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SUN-081 High Throughput Genetic Analysis Revealed Novel Genomic Loci and Candidate Genes Involved in Central Precocious Puberty Associated with Complex Phenotypes

Background: Central precocious puberty (CPP) is mostly described as an isolated entity. Few studies have shown an association of CPP with complex cases or genetic syndromes, but without making inferences on molecular causalities. Objective: To genetically investigate a cohort of patients with CPP as...

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Autores principales: Canton, Ana Pinheiro-Machado, Krepischi, Ana, Montenegro, Luciana Ribeiro, Costa, Silvia, Rosenberg, Carla, Ramos, Carolina, Faria, Aline Guimarães, Seraphim, Carlos Eduardo, Tinano, Flávia Rezende, Kawahira, Rachel, Kim, Chong, de Zegher, Francis Edouard, de Assis Funari, Mariana Ferreira, Jorge, Alexander Augusto Lima, Mendonca, Berenice Bilharinho, Brito, Vinicius Nahime, Latronico, Ana Claudia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7208635/
http://dx.doi.org/10.1210/jendso/bvaa046.822
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author Canton, Ana Pinheiro-Machado
Krepischi, Ana
Montenegro, Luciana Ribeiro
Costa, Silvia
Rosenberg, Carla
Ramos, Carolina
Faria, Aline Guimarães
Seraphim, Carlos Eduardo
Tinano, Flávia Rezende
Kawahira, Rachel
Kim, Chong
de Zegher, Francis Edouard
de Assis Funari, Mariana Ferreira
Jorge, Alexander Augusto Lima
Mendonca, Berenice Bilharinho
Brito, Vinicius Nahime
Latronico, Ana Claudia
author_facet Canton, Ana Pinheiro-Machado
Krepischi, Ana
Montenegro, Luciana Ribeiro
Costa, Silvia
Rosenberg, Carla
Ramos, Carolina
Faria, Aline Guimarães
Seraphim, Carlos Eduardo
Tinano, Flávia Rezende
Kawahira, Rachel
Kim, Chong
de Zegher, Francis Edouard
de Assis Funari, Mariana Ferreira
Jorge, Alexander Augusto Lima
Mendonca, Berenice Bilharinho
Brito, Vinicius Nahime
Latronico, Ana Claudia
author_sort Canton, Ana Pinheiro-Machado
collection PubMed
description Background: Central precocious puberty (CPP) is mostly described as an isolated entity. Few studies have shown an association of CPP with complex cases or genetic syndromes, but without making inferences on molecular causalities. Objective: To genetically investigate a cohort of patients with CPP associated with complex phenotypes using high throughput methodologies. Patients and methods: From a large cohort of patients with idiopathic CPP followed at a university hospital outpatient clinic, thirty-eight patients were selected for high throughput genetic investigation for presenting at least 3 additional clinical features and conditions, characterizing complex phenotypes. All had normal brain MRI. Pathogenic allelic variants in CPP known genes were initially excluded. All patients were submitted to genomic microarray (SNP or CGH arrays). A subset of patients was also submitted to whole-exome sequencing (11 cases) or target panel sequencing (18 cases). Results: Among the group of 38 patients (35 girls, 4 boys; 21 sporadic, 17 familial), mean age at puberty onset was 5.8 ±2.1 and 8.3 ±3.0 yr in girls and boys, respectively. The more prevalent clinical features described included metabolic, growth and neurocognitive phenotypes; less prevalent features included dysmorphic features and congenital anomalies. Pathogenic or probably pathogenic genetic defects were identified in 9 cases: 5 sporadic (all identified as de novo) and 4 familial. Defects in sporadic cases were as follows: three cases with 7q11.23 deletion (Williams syndrome); one girl with ventricular arrhythmia presenting a rare 1p31.3 duplication, involving NFIA gene coding a transcription factor of NFI family with hypothalamic expression; and one girl with imperforate anus and learning difficulties with rare frameshift variants in AREL1 gene (p.Ser229Aspfs*3) coding an ubiquitin ligase, and TNRC6B gene (p.Gly665Leufs*35) coding a regulator of translational inhibition. In the four familial cases, the genetic defects segregated with CPP in a dominant inheritance mode. Three cases from unrelated families presented growth phenotypes and Xp22.33 deletions, including SHOX gene and other elements. One boy with maternal familial CPP and autism had two rare potentially pathogenic variants: a frameshift deletion in MKKS gene (p.Phe144Leufs*14); and a missense variant (p.Pro267Leu) in UGT2B4 gene. Interestingly, the later gene encodes a protein involved in estrogen hydroxylation and is associated to menarche timing in GWAS. Conclusion: Novel genetic defects were identified in 23% cases of CPP associated with complex phenotypes. Three chromosomal regions represented loci potentially implicated in CPP: Xp22.33, 7q11.23 and 1p31.3. Five genes were identified as candidate genes associated with CPP: NFIA, AREL1, TNRC6B, MKKS and UGT2B4.
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spelling pubmed-72086352020-05-13 SUN-081 High Throughput Genetic Analysis Revealed Novel Genomic Loci and Candidate Genes Involved in Central Precocious Puberty Associated with Complex Phenotypes Canton, Ana Pinheiro-Machado Krepischi, Ana Montenegro, Luciana Ribeiro Costa, Silvia Rosenberg, Carla Ramos, Carolina Faria, Aline Guimarães Seraphim, Carlos Eduardo Tinano, Flávia Rezende Kawahira, Rachel Kim, Chong de Zegher, Francis Edouard de Assis Funari, Mariana Ferreira Jorge, Alexander Augusto Lima Mendonca, Berenice Bilharinho Brito, Vinicius Nahime Latronico, Ana Claudia J Endocr Soc Pediatric Endocrinology Background: Central precocious puberty (CPP) is mostly described as an isolated entity. Few studies have shown an association of CPP with complex cases or genetic syndromes, but without making inferences on molecular causalities. Objective: To genetically investigate a cohort of patients with CPP associated with complex phenotypes using high throughput methodologies. Patients and methods: From a large cohort of patients with idiopathic CPP followed at a university hospital outpatient clinic, thirty-eight patients were selected for high throughput genetic investigation for presenting at least 3 additional clinical features and conditions, characterizing complex phenotypes. All had normal brain MRI. Pathogenic allelic variants in CPP known genes were initially excluded. All patients were submitted to genomic microarray (SNP or CGH arrays). A subset of patients was also submitted to whole-exome sequencing (11 cases) or target panel sequencing (18 cases). Results: Among the group of 38 patients (35 girls, 4 boys; 21 sporadic, 17 familial), mean age at puberty onset was 5.8 ±2.1 and 8.3 ±3.0 yr in girls and boys, respectively. The more prevalent clinical features described included metabolic, growth and neurocognitive phenotypes; less prevalent features included dysmorphic features and congenital anomalies. Pathogenic or probably pathogenic genetic defects were identified in 9 cases: 5 sporadic (all identified as de novo) and 4 familial. Defects in sporadic cases were as follows: three cases with 7q11.23 deletion (Williams syndrome); one girl with ventricular arrhythmia presenting a rare 1p31.3 duplication, involving NFIA gene coding a transcription factor of NFI family with hypothalamic expression; and one girl with imperforate anus and learning difficulties with rare frameshift variants in AREL1 gene (p.Ser229Aspfs*3) coding an ubiquitin ligase, and TNRC6B gene (p.Gly665Leufs*35) coding a regulator of translational inhibition. In the four familial cases, the genetic defects segregated with CPP in a dominant inheritance mode. Three cases from unrelated families presented growth phenotypes and Xp22.33 deletions, including SHOX gene and other elements. One boy with maternal familial CPP and autism had two rare potentially pathogenic variants: a frameshift deletion in MKKS gene (p.Phe144Leufs*14); and a missense variant (p.Pro267Leu) in UGT2B4 gene. Interestingly, the later gene encodes a protein involved in estrogen hydroxylation and is associated to menarche timing in GWAS. Conclusion: Novel genetic defects were identified in 23% cases of CPP associated with complex phenotypes. Three chromosomal regions represented loci potentially implicated in CPP: Xp22.33, 7q11.23 and 1p31.3. Five genes were identified as candidate genes associated with CPP: NFIA, AREL1, TNRC6B, MKKS and UGT2B4. Oxford University Press 2020-05-08 /pmc/articles/PMC7208635/ http://dx.doi.org/10.1210/jendso/bvaa046.822 Text en © Endocrine Society 2020. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Pediatric Endocrinology
Canton, Ana Pinheiro-Machado
Krepischi, Ana
Montenegro, Luciana Ribeiro
Costa, Silvia
Rosenberg, Carla
Ramos, Carolina
Faria, Aline Guimarães
Seraphim, Carlos Eduardo
Tinano, Flávia Rezende
Kawahira, Rachel
Kim, Chong
de Zegher, Francis Edouard
de Assis Funari, Mariana Ferreira
Jorge, Alexander Augusto Lima
Mendonca, Berenice Bilharinho
Brito, Vinicius Nahime
Latronico, Ana Claudia
SUN-081 High Throughput Genetic Analysis Revealed Novel Genomic Loci and Candidate Genes Involved in Central Precocious Puberty Associated with Complex Phenotypes
title SUN-081 High Throughput Genetic Analysis Revealed Novel Genomic Loci and Candidate Genes Involved in Central Precocious Puberty Associated with Complex Phenotypes
title_full SUN-081 High Throughput Genetic Analysis Revealed Novel Genomic Loci and Candidate Genes Involved in Central Precocious Puberty Associated with Complex Phenotypes
title_fullStr SUN-081 High Throughput Genetic Analysis Revealed Novel Genomic Loci and Candidate Genes Involved in Central Precocious Puberty Associated with Complex Phenotypes
title_full_unstemmed SUN-081 High Throughput Genetic Analysis Revealed Novel Genomic Loci and Candidate Genes Involved in Central Precocious Puberty Associated with Complex Phenotypes
title_short SUN-081 High Throughput Genetic Analysis Revealed Novel Genomic Loci and Candidate Genes Involved in Central Precocious Puberty Associated with Complex Phenotypes
title_sort sun-081 high throughput genetic analysis revealed novel genomic loci and candidate genes involved in central precocious puberty associated with complex phenotypes
topic Pediatric Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7208635/
http://dx.doi.org/10.1210/jendso/bvaa046.822
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