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Doctoral Thesis
DOI
https://doi.org/10.11606/T.5.2020.tde-10032020-152009
Document
Author
Full name
Priscila Sales Barroso
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2019
Supervisor
Committee
Xavier, Ana Claudia Latrônico (President)
Gomes, Larissa Garcia
Miachon, Adriana Aparecida Siviero
Longui, Carlos Alberto
Title in Portuguese
Pesquisa de novos fatores genéticos no atraso constitucional do crescimento e desenvolvimento humano
Keywords in Portuguese
Crescimento
Desenvolvimento do adolescente
Genética humana
Hipogonadismo
Maturidade Sexual
Puberdade tardia
Sequenciamento de nova geração
Abstract in Portuguese
O atraso constitucional do crescimento e desenvolvimento (ACCD) e a causa mais prevalente de puberdade tardia em ambos os sexos. O principal diagnostico diferencial do ACCD e o hipogonadismo hipogonadotrofico isolado (HHI) congenito. Aproximadamente 50 a 75% dos pacientes com ACCD possuem historia familiar de puberdade atrasada e a heranca frequentemente e consistente com um padrao autossomico dominante, com ou sem penetrancia completa. No entanto, a base molecular do ACCD ainda nao e completamente compreendida. O objetivo deste estudo foi caracterizar as caracteristicas clinicas e geneticas de uma coorte de pacientes com ACCD. Cinquenta e nove individuos com ACCD (48 meninos e 11 meninas) foram submetidos a cuidadosa avaliacao clinica. Os criterios de inclusao foram ausencia de aumento testicular (volume <= 3 mL) em meninos com 13,5 anos de idade ou mais, ausencia de telarca em meninas com 13 anos de idade ou mais, baixos niveis sericos de esteroides sexuais para sexo e idade com baixos niveis sericos de gonadotrofinas, desenvolvimento puberal espontaneo ou apos tratamento transitorio com baixas doses de esteroides sexuais antes dos 18 anos de idade. Os criterios de exclusao foram doencas cronicas graves, deficiencia de hormonios hipofisarios, anosmia, criptorquidia ou micropenis na infancia. O seguimento de longo prazo excluiu outras causas de puberdade tardia como HHI congenito. A analise genetica foi realizada utilizando-se sequenciamento paralelo de larga escala por meio de painel genico personalizado contendo 36 genes conhecidos e candidatos relacionados ao HHI congenito, ACCD ou outros disturbios puberais. Os dados resultantes foram avaliados para selecao de variantes raras (MAF < 0,01) em bancos de dados publicos internacionais e nacionais. Priorizamos variantes localizadas em regioes exonicas e de sitio de splice e selecionamos variantes com base em seu potencial de patogenicidade de acordo com analise in silico. Sequenciamento de Sanger e analise de segregacao familiar foram realizados quando os DNAs dos pais estavam disponiveis. Predominancia do sexo masculino (81%), baixa estatura (91%) e historia familiar positiva (59%) foram as principais caracteristicas clinicas dessa coorte de ACCD. As analises geneticas revelaram 15 variantes raras do tipo missense em heterozigose em 15 pacientes com ACCD (25%) em sete genes diferentes (IGSF10, GHSR, CHD7, SEMA3A, IL17RD, SPRY4 e WDR11). IGSF10 e GHSR foram os genes afetados mais prevalentes neste grupo. Em conclusao, identificamos variantes raras do tipo missense em heterozigose em genes implicados na migracao do GnRH e no metabolismo em 25% dos pacientes com ACCD familiar ou esporadico, sugerindo heterogeneidade genetica nessa condicao pediatrica frequente
Title in English
Research of new genetic factors in the constitutional delay of growth and development in human
Keywords in English
Adolescent development
Growth
Human genetics
Hypogonadism
Next-generation sequencing
Puberty delayed
Sexual maturation
Abstract in English
Constitutional delay of growth and puberty (CDGP) is the most prevalent cause of delayed puberty in both sexes. The main differential diagnosis of CDGP is congenital isolated hypogonadotropic hypogonadism (IHH). Approximately 50 to 75% of patients with CDGP have a family history of delayed puberty and the inheritance often is consistent with an autosomal dominant pattern, with or without complete penetrance. However, the molecular basis of CDGP is not completely understood. The objective of this study was to characterize the clinical and genetic features of a CDGP cohort. Fifty-nine individuals with CDGP (48 boys and 11 girls) underwent careful clinical evaluation. Inclusion criteria were absence of testicular enlargement (volume <= 3 mL) in boys after 13.5 years of age, absence of thelarche in girls after 13 years of age, low serum levels of sexual steroids for sex and age with low serum levels of gonadotropins, and spontaneous pubertal development or after transient treatment with low doses of sexual steroids prior the age 18 years. Exclusion criteria were chronic diseases, deficiency of pituitary hormones, anosmia, cryptorchidism and/or micropenis in childhood. Long-term follow-up excluded other causes of delayed puberty as congenital IHH. Genetic analysis was performed using next-generation sequencing through a custom targeted gene panel designed to capture 36 known and candidate genes related to congenital IHH, CDGP, or other puberty disorders. Data were screened for selection of rare variants (MAF < 0.01) in public international and national databases. We prioritized variants located in exonic and splice site regions and we selected variants based on their pathogenicity potential according to in silico analysis. Sanger sequencing and family segregation analysis were performed when parent's DNAs were available. Male predominance (81%), short stature (91%) and positive family history (59%) were the main clinical characteristics of this CDGP cohort. Genetic analysis revealed 15 rare heterozygous missense variants in 15 CDGP patients (25%) in seven different genes (IGSF10, GHSR, CHD7, SEMA3A, IL17RD, SPRY4 and WDR11). IGSF10 and GHSR were the most prevalent affected genes in this group. In conclusion, we identified rare missense heterozygous variants in genes implicated in GnRH migration and metabolism in 25% of patients with sporadic or familial ACCD, suggesting genetic heterogeneity in this frequent pediatric condition
 
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Publishing Date
2020-03-10
 
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