title: A multi-exon deletion within WWOX is associated with a 46,XY disorder of sex development.
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.
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia. stefan.white@monash.edu
authors.forename: Stefan
authors.initials: S
authors.lastname: White
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Hewitt
authors.forename: Erin
authors.initials: E
authors.lastname: Turbitt
authors.forename: Yvonne
authors.initials: Y
authors.lastname: van der Zwan
authors.forename: Remko
authors.initials: R
authors.lastname: Hersmus
authors.forename: Stenvert
authors.initials: S
authors.lastname: Drop
authors.forename: Peter
authors.initials: P
authors.lastname: Koopman
authors.forename: Vincent
authors.initials: V
authors.lastname: Harley
authors.forename: Martine
authors.initials: M
authors.lastname: Cools
authors.forename: Leendert
authors.initials: L
authors.lastname: Looijenga
authors.forename: Andrew
authors.initials: A
authors.lastname: Sinclair
mesh_terms: D001483:Base Sequence; D055028:Comparative Genomic Hybridization; D058490:Disorder of Sex Development, 46,XY / Q000175:diagnosis / Q000235:genetics*; D005091:Exons; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D010088:Oxidoreductases / Q000235:genetics*; D017384:Sequence Deletion; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human
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