Here, we report the molecular etiology of a syndromic form of 46,XX DSD that includes genital virilization, congenital heart disease (CHD), and variable somatic anomalies including BPES and congenital diaphragmatic hernia (CDH). This syndrome is caused by protein-truncating mutations in the orphan nuclear receptor NR2F2 (MIM: 107773). NR2F2 encodes the transcription factor chicken ovalbumin upstream promoter transcription factor 2 (COUP-TF2).12 Our data indicate that in the early developing human chromosomal female XX gonad, COUP-TF2 is a human “pro-ovary” and “anti-testis” sex-determining factor.