De novo rare EMX2 variants lead to idiopathic hypogonadotropic hypogonadism.
PURPOSE: The genetic etiology of infertility remains unknown. To identify genes for human infertility, we applied a de novo variant analysis in 142 parent-proband trios with idiopathic hypogonadotropic hypogonadism (IHH), an infertility disorder caused by gonadotropin-releasing hormone (GnRH) deficiency. METHODS: Rare de novo copy-number and single-nucleotide variants (CNVs and SNVs) were called from exome sequencing data of the IHH trios. An association study of common EMX2 variants and disease outcomes was performed in the Massachusetts General Brigham Biobank (N = 65,253). GnRH neuronal development and migration was studied in organotypic explants with knocked down of Emx2 and in a mouse model lacking Emx2. RESULTS: We identified that the gene EMX2 harbored both rare de novo CNVs and SNVs. Rare de novo EMX2 variants led to IHH, developmental delay, and hearing loss. Common EMX2 variants were linked to infertility, Parkinson disease, and hearing loss. Knockdown of Emx2 in nasal explants resulted in attenuated GnRH cell migration and GnRH cells were confined to nasal regions of Emx2 knockout (KO) mice, consistent with IHH pathogenesis. CONCLUSION: By utilizing a de novo variant analysis and cellular assays, EMX2 was uncovered as a gene for human infertility.