Rare Variants in the MECP2 Gene in Girls with Central Precocious Puberty

BACKGROUND: Identification of genetic causes of central precocious puberty (CPP) has revealed epigenetic mechanisms as regulators of human pubertal timing. Methyl-CpG-binding protein 2 (MECP2), an X-linked gene, encodes a chromatin-associated protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a severe neurodevelopmental disorder. Early pubertal development was demonstrated in several patients with Rett syndrome. METHODS: We investigated a multiethnic cohort of 404 patients (383 girls) with idiopathic CPP for potentially damaging variants in MECP2, evaluating whether MECP2 might contribute to CPP etiology. We performed high-throughput sequencing in 133 patients and Sanger sequencing of MECP2 in further 271 patients. Mice hypothalamic expression of Mecp2 and colocalization with GnRH neurons were determined. FINDINGS: We identified three rare heterozygous likely damaging coding variants in MECP2 in five girls: a de novo missense variant (p.Arg97Cys) in two monozygotic twin sisters with CPP and microcephaly; a de novo missense variant (p.Ser176Arg) in one girl with sporadic CPP, obesity and autism; and an insertion (p.Ala6_Ala8dup) in two unrelated girls with sporadic CPP. Additionally, we identified one rare heterozygous 3 ’UTR MECP2 insertion (c.*36_*37insT) in two unrelated girls with sporadic CPP. None of them manifested Rett syndrome. Mecp2 protein co-localized with GnRH expression in mice hypothalamic nuclei key for GnRH regulation. INTERPRETATION: Rare MECP2 variants were demonstrated in girls with idiopathic CPP, with or without mild neurodevelopmental abnormalities. MECP2 may have a role in the hypothalamic control of human pubertal timing, increasing evidence of (epi)genetic mechanisms in this biological process.