Targeted Next-Generation Sequencing Indicates a Frequent Oligogenic Involvement in Primary Ovarian Insufficiency Onset

Primary ovarian insufficiency (POI) is one of the major causes of female infertility associated with the premature loss of ovarian function in about 3.7% of women before the age of 40. This disorder is highly heterogeneous and can manifest with a wide range of clinical phenotypes, ranging from ovari...

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Autores principales:	Raffaella Rossetti, Silvia Moleri, Fabiana Guizzardi, Davide Gentilini, Laura Libera, Anna Marozzi, Costanzo Moretti, Francesco Brancati, Marco Bonomi, Luca Persani
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	primary ovarian insufficiency primary amenorrhea secondary amenorrhea oligogenic disease next-generation sequencing Diseases of the endocrine glands. Clinical endocrinology RC648-665
Acceso en línea:	https://doaj.org/article/00700cf521134521bf5d875a717a7102
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spelling	oai:doaj.org-article:00700cf521134521bf5d875a717a71022021-11-04T09:10:05ZTargeted Next-Generation Sequencing Indicates a Frequent Oligogenic Involvement in Primary Ovarian Insufficiency Onset1664-239210.3389/fendo.2021.664645https://doaj.org/article/00700cf521134521bf5d875a717a71022021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fendo.2021.664645/fullhttps://doaj.org/toc/1664-2392Primary ovarian insufficiency (POI) is one of the major causes of female infertility associated with the premature loss of ovarian function in about 3.7% of women before the age of 40. This disorder is highly heterogeneous and can manifest with a wide range of clinical phenotypes, ranging from ovarian dysgenesis and primary amenorrhea to post-pubertal secondary amenorrhea, with elevated serum gonadotropins and hypoestrogenism. The ovarian defect still remains idiopathic in some cases; however, a strong genetic component has been demonstrated by the next-generation sequencing (NGS) approach of familiar and sporadic POI cases. As recent evidence suggested an oligogenic architecture for POI, we developed a target NGS panel with 295 genes including known candidates and novel genetic determinants potentially involved in POI pathogenesis. Sixty-four patients with early onset POI (range: 10–25 years) of our cohort have been screened with 90% of target coverage at 50×. Here, we report 48 analyzed patients with at least one genetic variant (75%) in the selected candidate genes. In particular, we found the following: 11/64 patients (17%) with two variants, 9/64 (14%) with three variants, 9/64 (14%) with four variants, 3/64 (5%) with five variants, and 2/64 (3%) with six variants. The most severe phenotypes were associated with either the major number of variations or a worse prediction in pathogenicity of variants. Bioinformatic gene ontology analysis identified the following major pathways likely affected by gene variants: 1) cell cycle, meiosis, and DNA repair; 2) extracellular matrix remodeling; 3) reproduction; 4) cell metabolism; 5) cell proliferation; 6) calcium homeostasis; 7) NOTCH signaling; 8) signal transduction; 9) WNT signaling; 10) cell death; and 11) ubiquitin modifications. Consistently, the identified pathways have been described in other studies dissecting the mechanisms of folliculogenesis in animal models of altered fertility. In conclusion, our results contribute to define POI as an oligogenic disease and suggest novel candidates to be investigated in patients with POI.Raffaella RossettiSilvia MoleriFabiana GuizzardiFabiana GuizzardiDavide GentiliniLaura LiberaAnna MarozziCostanzo MorettiFrancesco BrancatiFrancesco BrancatiMarco BonomiMarco BonomiLuca PersaniLuca PersaniFrontiers Media S.A.articleprimary ovarian insufficiencyprimary amenorrheasecondary amenorrheaoligogenic diseasenext-generation sequencingDiseases of the endocrine glands. Clinical endocrinologyRC648-665ENFrontiers in Endocrinology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	primary ovarian insufficiency primary amenorrhea secondary amenorrhea oligogenic disease next-generation sequencing Diseases of the endocrine glands. Clinical endocrinology RC648-665
spellingShingle	primary ovarian insufficiency primary amenorrhea secondary amenorrhea oligogenic disease next-generation sequencing Diseases of the endocrine glands. Clinical endocrinology RC648-665 Raffaella Rossetti Silvia Moleri Fabiana Guizzardi Fabiana Guizzardi Davide Gentilini Laura Libera Anna Marozzi Costanzo Moretti Francesco Brancati Francesco Brancati Marco Bonomi Marco Bonomi Luca Persani Luca Persani Targeted Next-Generation Sequencing Indicates a Frequent Oligogenic Involvement in Primary Ovarian Insufficiency Onset
description	Primary ovarian insufficiency (POI) is one of the major causes of female infertility associated with the premature loss of ovarian function in about 3.7% of women before the age of 40. This disorder is highly heterogeneous and can manifest with a wide range of clinical phenotypes, ranging from ovarian dysgenesis and primary amenorrhea to post-pubertal secondary amenorrhea, with elevated serum gonadotropins and hypoestrogenism. The ovarian defect still remains idiopathic in some cases; however, a strong genetic component has been demonstrated by the next-generation sequencing (NGS) approach of familiar and sporadic POI cases. As recent evidence suggested an oligogenic architecture for POI, we developed a target NGS panel with 295 genes including known candidates and novel genetic determinants potentially involved in POI pathogenesis. Sixty-four patients with early onset POI (range: 10–25 years) of our cohort have been screened with 90% of target coverage at 50×. Here, we report 48 analyzed patients with at least one genetic variant (75%) in the selected candidate genes. In particular, we found the following: 11/64 patients (17%) with two variants, 9/64 (14%) with three variants, 9/64 (14%) with four variants, 3/64 (5%) with five variants, and 2/64 (3%) with six variants. The most severe phenotypes were associated with either the major number of variations or a worse prediction in pathogenicity of variants. Bioinformatic gene ontology analysis identified the following major pathways likely affected by gene variants: 1) cell cycle, meiosis, and DNA repair; 2) extracellular matrix remodeling; 3) reproduction; 4) cell metabolism; 5) cell proliferation; 6) calcium homeostasis; 7) NOTCH signaling; 8) signal transduction; 9) WNT signaling; 10) cell death; and 11) ubiquitin modifications. Consistently, the identified pathways have been described in other studies dissecting the mechanisms of folliculogenesis in animal models of altered fertility. In conclusion, our results contribute to define POI as an oligogenic disease and suggest novel candidates to be investigated in patients with POI.
format	article
author	Raffaella Rossetti Silvia Moleri Fabiana Guizzardi Fabiana Guizzardi Davide Gentilini Laura Libera Anna Marozzi Costanzo Moretti Francesco Brancati Francesco Brancati Marco Bonomi Marco Bonomi Luca Persani Luca Persani
author_facet	Raffaella Rossetti Silvia Moleri Fabiana Guizzardi Fabiana Guizzardi Davide Gentilini Laura Libera Anna Marozzi Costanzo Moretti Francesco Brancati Francesco Brancati Marco Bonomi Marco Bonomi Luca Persani Luca Persani
author_sort	Raffaella Rossetti
title	Targeted Next-Generation Sequencing Indicates a Frequent Oligogenic Involvement in Primary Ovarian Insufficiency Onset
title_short	Targeted Next-Generation Sequencing Indicates a Frequent Oligogenic Involvement in Primary Ovarian Insufficiency Onset
title_full	Targeted Next-Generation Sequencing Indicates a Frequent Oligogenic Involvement in Primary Ovarian Insufficiency Onset
title_fullStr	Targeted Next-Generation Sequencing Indicates a Frequent Oligogenic Involvement in Primary Ovarian Insufficiency Onset
title_full_unstemmed	Targeted Next-Generation Sequencing Indicates a Frequent Oligogenic Involvement in Primary Ovarian Insufficiency Onset
title_sort	targeted next-generation sequencing indicates a frequent oligogenic involvement in primary ovarian insufficiency onset
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/00700cf521134521bf5d875a717a7102
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Targeted Next-Generation Sequencing Indicates a Frequent Oligogenic Involvement in Primary Ovarian Insufficiency Onset

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