Investigation of genetic basis of Familial Central Precocious Puberty of maternal inheritance

Abstract

Precocious Puberty is defined as the appearance of secondary sex characteristics before 8 years of age in girls and before 9 years of age in boys, and leads to rapid advancement of skeletal maturation, causing loss of potential adult height, besides emotional and psychosocial impact. The most common mechanism of precocious puberty is the early activation of pulsatile GnRH secretion, known as Central Precocious Puberty (CPP), which was traditionally divided into those caused by central nervous system lesions or unknown etiology (idiopathic). Among the idiopathic cases, it is known that many of them have genetic etiology today because the notable progress in the molecular basis of CPP in the last decade. Familial Precocious Puberty is defined when it happens in more than one family member. The prevalence of Precocious Familial Puberty of maternal inheritance appears to be high, and perhaps even higher than the paternal one. While in paternally inherited CPP two important genes were already elucidated, MKRN3 and DLK1, the molecular basis of the maternally inherited cases is still unclear. The study´s objective is to characterize families with maternally inherited Precocious Puberty, in order to: 1) study it's clinical, hormonal and epidemiological characteristics; 2) seek for possible pathogenic variants through global exomic sequencing; 3) determine the inheritance pattern through segregation analysis; 4) correlate the new variants found with the phenotype of patients with CPP. We will study patients with familial CPP who are clinically evaluated at Hospital das Clinicas from Sao Paulo Medical School, Sao Paulo University, and also patients from other university partners. Inclusion criteria will be: 1) onset of secondary sexual characteristics before 8 years in girls and 9 years in boys; 2) LH concentrations at baseline and/or after stimulation with exogenous GnRH or with depot GnRH analogue (leuprolide acetate) at pubertal concentrations; 3) magnetic resonance imaging of the central nervous system without abnormalities; 4) presence of one or more members of the maternal family with a history of early sexual development. The molecular evaluation will be performed after the extraction of genomic DNA from peripheral blood leukocytes, and the exomic sequencing will be performed at the SELA laboratory of the University of São Paulo Medical School, using molecular cloning technology IlluminaHiSeq 2000 (IlluminaInc, San Diego, CA). Each variant found will be classified according to the guidelines of the American College of Medical Genetics and Genomics in: "pathogenic", "likely pathogenic", "uncertain significance", "likely benign" or "benign." The data will be analyzed and correlated with the phenotypes of the patients, and the results will be disseminated to the scientific community through publication of manuscript. (AU)