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To search for disease-related copy number variations (CNVs) in families with a high frequency of germ cell tumours (GCT), we analysed 16 individuals from four families by array comparative genomic hybridization (aCGH) and applied an integrative systems biology algorithm that prioritizes risk-associated genes among loci targeted by CNVs. The top-ranked candidate, RLN1, encoding a Relaxin-H1 peptide, although only detected in one of the families, was selected for further investigations. Validation of the CNV at the RLN1 locus was performed as an association study using qPCR with 106 sporadic testicular GCT patients and 200 healthy controls. Observed CNV frequencies of 1.9% among cases and 1.5% amongst controls were not significantly different and this was further confirmed by CNV data extracted from a genome-wide analysis of 189 cases and 380 controls, where similar frequencies of 2.2% were observed in both groups (p = 1). Immunohistochemistry for Relaxin-H1 (RLN1), Relaxin- H2 (RLN2) and their cognate receptor, RXFP1, detected one, and in some cases both, of the relaxins in Leydig cells, Sertoli cells and a subset of neoplastic germ cells, whereas the receptor was present in Leydig cells and spermatids. Collectively, the findings show that a heterozygous loss at the RLN1 locus is not a genetic factor mediating high population-wide risk for testicular germ cell tumour, but do not exclude a contribution of this aberration in some cases of cancer. The preliminary expression data suggest a possible role of the relaxin peptides in spermatogenesis and warrant further studies. [ABSTRACT FROM AUTHOR]