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Molecular genetic diagnostics of hypogonadotropic hypogonadism: from panel design towards result interpretation in clinical practice

Congenital hypogonadotropic hypogonadism (CHH) is a clinically and genetically heterogeneous congenital disease. Symptoms cover a wide spectrum from mild forms to complex phenotypes due to gonadotropin-releasing hormone (GnRH) deficiency. To date, more than 40 genes have been identified as pathogeni...

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Autores principales: Butz, Henriett, Nyírő, Gábor, Kurucz, Petra Anna, Likó, István, Patócs, Attila
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864839/
https://www.ncbi.nlm.nih.gov/pubmed/32222824
http://dx.doi.org/10.1007/s00439-020-02148-0
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author Butz, Henriett
Nyírő, Gábor
Kurucz, Petra Anna
Likó, István
Patócs, Attila
author_facet Butz, Henriett
Nyírő, Gábor
Kurucz, Petra Anna
Likó, István
Patócs, Attila
author_sort Butz, Henriett
collection PubMed
description Congenital hypogonadotropic hypogonadism (CHH) is a clinically and genetically heterogeneous congenital disease. Symptoms cover a wide spectrum from mild forms to complex phenotypes due to gonadotropin-releasing hormone (GnRH) deficiency. To date, more than 40 genes have been identified as pathogenic cause of CHH. These genes could be grouped into two major categories: genes controlling development and GnRH neuron migration and genes being responsible for neuroendocrine regulation and GnRH neuron function. High-throughput, next-generation sequencing (NGS) allows to analyze numerous gene sequences at the same time. Nowadays, whole exome or whole genome datasets could be investigated in clinical genetic diagnostics due to their favorable cost–benefit. The increasing genetic data generated by NGS reveal novel candidate genes and gene variants with unknown significance (VUSs). To provide clinically valuable genetic results, complex clinical and bioinformatics work are needed. The multifaceted genetics of CHH, the variable mode of inheritance, the incomplete penetrance, variable expressivity and oligogenic characteristics further complicate the interpretation of the genetic variants detected. The objective of this work, apart from reviewing the currently known genes associated with CHH, was to summarize the advantages and disadvantages of the NGS-based platforms and through the authors’ own practice to guide through the whole workflow starting from gene panel design, performance analysis and result interpretation. Based on our results, a genetic diagnosis was clearly identified in 21% of cases tested (8/38). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00439-020-02148-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-78648392021-02-16 Molecular genetic diagnostics of hypogonadotropic hypogonadism: from panel design towards result interpretation in clinical practice Butz, Henriett Nyírő, Gábor Kurucz, Petra Anna Likó, István Patócs, Attila Hum Genet Review Congenital hypogonadotropic hypogonadism (CHH) is a clinically and genetically heterogeneous congenital disease. Symptoms cover a wide spectrum from mild forms to complex phenotypes due to gonadotropin-releasing hormone (GnRH) deficiency. To date, more than 40 genes have been identified as pathogenic cause of CHH. These genes could be grouped into two major categories: genes controlling development and GnRH neuron migration and genes being responsible for neuroendocrine regulation and GnRH neuron function. High-throughput, next-generation sequencing (NGS) allows to analyze numerous gene sequences at the same time. Nowadays, whole exome or whole genome datasets could be investigated in clinical genetic diagnostics due to their favorable cost–benefit. The increasing genetic data generated by NGS reveal novel candidate genes and gene variants with unknown significance (VUSs). To provide clinically valuable genetic results, complex clinical and bioinformatics work are needed. The multifaceted genetics of CHH, the variable mode of inheritance, the incomplete penetrance, variable expressivity and oligogenic characteristics further complicate the interpretation of the genetic variants detected. The objective of this work, apart from reviewing the currently known genes associated with CHH, was to summarize the advantages and disadvantages of the NGS-based platforms and through the authors’ own practice to guide through the whole workflow starting from gene panel design, performance analysis and result interpretation. Based on our results, a genetic diagnosis was clearly identified in 21% of cases tested (8/38). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00439-020-02148-0) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2020-03-28 2021 /pmc/articles/PMC7864839/ /pubmed/32222824 http://dx.doi.org/10.1007/s00439-020-02148-0 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Review
Butz, Henriett
Nyírő, Gábor
Kurucz, Petra Anna
Likó, István
Patócs, Attila
Molecular genetic diagnostics of hypogonadotropic hypogonadism: from panel design towards result interpretation in clinical practice
title Molecular genetic diagnostics of hypogonadotropic hypogonadism: from panel design towards result interpretation in clinical practice
title_full Molecular genetic diagnostics of hypogonadotropic hypogonadism: from panel design towards result interpretation in clinical practice
title_fullStr Molecular genetic diagnostics of hypogonadotropic hypogonadism: from panel design towards result interpretation in clinical practice
title_full_unstemmed Molecular genetic diagnostics of hypogonadotropic hypogonadism: from panel design towards result interpretation in clinical practice
title_short Molecular genetic diagnostics of hypogonadotropic hypogonadism: from panel design towards result interpretation in clinical practice
title_sort molecular genetic diagnostics of hypogonadotropic hypogonadism: from panel design towards result interpretation in clinical practice
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864839/
https://www.ncbi.nlm.nih.gov/pubmed/32222824
http://dx.doi.org/10.1007/s00439-020-02148-0
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