a possible association of these deletions with Y-chromosome instability. ß 2005 Wiley-Liss, Inc. KEY WORDS: sex chromosome mosaicism; Ullrich–Turner Syndrome; Y deletions; AZF; Y instability INTRODUCTION The Y chromosome contains genes necessary for the differentiation and function of the male gonads [McElreavey et al., 2000]. Several molecular and cytogenetic anomalies of the Y chromosome have been described and are associated with specific clinical characteristics. Loss of Y-chromosome sequences has been detected in men with azoospermia or severe oligospermia leading to the definition of three azoos- permia factor regions (AZF) [Vogt et al., 1996]. About 10%– 12% of phenotypically normal men with idiopathic infertility and a cytogenetically normal Y chromosome carry AZF microdeletions [Krausz et al., 2001]. This region has been mapped to Yq11.22-23 and consists of three subregions called AZFa, AZFb, and AZFc [Vogt et al., 1996]. Other cytogenetically visible Y-chromosome anomalies involve deletions, translocations, rings, supernumerary mar- ker chromosomes (SMC), derivatives, and isochromosomes. Interestingly, most Y-chromosome anomalies have been reported in mosaic form, usually in association with a 45,X cell line [Hsu, 1994; Jaruzelska et al., 2001]. These forms of sex- chromosome mosaicism that is associated with Y-chromosome anomalies are relatively frequent and are associated with a wide spectrum of phenotypes. The phenotypic sex and the clinical diagnosis of these individuals varies from female with Ullrich–Turner syndrome (UTS) to undervirilized male with mixed gonadal dysgenesis (MGD) to a normal virilized male with azoospermia. These patients can exhibit gonadal anoma- lies (MGD, streak gonad(s)) and undervirilization (hypospa- dias, cryptorchidism), and/or have somatic anomalies characteristic of UTS (short stature, cardiac anomalies, etc. [Ogata and Matsuo, 1995]). Very little is known about the association of the various phenotypic characteristics with the presence or absence of Y-chromosomal loci, hosting genes other than SRY. It is also observed that most of the constitutional karyotypes that include Y-chromosome anomalies are mosaics consisting of a 45,X cell line and a second cell line with 46 chromosomes including a Y origin abnormal chromosome [Hsu, 1994]. More recently, Y-chromosome microdeletions have been identified in a small number of such 45,X/46,XY mosaic karyotypes [Patsalis et al., 1997; Yoshida et al., 1997; Oliva et al., 1998; Jaruzelska et al., 2001]. This intriguing data suggests a potential link between Y deletions and the complete loss of the Y chromosome. This study investigated 17 clinically well-characterized patients with sex chromosome mosaicism by FISH and high density STS marker analysis to identify the frequency, size, *Correspondence to: Dr. Philippos C. Patsalis, Head, Depart- ment of Cytogenetics, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683 Nicosia, Cyprus. E-mail: patsalis@cing.ac.cy Received 8 September 2004; Accepted 14 January 2005 DOI 10.1002/ajmg.a.30712 ß 2005 Wiley-Liss, Inc.