Abstract for presentation at 11th International Congress of Human Genetics

A new approach to identifying the molecular basis of gonadal dysfunction in sex reversed patients

  • Prof Andrew Sinclair, Murdoch Children's Research Institute, Australia
  • Dr Craig Smith, Murdoch Children's Research Institute, Australia
  • Sonja Gustin, Murdoch Children's Research Institute, Australia
  • Dr Susan Forrest, Australian Genome Research Facility, Australia
  • Dr Melanie Bahlo, Walter and Eliza Hall Institute for Medical Research, Australia
  • Dr Henrik Bengtsson, Walter and Eliza Hall Institute for Medical Research, Australia
  • Prof Terry Speed, Walter and Eliza Hall Institute for Medical Research, Australia

    • Intersex disorders, ranging in severity from genital abnormalities to complete sex reversal, are surprisingly common and as such represent a major paediatric concern. Uncertainty about a child’s gender is extremely traumatic for the individual, parents and other family members. The cause of these problems is most often the failure of the complex network of genes that regulate development of testes or ovaries. However, we understand relatively little of this regulatory network. Mutations in the critical testis-determining genes SRY and SOX9 account for approximately 20% of XY females with gonadal dysgenesis. We have little idea about what other genes may be involved to account for the remaining 80% of patients. By contrast, 90% of XX males with gonadal dysgenesis are due to Y translocations that include SRY. Consequently, 10% of XX males with gonadal dysgenesis are potentially affected by mutations in unknown genes. In order to redress this lack of understanding about the underlying cause of gonadal failure in these patients and to provide new molecular insights into the normal regulatory network that governs testis and ovary development we used these sex reversed patients to screen Single Nucleotide Polymorphism (SNP) chips. We have collected DNA from sex-reversed patients with gonadal dysgenesis (XX males lacking SRY and XY females without mutations in SRY). We have used the newly released Affymetrix 500,000 SNP array that has over 80% of the genome within 10kb of a SNP and a median inter-marker distance of 3.3kb. This array has the highest SNP density currently available. This chip was used to screen the genome of sex-reversed patients for micro-deletions or micro-duplications. Critically, we have developed new effective algorithms to analyse this data to account for the high level of SNP variation in the human genome. Data from this study will be presented and the efficacy and future potential of this approach will be discussed.

    Conference Organiser - ICMS Pty Ltd