Clinical Exome Sequencing Reveals <b><i>MKRN3</i></b> Pathogenic Variants in Familial and Nonfamilial Idiopathic Central Precocious Puberty

Abstract

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.

MKRN3 and KISS1R mutations in precocious and early puberty

“…In 6 out of 19 (31.5%) patients (3/13 CPP patients and 3/6 EP patients) we found the synonymous variant c.663C > T (rs2239669). According to ExAC, the allele frequency of this polymorphism is 0.2815 [16]. Another synonymous variant (rs140467331) was found in one of our CPP patients, as well as one missense variant (rs760981395) in another CPP patient.…”

“…Our paper confirms the presence (and expands the phenotype) of mutations and polymorphisms of KISS1R and MKRN3 genes, not only in ICPP patients but also in early puberty subjects. However, our study has some limitations: we were not able to perform functional studies to demonstrate the pathogenicity of the variants we found; in addition, it was not possible to obtain DNA samples from the fathers of patients with mutations in order to verify paternal inheritance, which had been demonstrated in previous reports [16]; finally, our sample scale was quite small.…”

Pioneering studies on monogenic central precocious puberty

“…In another study, Bessa and cols.. (16) reported MKRN3 mutations in 8 out of 20 boys with apparently idiopathic CPP, reporting a high frequency of MKRN3 mutations in male with CPP previously classified as idiopathic. Further studies performed in centers from different countries, as well as a recent systematic review, confirmed that defects in MKRN3 are the most common cause of genetic CPP, with prevalence ranging from 33 to 46% in familial cases (15,17), and 0.4 to 5% in sporadic cases (16,(18)(19)(20).…”

Evolutionary Conservation of MKRN3 and Other Makorins and Their Roles in Puberty Initiation and Endocrine Functions

“…18 Subsequently, mutations in MKRN3 have been described in many additional patients with CPP throughout the world. [21][22][23][24][25][26][27][28][29][30][31][32] For a recent systematic review and meta-analysis of the MKRN3 mutations identified in patients with CPP to date, see the study by Valadares et al 33 Precocious puberty is clinically defined by the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys, which corresponds to 2.5 to 3 standard deviations below the mean age of puberty onset, as defined by population studies. 34 Early age of puberty has been associated with many deleterious health effects such as cancer, cardiovascular disease, and metabolic and behavioral disorders.…”