Six Novel Variants in the MKRN3 Gene Causing Central Precocious Puberty

Area of Science:

• Pediatric Endocrinology
• Genetics
• Reproductive Medicine

Background:

• Idiopathic central precocious puberty (iCPP) involves early activation of the reproductive axis, leading to premature sexual development.
• Loss-of-function variants in the MKRN3 gene are now recognized as the most frequent genetic cause of iCPP.
• Understanding the genetic basis of iCPP is crucial for accurate diagnosis and management.

Purpose of the Study:

• To investigate the clinical presentation and genetic basis of iCPP in families with pathogenic MKRN3 variants.
• To document the pubertal course in individuals with MKRN3-related central precocious puberty.
• To assess the utility of genetic analysis for MKRN3 in diagnosing iCPP, particularly with a history of paternal inheritance.

Main Methods:

• An observational case series design was employed, focusing on patients with central precocious puberty (CPP) due to MKRN3 variants.
• Genetic analysis of the MKRN3 gene was performed on 28 unrelated patients with iCPP and specific inheritance patterns.
• Family segregation studies were conducted to confirm the inheritance of identified MKRN3 variants.

Main Results:

• Six novel and two previously described pathogenic variants in the MKRN3 gene were identified in 9 girls and 1 boy with iCPP.
• All identified MKRN3 mutations were predicted to be deleterious based on in silico analyses.
• Family segregation studies revealed MKRN3 variants in asymptomatic prepubertal siblings, indicating potential for early onset.

Conclusions:

• Loss-of-function mutations in MKRN3 are a significant cause of paternally inherited central precocious puberty.
• Genetic testing for MKRN3 variants should be considered in cases of iCPP with a suggestive family history.
• The identification of variants in asymptomatic family members raises important questions regarding screening and management strategies for at-risk individuals.