NOVEL MUTATION IN THE PUTATIVE DNA HELICASE XH2 IS RESPONSIBLE FOR MALE-TO-FEMALE SEX REVERSAL ASSOCIATED WITH AN ATYPICAL FORM OF THE ATR-X SYNDROME

We describe a pedigree presenting X-linked severe mental retardation a ssociated with multiple congenital abnormalities and 46,XY gonadal dys genesis, leading in one family member to female gender assignment. Fem ale carriers are unaffected. The dysmorphic features are similar to th ose described in the alpha-thalassemia and mental retardation (ATR-X) syndrome, although there is no clinical evidence of alpha-thalassemia in this family. In addition, the family had other clinical features no t previously observed in the ATR-X syndrome, including partial optic-n erve atrophy and partial ocular albinism. Mutations in a putative DNA helicase, termed XH2, have been reported to give rise to the ATR-X syn drome. We screened the XH2 gene for mutations in affected members of t he family and identified a 4-bp deletion at an intron/exon boundary th at removes an invariant 3' splice-acceptor site. The mutation cosegreg ates with the syndrome. The genomic deletion causes missplicing of the pre-mRNA, which results in the loss of 8 bp of coding sequence, there by generating a frameshift and a downstream premature stop codon. Our finding increases the range of clinical features associated with mutat ions in the XH2 gene.