Disorders of Sex Development : Clinical outcomes, (epi)genetic regulation and germ cell cancer

__Abstract__ One of the most fundamental aspects of early human development is establishment of sex, which can be defined as the biological qualities that differentiate between male and female. The process of normal sex development is strictly controlled by functionality of a number of genes, both protein encoding- and noncoding-, in which the existing networks can act both on transcription (formation of RNA) and translation (formation of protein) regulation. Sexually dimorphic development of the reproductive system is the result of three sequential processes: chromosomal sex, formation and subsequent differentiation of the bipotential gonad into either testis or ovary (referred to as sex determination), and finally sex-specific development of the reproductive tracts and external genitalia under influence of hormones produced by the gonads (referred to as sex differentiation)

DMRforPairs: Identifying Differentially Methylated Regions between unique samples using array based methylation profiles

Background: Array based methylation profiling is a cost-effective solution to study the association between genome methylation and human disease & development. Available tools to analyze the Illumina Infinium HumanMethylation450 BeadChip focus on comparing methylation levels per locus. Other tools combine multiple probes into a range, identifying differential methylated regions (DMRs). These tools all require groups of samples to compare. However, comparison of unique, individual samples is essential in situations where larger sample sizes are not possible.Results: DMRforPairs was designed to compare regional methylation status between unique samples. It identifies probe dense genomic regions and quantifies/tests their (difference in) methylation level between the samples. As a proof of concept, DMRforPairs is applied to public data from four human cell lines: two lymphoblastoid cell lines from healthy individuals and the cancer cell lines A431 and MCF7 (including 2 technical replicates each). DMRforPairs identified an increasing number of DMRs related to the sample phenotype when biological similarity of the samples decreased. DMRs identified by DMRforPairs were related to the biological origin of the cell lines.Conclusion: To our knowledge, DMRforPairs is the first tool to identify and visualize relevant and significant differentially methylated regions between unique samples

A 46,XY female DSD patient with bilateral gonadoblastoma, a novel SRY missense mutation combined with a WT1 KTS splice-site mutation

Patients with Disorders of Sex Development (DSD), especially those with gonadal dysgenesis and hypovirilization are at risk of developing malignant type II germ cell tumors/cancer (GCC) (seminoma/dysgerminoma and nonseminoma), with either carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesion. In 10-15% of 46,XY g