Abstract

Transsexualism is an extreme form of gender identity disorder (GID), characterized by the conviction of having been born in the wrong body. Male-to-female (MtF) and female to-male (FtM) transsexuals are characterized by persistent other-sex identification and uneasiness with their assigned gender. It is not possible to identify a single cause for transsexualism, rather, its origin seems to be multifactorial. Some biological studies have shown it is associated with neurodevelopmental processes of the brain, while others imply the involvement of genetic factors. Aim. To investigate the possible influence of the genetic factor on the etiology of transsexualism. Methods. We carried out a cytogenetic and molecular analysis in 442 MtF, 273 FtM, 473 control males and 371 control females. Karyotype was investigated by G-banding and High-Density (HD) Array. The molecular analysis involved a single nucleotide polymorphism CYP17A1 -34T>C, (r2743572) and three variable tandem regions: CA tandem repeats in intron 5 of ERβ, CAG tandem repeats in exon 1 of AR and TTTA tandem repeats in intron 4 of CYP19A1. Genomic DNA was extracted from peripheral blood using the DNeasy Blood & Tissue Kit from Qiagen. The genome-wide DNA copy number analyses were performed with CytoScan™ HD array (Affymetrix) in accordance with the manufacturer's instructions. The samples were whole genome-amplified, fragmented, hybridized, fluorescently tagged and scanned, according to the manufacturer’s protocol. CYP17A1 genotyping was performed by PCR amplification and posterior digestion with MspA1I. The polymorphic regions were amplified by PCR and the fragments analyzed by automated capillary electrophoresis using the 3130 XL Genetic Analyzer from Applied Biosystems. Results. The HD array analysis allowed us to examine the karyotype at molecular level in the transsexual population. Nine MtF transsexuals (2.04%) and 11 (4.03%) from the FtM group were excluded for small pericentromeric inversions, translocations or Klinefelter syndrome, but we were unable to find any karyotypic alteration specific to transsexualism. In accordance with previous data on aneuploidy in transsexual populations, our data show a low incidence of chromosomal abnormalities in the transsexual population, but it is higher than in the general population. With respect to molecular analysis, no significant differences were found regarding either allelic or genotypic distribution of any of the genes examined between the MtF and control male groups. There is no evidence of an association between the genes ERβ, AR, CYP19A1 or CYP17A1 and MtF transsexualism. However, we found that the ERβ is a candidate gen for FtM transsexualism. Conclusions: The analysis by HD arrays did not allow us to find any karyotypic alteration specific to transsexualism, which is in in agreement with earlier reports based on the analysis of the karyotype from G bands. Our data show a low incidence of chromosomal abnormalities in the transsexual population, but it is higher than in the general population. The genes analyzed (CYP17A1, ERβ, AR, and CYP19A1) are not associated with MtF transsexualism, although there is an association between FtM transsexualism and the gen ERβ.