MECP2 Rare Variants in Boys With Central Precocious Puberty

Abstract

Context: Central precocious puberty (CPP) has strong genetic and epigenetic influences. MECP2, an X-linked gene, encodes a DNA methylation reader with a role in gene transcription regulation. MECP2 loss-of-function mutations are linked to neurodevelopmental disorders, particularly with Rett syndrome, a severe disorder that may be associated with early puberty. MECP2 variants were identified in girls with CPP with or without neurodevelopmental disorders.

Objective: This work aimed to investigate potential MECP2 variants in boys with idiopathic CPP at 3 academic hospitals.

Methods: MECP2 DNA sequencing was performed in 10 boys with idiopathic CPP to screen for coding variants (5 exome; 5 Sanger sequencing). There were no mutations in other CPP-causing genes (MKRN3 and DLK1). MECP2 protein levels of wild-type and identified variants were assessed in a gonadotropin-releasing hormone neuronal cell line.

Results: We identified 2 hemizygous missense MECP2 variants in 2 unrelated boys. Patient 1 had very early sporadic CPP, speech delay, and autism. He harbored a p.Val312Ile variant, an extremely rare variant located in a critical MECP2 domain. Patient 2 had sporadic CPP with no apparent neurodevelopmental disorders. He harbored a rare variant, p.Arg366Cys. Both MECP2 variants were inherited from mothers with normal puberty. Neither patient had features of Rett syndrome. Both variants had reduced MECP2 protein levels, suggesting a potential deleterious effect.

Conclusion: MECP2 rare variants were identified in boys with sporadic CPP, expanding this association as previously described in girls. Our findings provide additional evidence for a role of MECP2, an epigenetic factor, in hypothalamic control of pubertal timing.

Keywords: MECP2; X-linked precocious puberty; central precocious puberty; genetics of puberty.