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Dryad

Pathogenic and low frequency variants in children with central precocious puberty

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Sep 16, 2021 version files 61.83 KB

Abstract

Background Central precocious puberty (CPP) due 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 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 MKRN3, DLK1, KISS1, KISS1R and MAGEL2 genes are reported in patients with CPP.

Methods 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 in silico computational algorithms and confirmed by Sanger sequencing. Additionally, a genetic network for the MKRN3 gene mimicking a holistic regulatory depiction of the crosstalk between MKRN3 and other genes is designed.

Results Three previously described pathogenic MKRN3 variants in the coding region of the gene occurred in 12 index females with CPP. With the p.Gly312Asp pathogenic variant of the MKRN3 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 MKRN3 gene were also observed. In addition to the MKRN3 variants, a total of 16 other rare variants in DLK1, KISS1 and MAGEL2 were also identified in other CPP patients from the same cohort. Interestingly, the frequent variant rs10407968 (p.Gly8Ter) of the KISS1R gene appeared to be less frequent in the cohort of patients with CPP.

Conclusion The results of the present study denote the key role of the imprinted MKRN3 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.