ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2011) 25 CM4.4

New approaches to molecular diagnosis

John Achermann


UCL Institute of Child Health, University College London, London, UK.


It is now around 20 years since the identification of SRY as a primary testis-determining gene and the molecular characterisation of many of the key enzymes and receptors involved in androgen synthesis and action. Although significant progress has been made since then in identifying other components involved in sex development, we are still unable to find an underlying genetic cause in many individuals with these conditions. Efforts to identify specific genetic causes of DSD are impeded by several factors such as phenotypic variability, the lack of specific biochemical markers and the high frequency of ‘unusual’ genetic mechanisms such as sex-limited dominant inheritance or de-novo events. Indeed, as DSD is usually associated with infertility, classic large pedigrees amenable to linkage or mapping studies are relatively rare. Traditionally, a candidate gene approach has been used to identify many cases of DSD, which can be time consuming and costly. However, the development of new nano-technologies means that we could potentially identify the genetic causes of DSD on a high-throughput scale, and can start to address some newer genetic mechanisms that might be important in influencing disease phenotype (e.g. digenic or oligogenic inheritance, gene dosage, epigenetic regulation). Here, I will provide an overview of new approaches to: i) karyotyping and the assessment of copy number variation (e.g. array CGH, SNP-based technologies); ii) high-throughput sequencing (such as ‘resequencing’ microarrays and next generation sequencing technologies); iii) determining protein or methylation ‘signatures’. The challenges will be cost, scale, organisation/collaboration, bioinformatics, bioethics, predicting in vivo functional effects, and integrating this wealth of information into an appropriate systems model relevant to DSD and of positive benefit to individuals with these conditions.

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