1. Início
  2. Publicações
  3. Genetic architecture of congenital hypogonadotropic hypogonadism: insights from analysis of a Portuguese cohort

Genetic architecture of congenital hypogonadotropic hypogonadism: insights from analysis of a Portuguese cohort

Data de publicação:

Autores da FMUP

  • Davide Maurício Costa Carvalho

    Autor

Participantes de fora da FMUP

  • Carrico, Josianne Nunes
  • Goncalves, Catarina Ines
  • Al-Naama, Asma
  • Syed, Najeeb
  • Aragues, Jose Maria
  • Bastos, Margarida
  • Fonseca, Fernando
  • Borges, Teresa
  • Pereira, Bernardo Dias
  • Pignatelli, Duarte
  • Cunha, Filipe
  • Saavedra, Ana
  • Rodrigues, Elisabete
  • Saraiva, Joana
  • Ruas, Luisa
  • Vicente, Nuno
  • Martins, Joao Martin
  • De Sousa Lages, Adriana
  • Oliveira, Maria Joao
  • Castro-Correia, Cintia
  • Melo, Miguel
  • Martins, Raquel Gomes
  • Couto, Joana
  • Moreno, Carolina
  • Martins, Diana
  • Oliveira, Patricia
  • Martins, Teresa
  • Martins, Sofia Almeida
  • Marques, Olinda
  • Meireles, Carla
  • Garrao, Antonio
  • Nogueira, Claudia
  • Baptista, Carla
  • Gama-de-Sousa, Susana
  • Amaral, Claudia
  • Martinho, Mariana
  • Limbert, Catarina
  • Barros, Luisa
  • Vieira, Ines Henriques
  • Sabino, Teresa
  • Saraiva, Luis R.
  • Lemos, Manuel Carlos

Unidades de investigação

Abstract

STUDY QUESTION: What is the contribution of genetic defects in Portuguese patients with congenital hypogonadotropic hypogonadism (CHH)? SUMMARY ANSWER: Approximately one-third of patients with CHH were found to have a genetic cause for their disorder, with causal pathogenic and likely pathogenic germline variants distributed among 10 different genes; cases of oligogenic inheritance were also included. WHAT IS KNOWN ALREADY: CHH is a rare and genetically heterogeneous disorder characterized by deficient production, secretion, or action of GnRH, LH, and FSH, resulting in delayed or absent puberty, and infertility. STUDY DESIGN, SIZE, DURATION: Genetic screening was performed on a cohort of 81 Portuguese patients with CHH (36 with Kallmann syndrome and 45 with normosmic hypogonadotropic hypogonadism) and 263 unaffected controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: The genetic analysis was performed by whole-exome sequencing followed by the analysis of a virtual panel of 169 CHH-associated genes. The main outcome measures were non-synonymous rare sequence variants (population allele frequency <0.01) classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS). MAIN RESULTS AND THE ROLE OF CHANCE: A genetic cause was identified in 29.6% of patients. Causal pathogenic and likely pathogenic variants were distributed among 10 of the analysed genes. The most frequently implicated genes were GNRHR, FGFR1, ANOS1, and CHD7. Oligogenicity for pathogenic and likely pathogenic variants was observed in 6.2% of patients. VUS and oligogenicity for VUS variants were observed in 85.2% and 54.3% of patients, respectively, but were not significantly different from that observed in controls. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The identification of a large number of VUS presents challenges in interpretation and these may require reclassification as more evidence becomes available. Non-coding and copy number variants were not studied. Functional studies of the variants were not undertaken. WIDER IMPLICATIONS OF THE FINDINGS: This study highlights the genetic heterogeneity of CHH and identified several novel variants that expand the mutational spectrum of the disorder. A significant proportion of patients remained without a genetic diagnosis, suggesting the involvement of additional genetic, epigenetic, or environmental factors. The high frequency of VUS underscores the importance of cautious variant interpretation. These findings contribute to the understanding of the genetic architecture of CHH and emphasize the need for further studies to elucidate the underlying mechanisms and identify additional causes of CHH.

Dados da publicação

ISSN/ISSNe:
2399-3529, 2399-3529

Human Reproduction Open  OXFORD UNIV PRESS

Tipo:
Article
Páginas:
-
Link para outro recurso:
www.scopus.com

Documentos

  • Não há documentos

Métricas

Filiações mostrar / ocultar

Keywords

  • congenital hypogonadotropic hypogonadism; Kallmann syndrome; whole-exome sequencing; genetics; mutation

Campos de estudo

Proyectos asociados

Male sex, the levels of prolactin, presence of hypopituitarism and suprasellar extension are predictors of prolactinomas resistance to medical therapy

Investigador Principal: Davide Maurício Costa Carvalho

Estudo Clínico Académico (Prolactinomas) . 2023

Acromegalia: Metabolismo da Glicose Como Possível Preditor de Tumores Mais Agressivos

Investigador Principal: Davide Maurício Costa Carvalho

Estudo Clínico Académico . 2022

Diabetic Neuropathy, Central Nervous System Plasticity and Metabolic Disfunction

Investigador Principal: Davide Maurício Costa Carvalho

Estudo Clínico Académico . 2020

Citar a publicação

Partilhar a publicação