Insights from the genetic characterization of central precocious puberty associated with multiple anomalies

Author(s):Show less -

Machado Canton, Ana Pinheiro ^[1] ; Victorino Krepischi, Ana Cristina ^[2] ; Montenegro, Luciana Ribeiro ^[1] ; Costa, Silvia ^[2] ; Rosenberg, Carla ^[2] ; Steunou, Virginie ^[3] ; Sobrier, Marie-Laure ^[3] ; Santana, Lucas ^[4] ; Honjo, Rachel Sayuri ^[5] ; Kim, Chong Ae ^[5] ; de Zegher, Francis ^[6] ; Idkowiak, Jan ^{[7, 8]} ; Gilligan, Lorna C. ^[7] ; Arlt, Wiebke ^[7] ; de Assis Funari, Mariana Ferreira ^[1] ; de Lima Jorge, Alexander Augusto ^{[1, 4]} ; Mendonca, Berenice Bilharinho ^[1] ; Netchine, Irene ^{[3, 9]} ; Brito, Vinicius Nahime ^[1] ; Latronico, Ana Claudia ^[1]

Affiliation

^[1] Univ Sao Paulo, Dev Endocrinol Unit, Lab Hormones & Mol Genet, LIM42, Dept Endocrinol & Metab, Clin Hosp, Fac Med, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Dept Genet & Evolutionary Biol, Inst Biosci, Sao Paulo - Brazil

^[3] Univ Sorbonne, INSERM, UMR S 938, St Antoine Res Ctr, Paris - France

^[4] Univ Sao Paulo, Genet Endocrinol Unit, LIM25, Dept Endocrinol & Metab, Clin Hosp, Fac Med, Sao Paulo - Brazil

^[5] Univ Sao Paulo, Clin Genet Unit, Childrens Inst, Clin Hosp, Fac Med, Sao Paulo - Brazil

^[6] Univ Leuven, Dept Dev & Regenerat, Leuven - Belgium

^[7] Univ Birmingham, Inst Metab & Syst Res IMSR, Coll Med & Dent Sci, Birmingham, W Midlands - England

^[8] Birmingham Womens & Childrens Hosp NHS Fdn Trust, Dept Endocrinol & Diabet, Birmingham, W Midlands - England

^[9] Armand Trousseau Hosp, AP HP, Endocrine Funct Explorat Serv, Paris - France

• Document type: Journal article
• Source: Human Reproduction; v. 36, n. 2, p. 506-518, FEB 2021.
• Web of Science Citations: 1

Abstract

STUDY QUESTION: Is there an (epi)genetic basis in patients with central precocious puberty (CPP) associated with multiple anomalies that unmasks underlying mechanisms or reveals novel genetic findings related to human pubertal control? SUMMARY ANSWER: In a group of 36 patients with CPP associated with multiple phenotypes, pathogenic or likely pathogenic (epi)genetic defects were identified in 12 (33%) patients, providing insights into the genetics of human pubertal control. WHAT IS KNOWN ALREADY: A few studies have described patients with CPP associated with multiple anomalies, but without making inferences on causalities of CPP. Genetic-molecular studies of syndromic cases may reveal disease genes or mechanisms, as the presentation of such patients likely indicates a genetic disorder. STUDY DESIGN, SIZE, DURATION: This translational study was based on a genetic-molecular analysis, including genome-wide high throughput methodologies, for searching structural or sequence variants implicated in CPP and DNA methylation analysis of candidate regions. PARTICIPANTS/MATERIALS, SETTING, METHODS: A cohort of 197 patients (188 girls) with CPP without structural brain lesions was submitted to a detailed clinical evaluation, allowing the selection of 36 unrelated patients (32 girls) with CPP associated with multiple anomalies. Pathogenic allelic variants of genes known to cause monogenic CPP (KISS1R, KISS1, MKRN3 and DLK1) had been excluded in the entire cohort (197 patients). All selected patients with CPP associated with multiple anomalies (n = 36) underwent methylation analysis of candidate regions and chromosomal microarray analysis. A subset (n = 9) underwent whole-exome sequencing, due to presenting familial CPP and/or severe congenital malformations and neurocognitive abnormalities. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 36 selected patients with CPP, the more prevalent associated anomalies were metabolic, growth and neurocognitive conditions. In 12 (33%) of them, rare genetic abnormalities were identified: six patients presented genetic defects in loci known to be involved with CPP (14q32.2 and 7q11.23), whereas the other six presented defects in candidate genes or regions. In detail, three patients presented hypomethylation of DLK1/MEG3:IG-DMR (14q32.2 disruption or Temple syndrome), resulting from epimutation (n = 1) or maternal uniparental disomy of chromosome 14 (n = 2). Seven patients presented pathogenic copy number variants: three with de novo 7q11.23 deletions (Williams-Beuren syndrome), three with inherited Xp22.33 deletions, and one with de novo 1p31.3 duplication. Exome sequencing revealed potential pathogenic variants in two patients: a sporadic female case with frameshift variants in TNRC6B and AREL1 and a familial male case with a missense substitution in UGT2B4 and a frameshift deletion in MKKS. LIMITATIONS, REASONS FOR CAUTION: The selection of patients was based on a retrospective clinical characterization, lacking a longitudinal inclusion of consecutive patients. In addition, future studies are needed, showing the long-term (mainly reproductive) outcomes in the included patients, as most of them are not in adult life yet. WIDER IMPLICATIONS OF THE FINDINGS: The results highlighted the relevance of an integrative clinical-genetic approach in the elucidation of mechanisms and factors involved in pubertal control. Chromosome 14q32.2 disruption indicated the loss of imprinting of DLK1 as a probable mechanism of CPP. Two other chromosomal regions (7q11.23 and Xp22.33) represented new candidate loci potentially involved in this disorder of pubertal timing. (AU)

• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 18/03198-0 - Comprehensive genetic investigation of patients with Central Precocious Puberty associated with complex phenotypes
• Grantee: Ana Pinheiro Machado Canton
• Support Opportunities: Scholarships in Brazil - Post-Doctoral