Clinical Exome Sequencing Reveals MKRN3 Pathogenic Variants in Familial and Nonfamilial Idiopathic Central Precocious Puberty.

Background/aims: Idiopathic central precocious puberty (ICPP) is the premature activation of the hypothalamic-pituitary-gonadal axis in the absence of organic disease. Up to now, just gain-of-function mutations of KISS1/KISS1R and loss-of-function mutations of the maternally imprinted gene MKRN3 are the known genetic causes of ICPP. Our intention is to evaluate variants present in genes related to the pubertal onset pathway that could act as disease-causing or predisposing variants.

Methods: We studied the clinical exome of 20 patients diagnosed with ICPP using the Illumina platform. The bioinformatics analysis was performed using 2 different programs, and the variants were filtered according to a list of genes related to the gonadotropin-releasing hormone pathway.

Results: In a "sporadic case," we found a missense variant in MKRN3 NM_005664.3: c.203G>A, causing the protein change NP_005655.1:p.Arg68His, predicted as pathogenic by 2 informatics tools. The proband carrying this variant was diagnosed with ICPP at 7.75 years of age. We did not find any pathogenic variants in KISS1, KISS1R, LIN28, GNRH, GNRHR, TACR3, and TAC3.

Conclusion: MKRN3 is the most frequent genetic cause of familial ICPP, so it is wise to screen for MKRN3 mutations in all patients with familial ICPP and in patients with an unclear paternal pubertal history.