Comprehensive genetic investigation of patients with Central Precocious Puberty associated with complex phenotypes

• Grant number: 18/03198-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): May 01, 2018
• Effective date (End): June 30, 2021
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Ana Claudia Latronico Xavier
• Grantee: Ana Pinheiro Machado Canton
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 13/03236-5 - New approaches and methodologies in molecular-genetic studies of growth and pubertal development disorders, AP.TEM

Abstract

Recently, monogenic causes of Central Precocious Puberty (CPP) have been reported, increasing our knowledge about the reproductive axis modulation. Among them, it is noted the discovery of inactivating mutations in two imprinted genes, highlighting the involvement of epigenetic mechanisms in pubertal control: MKRN3, accounting for 33-45% of familial CPP cases; and DLK1, with a complex defect associated to CPP in one extended family. Besides that, CPP phenotype has recently been described in association with comorbidities and complex phenotypes in distinct and rare cases of chromosomal abnormalities. In this context, it is noteworthy to highlight that defects in imprinting clusters regions are associated with clinical syndromes with a high CPP prevalence: 1) chromosome 14q32.2: DLK1locus and Temple syndrome critical region (a syndrome mostly caused by maternal uniparental disomy of chromosome 14 and with CPP in 80% of cases); 2) chromosome 7: maternal uniparental disomy of chromosome 7 (CPP in 25% and early puberty in 50% of cases) and 7q11.23 deletion syndrome (CPP in 18% and early puberty in up to 50% of cases). Therefore, the overall aim of the project is to investigate patients with CPP associated with comorbidities and complex phenotypes through genetic and epigenetic analysis to identify genomic loci implicated in pubertal control. The workflow comprises two investigative arms: 1) a candidate locus approach through multiplex ligation dependent probe amplification, for which patients with suspect of chromosome 14q32.2 defects or chromosome 7q11.23 defects will be selected; 2) a genome-wide analysis approach with copy number variants analysis through single nucleotide polymorphism microarray and with exomic mutations analysis through whole-exome sequencing, for which patients with CPP associated with comorbidities or complex phenotypes not characterized as known syndromes will be selected. The studies proposed in this project might extend our knowledge concerning the involvement of genetic and epigenetic mechanisms in human pubertal control. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SERAPHIM, CARLOS EDUARDO; CANTON, ANA PINHEIRO MACHADO; MONTENEGRO, LUCIANA; PIOVESAN, MAIARA RIBEIRO; MACEDO, DELANIE B.; CUNHA, MARINA; GUIMARAES, ALINE; OLIVEIRA RAMOS, CAROLINA; FIGUEIREDO BENEDETTI, ANNA FLAVIA; DE CASTRO LEAL, ANDREA; et al. Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, v. 106, n. 4, p. 1041-1050, APR 2021. (13/03236-5, 18/03198-0)

MACHADO CANTON, ANA PINHEIRO; VICTORINO KREPISCHI, ANA CRISTINA; MONTENEGRO, LUCIANA RIBEIRO; COSTA, SILVIA; ROSENBERG, CARLA; STEUNOU, VIRGINIE; SOBRIER, MARIE-LAURE; SANTANA, LUCAS; HONJO, RACHEL SAYURI; KIM, CHONG AE; et al. Insights from the genetic characterization of central precocious puberty associated with multiple anomalies. Human Reproduction, v. 36, n. 2, p. 506-518, FEB 2021. (13/08028-1, 18/03198-0)