Sex reversal mutation analysis in a family with pure gonadal dysgenesis of the XY female type (Swyer syndrome)

Gonadal dysgenesis with XY male-to-female sex reversal has been attributed to mutations and gene dosage differences in at least seven genes. We present a family of three sisters with a pure gonadal dysgenesis (Swyer syndrome) with an 46, XY karyotype. The sisters have a common X-chromosomal haplotype in Xp21.3-p11.3, the region of the X-chromosomal Swyer syndrome which includes NR0B1. We excluded mutations in SRY and flanking sequences, in NR0B1and its promoter, in DMRT1, WT1, SOX9, and NR5A1. Also the X-chromosomal ATRX region and the SOX3 gene were excluded by segregation analysis with polymorphic markers. We excluded a duplication of NR0B1 and a deletion of DMRT1 by gene copy dosage measurement. Since the pedigree suggests an X-chromosomal mode of inheritance, we suggest that there is either another yet unknown gene in the common interval on Xp which may cause Swyer syndrome or, more likely, that a gene in this interval is aberrantly regulated during gonad differentiation. Our data do not formally exclude another autosomal gene.