A novel human sex-determining gene linked to Xp11.21-11.23.

CONTEXT The molecular basis for about 70-80% of 46,XY sex-reversed females remains unexplained, because they carry normal copies of the genes (SRY, SOX9, DAX1, DMRT, SF1, WT1) involved in sex determination pathway. OBJECTIVE The objective of this study is to map the chromosomal locus responsible for an unexplained sex-reversed phenotype. DESIGN The study implemented a genome-wide scan using families with multiple sex-reversed individuals. SETTING The patients, along with the family members, were selected from different hospitals/reproductive centers. PARTICIPANTS Sex-reversed individuals and their siblings and parents participated in the study. MAIN OUTCOME MEASURES Identification of the chromosomal locus responsible for sex reversal in these families and sequence analysis of candidate genes were the main outcome measures. RESULTS Parametric linkage analysis revealed a maximum two-point LOD score of 5.70 with marker DXS991 (Xp11.21) and 4.57 with marker DXS1039 (Xp11.23-Xp11.22), and a multipoint LOD score of 5.77 with marker DXS991 and 5.22 with marker DXS1039. The two markers (DXS991 and DXS1039) with highest LOD score span approximately 3.41 cM (75.79-79.2 cM) on the short arm of the X-chromosome. CONCLUSION Our findings provide evidence for a major susceptibility locus for sex reversal/gonadal dysgenesis on the short arm of the X-chromosome (Xp11.21-11.23). Furthermore, molecular exploration of the expression of candidate genes in the embryonic gonad/gonadal ridge will help in the identification of the underlying gene for sex reversal.