ESPE Abstracts (2016) 86 RFC12.3

Next Generation Sequencing and Precocious Puberty: A New Diagnostic Challenge to Identify the Molecular Basis of Complex Diseases

Andrea La Barberaa, Aldesia Provenzanob, Rosangela Artusoa, Valerio Orlandinib, Sabrina Giglioa & Stefano Stagic

aMedical Genetics Unit, Meyer Children’s University Hospital, Florence, Italy; bDepartment of Clinical and Experimental Biomedical Sciences ‘Mario Serio’, Medical Genetics Unit, University of Florence, Florence, Italy; cHealth Sciences Department, University of Florence, Anna Meyer Children’s University Hospital, Florence, Italy

Background: Precocious puberty is defined as the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. This condition results from a constant and complex interplay between predisposing genes and environmental factors. To date, the molecular analysis are all focused on reproductive-endocrine disorders such as Kallmann syndrome and hypogonadotropic hypogonadism, while the genetic bases of pubertal timing are still unclear.

Objective and hypotheses: The identification of genes involving in this process is difficult because pubertal timing is a complex genetic trait, where a direct relationship between genotype and phenotype does not exist due to multigenic influences and interactions between genetic variants and environmental exposures. On the bases of this observation, we decided to analyse 27 patients through Next Generation Sequencing (NGS) technology.

Method: By searching the available literature on puberty we selected 34 genes all implicated in several hormonal, nervous and metabolic pathways involved in the onset of puberty, followed by NGS.

Results: In 16 cases we identified rare variants of unknown significance (VUSs) in hormones and hormone receptors. In one case we found a SNP recently reported in literature in association with puberty onset; in two cases we found VUSs in a gene which is required in rats for the organization of somatic cells and oocytes into discrete follicular structures.

Conclusion: Additional studies will be required to confirm the pathogenetic role of these variants. However different genetic variants may display a differential response to therapeutic agents. The knowledge of the genetic background is essential not only for an accurate diagnosis, but also for the development of the most appropriate therapeutic strategies.

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