A multi-exon deletion within WWOX is associated with a 46,XY disorder of sex development

Eur J Hum Genet. 2012 Mar;20(3):348-51. doi: 10.1038/ejhg.2011.204. Epub 2011 Nov 9.

Abstract

Disorders of sex development (DSD) are congenital conditions where chromosomal, gonad or genital development is atypical. In a significant proportion of 46,XY DSD cases it is not possible to identify a causative mutation, making genetic counseling difficult and potentially hindering optimal treatment. Here, we describe the analysis of a 46,XY DSD patient that presented at birth with ambiguous genitalia. Histological analysis of the surgically removed gonads showed bilateral undifferentiated gonadal tissue and immature testis, both containing malignant germ cells. We screened genomic DNA from this patient for deletions and duplications using an Illumina whole-genome SNP microarray. This analysis revealed a heterozygous deletion within the WWOX gene on chromosome 16, removing exons 6-8. Analysis of parental DNA showed that the deletion was inherited from the mother. cDNA analysis confirmed that the deletion maintained the reading frame, with exon 5 being spliced directly onto exon 9. This deletion is the first description of a germline rearrangement affecting the coding sequence of WWOX in humans. Previously described Wwox knockout mouse models showed gonadal abnormalities, supporting a role for WWOX in human gonad development.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Comparative Genomic Hybridization
  • Disorder of Sex Development, 46,XY / diagnosis
  • Disorder of Sex Development, 46,XY / genetics*
  • Exons*
  • Humans
  • Infant, Newborn
  • Male
  • Oxidoreductases / genetics*
  • Sequence Deletion*
  • Tumor Suppressor Proteins / genetics*
  • WW Domain-Containing Oxidoreductase

Substances

  • Tumor Suppressor Proteins
  • Oxidoreductases
  • WW Domain-Containing Oxidoreductase
  • WWOX protein, human