Gene dosage imbalances in patients with 46,XY gonadal DSD detected by an in-house-designed synthetic probe set for multiplex ligation-dependent probe amplification analysis

Clin Genet. 2008 May;73(5):453-64. doi: 10.1111/j.1399-0004.2008.00980.x. Epub 2008 Apr 2.

Abstract

The development of a testis requires the proper spatiotemporal expression of the SRY gene and other genes that act in a dosage-sensitive manner. Mutations in the SRY gene account for only 10-15% of patients with 46,XY gonadal disorder of sex development (DSD). To enable the diagnostics of deletions and duplications of genes known to be involved in different forms of DSD, we developed a synthetic probe set for multiplex ligation-dependent probe amplification (MLPA) analysis. Here, we report the results from the analysis of 22 patients with 46,XY gonadal DSD. The analysis with the DSD probe set has led to the identification of two copy number variations, an 800-kb NR0B1 (DAX1) locus duplication on Xp21 in a patient with isolated partial gonadal dysgenesis and a duplication of the SRD5A2 gene that represents a rare normal variant. The described MLPA kit represents an optimal complement to DNA sequence analysis in patients with DSD, enabling screening for deletions and duplications of several genes simultaneously. Furthermore, the second identification of an NR0B1 locus duplication in a patient with isolated gonadal dysgenesis, without dysmorphic features and/or mental retardation, highlights the importance of evaluating NR0B1 duplication in patients with gonadal dysgenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins / analysis*
  • DNA-Binding Proteins / genetics
  • Female
  • Gene Amplification
  • Gene Dosage*
  • Gene Duplication
  • Gonadal Dysgenesis, 46,XY / genetics*
  • Humans
  • Male
  • Nucleic Acid Amplification Techniques / methods*
  • Oligonucleotide Probes
  • Receptors, Retinoic Acid / analysis*
  • Receptors, Retinoic Acid / genetics
  • Repressor Proteins / analysis*
  • Repressor Proteins / genetics

Substances

  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins
  • NR0B1 protein, human
  • Oligonucleotide Probes
  • Receptors, Retinoic Acid
  • Repressor Proteins