Pathogenic and low frequency variants in children with central precocious puberty

<p><b>Background </b>Central precocious puberty (CPP) due<span> to premature activation of GnRH secretion results in early epiphyseal fusion and to a significant compromise in the achieved final adult height.  CPP is usually idiopathic and is disproportionally observed in girls compared to boys. Currently, only few </span>genetic determinants of children with CPP have been described and the role they exert on the development of the disorder. In this original study rare variants in <i>MKRN3</i>, <i>DLK1</i>, <i>KISS1</i>, <i>KISS1R</i> and <i>MAGEL2</i> genes are reported in patients with CPP.</p> <p><b>Methods </b>Fifty-four index females and 2 index males with CPP underwent whole exome sequencing (WES) by Next Generation Sequencing (NGS). The identified rare variants were initially examined by <i>in silico</i> computational algorithms and confirmed by Sanger sequencing. Additionally, a genetic network for the <i>MKRN3</i> gene mimicking a holistic regulatory depiction of the crosstalk between <i>MKRN3</i> and other genes is designed.</p> <p><b>Results </b>Three previously described pathogenic <i>MKRN3</i> variants in the coding region of the gene occurred in 12 index females with CPP. With the p.Gly312Asp pathogenic variant of the <i>MKRN3 </i>gene being the most prevalent and exclusively found among the Cypriot CPP cohort, it is projected to be the result of founder effect phenomenon. In seven additional CPP patients from the same cohort several other likely and rare pathogenic upstream variants in the <i>MKRN3</i> gene were also observed. In addition to the <i>MKRN3</i> variants, a total of 16 other rare variants in <i>DLK1</i>, <i>KISS1</i> and <i>MAGEL2 </i>were also identified in other CPP patients from the same cohort. Interestingly, the frequent variant rs10407968 (p.Gly8Ter) of the <i>KISS1R</i> gene appeared to be less frequent in the cohort of patients with CPP.</p> <p><b>Conclusion</b> The results of the present study denote the key role of the imprinted <i>MKRN3</i> gene in puberty. Additionally, pathogenic variants can also exist in the noncoding region of the MKRN3 gene such as the proximal promoter and 5'-UTR region and which can also be considered as contributing factors to CPP.  Overall, the results of present study have emphasised the necessity of the allied genetic and clinical approach which is necessary for the management and treatment of CPP.</p>