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.