American Journal of Medical Genetics 123A:79–83 (2003) Reciprocal Translocation Associated With Multiple Exostoses in Seven Members of a Three Generation Family and Discovered Through an Infertile Male Tiziano Pramparo, 1 Giuliana Gregato, 1 Manuela De Gregori, 1 Alessandra Friso, 2 Maurizio Clementi, 2 Patrizia Ardenghi, 2 Mariano Rocchi, 3 Orsetta Zuffardi, 1,4 and Romano Tenconi 2 * 1 Biologia Generale e Genetica Medica, University of Pavia, Pavia, Italy 2 Genetica Clinica, University of Padova, Padova, Italy 3 Sezione di Genetica, DAPEG, University of Bari, Bari, Italy 4 IRCCS Policlinico San Matteo, Pavia, Italy We report a four generations family with multiple exostoses segregating with a reci- procal translocation t(8;19)(q24.11;q13.13) in 8 members of three generations. FISH investigations detected a breakage of the dosage-sensitive EXT1 gene. Although three members of the family died perinatally from unknown causes and one carrier had four spontaneous abortions, the translocation was discovered only when the cytogenetic analysis was requested in an affected male because of oligozoospermia. In fact, it is well known that infertile males may be carriers of reciprocal or Robertsonian translocations with a higher frequency than the general population. This family stresses the impor- tance of requesting the cytogenetic analysis in all cases in which a dominant disease segregates with repeated miscarriages and/ or newborn deaths of unknown cause. ß 2003 Wiley-Liss, Inc. KEY WORDS: multiple exostoses; recipro- cal translocations; EXT1 INTRODUCTION Reciprocal translocations associated with autosomal- dominant or X-linked phenotypes have been instru- mental in the identification of many disease genes [Bugge et al., 2000]. The breakage of one or both chro- mosomes can cause loss of function phenotypes by disrupting the coding sequence of dosage-sensitive genes (see for example, elastin and supravalvular aortic stenosis: [Curran et al., 1993]) or by separating the genes from the nearby regulatory sequences (see for example, SOX9 and campomelic dwarfism: [Pfeifer et al., 1999]). Alternatively, the translocation may cause gain of function phenotypes by switching the regulatory sequences from one gene to another, thus leading to inappropriate expression or by producing a chimeric gene coding for a new chimeric protein. This is a common mechanism leading to tumor processes in leukemias, lymphomas and sarcomas [for a review, see Rego and Pandolfi, 2002]. In other cases one of the breakpoints of the chromosomes involved in the re- ciprocal translocation lose submicroscopic portions containing dosage-sensitive gene(s). See, for example, SOX2 and anophthalmia: Fantes et al., 2003. We report a translocation associated with multiple exostoses. Hereditary multiple exostoses (HME) is an autosomal dominant fully penetrant disorder characterized by multiple cartilaginous excrescenses (exostoses) devel- oping from the diaphyseal ends of the long bones. In a few percent of cases, exostoses may degenerate into chondrosarcomas [Hennekam, 1991]. Two main loci have been associated with HME, EXT1 (OMIM *133700) that have been mapped to chromosome 8q23-24 15 and EXT2 (OMIM *133701) mapped to chromosome 11p11- 12 16; a third minor locus has been mapped to chro- mosome 19p (OMIM *600209). Multiple exostoses are also part of the Langer-Giedion contiguous gene syn- drome (OMIM #150230) associated with a 2 Mb deletion in 8q24.1 including TRPS1 and EXT1 and characterized by bulbous nose, sparse hair, mental retardation, microcephaly, and multiple exostoses. Patients with isolated multiple exostoses showed predominantly (70 – 90%) mutations over two genes, EXT1 and EXT2 [Legeai-Mallet et al., 1997, Wuyts and Van Hul, 2000; Francannet et al., 2001], encoding endoplasmic reticu- lum-localized transmembrane glycoprotein associated Grant sponsor: cofin02-MIUR (to O.Z.); Grant sponsor: Italian Telethon Foundation (to O.Z.); Grant number: GP0247Y01. *Correspondence to: Dr. Romano Tenconi, Department of Pediatrics, Genetica Clinica ed Epidemiologica, University of Padova, Italy. E-mail: romano.tenconi@unipd.it Received 11 July 2003; Accepted 14 July 2003 DOI 10.1002/ajmg.a.20498 ß 2003 Wiley-Liss, Inc.