Six Novel Variants in the MKRN3 Gene Causing Central Precocious Puberty

Abstract

Context: Idiopathic central precocious puberty (iCPP) is defined by the premature reactivation of the hypothalamic-pituitary-gonadal axis with normal magnetic resonance imaging scan of the central nervous system, causing the development of secondary sexual characteristics before age 8 years in girls and 9 years in boys. MKRN3 loss of function variants now represent the most common genetic cause of iCPP.

Objective: This work aims to document the clinical course of puberty in 8 families harboring pathogenic MKRN3 variants.

Methods: This is an observational case series study of patients with CPP due to MKRN3 variants followed in a single center.

Results: Genetic analysis of MKRN3 was carried out in 28 unrelated patients with iCPP and a family history of paternal inheritance or no/unavailable maternal inheritance, particularly in case of very early and rapidly evolving CPP. We identified 6 novel and 2 recently described variants in the MKRN3 gene in 9 girls, 1 boy, and their family members. These mutations were all predicted to be deleterious by in silico prediction programs.

Conclusion: We have identified 6 novel MKRN3 mutations in children with CPP. An MKRN3 loss of function should be considered after careful history pinpointing paternally inherited CPP. A family segregation study allowed the detection of an MKRN3 variant in 2 young brothers still prepubertal, raising the question of screening and management of asymptomatic prepubertal family members.

Keywords: MKRN3; familial CPP; genetics of puberty; precocious puberty.

Figure 1.

Pedigrees of the 8 families with MKRN3 pathogenic variants. Arrows: proband; square: male; circle: female; black symbols: clinically affected individuals; gray symbols: self-reported central precocious puberty; question mark: unknown phenotype/very young patient; black dot: asymptomatic carriers; NM: nonmutated allele; roman numerals: generation; arabic numerals: individuals in each generation.

Figure 2.

Schematic structure of the MKRN3 human protein with the variants identified in our families. The MKRN3 protein is composed of 3 C3H zinc fingers, the MKRN-type Cys-His region, and 1 C3HC4 RING finger. The numbers indicate the amino acid positions in the protein. The arrows indicate the location of the variants identified in the study.