Enlightenment of molecular pathology with next generation sequencing in central precocious puberty

The development of secondary sex characteristics before the age of eight in girls and nine in boys is defined as precocious puberty. True/Central precocious puberty (CPP) occurs upon early activation of the hypothalamic-pituitary-gonadal axis that releases gonadotropins. CPP, higher frequency in girls, reveals 60-80% genetic cause and ~27.5% is autosomal dominant. Today, >40 genes have been revealed in puberty, but few (KISS1, KISS1R, MKRN3, DLK1, and PROKR2) are associated with CPP. In our study, 18 familial CPP patients are stepwise investigated by Sanger sequencing (SD) for known genes and two families by whole-exome-sequencing (WES). In DLK1, two different novel (c.67+78C>T and c.357C>G;p.(Tyr119Ter)) and in MKRN3 one known variant (c.982C>T;p.(Arg328Cys)), all in females, are revealed. Segregation analysis confirmed all are paternaly inherited, complying with maternal imprinted. As a result, DLK1 and MKRN3 were found responsible for 17% of our CPP. No associated variant was identified in one family with WES, while c.1225-1G>A was shown in the splicing acceptor region of CDHR3 segregating in affected members in the second family. CDHR3, a member of the cadherin protein family that plays a role in cell-cell interaction and the regulation of cell-skeleton complex with the structure of calcium-dependent adhesion in the cell membrane, has not been associated with any phenotype before. In the future, a functional investigation is planned for this variant. It was thought that a better understanding of puberty pathways by identifying new genes in CPP could contribute to the development of new strategies for prepubertal children in presymptomatic diagnosis and treatment.