{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T17:46:27Z","timestamp":1788371187211,"version":"build-2803163510"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,26]],"date-time":"2021-01-26T00:00:00Z","timestamp":1611619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009890","name":"Provincia Autonoma di Trento","doi-asserted-by":"publisher","award":["dpg 1045\/2017"],"award-info":[{"award-number":["dpg 1045\/2017"]}],"id":[{"id":"10.13039\/501100009890","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Infertility affects about 7% of the general male population. The underlying cause of male infertility is undefined in about 50% of cases (idiopathic infertility). The number of genes involved in human spermatogenesis is over two thousand. Therefore, it is essential to analyze a large number of genes that may be involved in male infertility. This study aimed to test idiopathic male infertile patients negative for a validated panel of \u201cdiagnostic\u201d genes, for a wide panel of genes that we have defined as \u201cpre-diagnostic.\u201d<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We developed a next-generation sequencing (NGS) gene panel including 65 pre-diagnostic genes that were used in 12 patients who were negative to a diagnostic genetic test for male infertility disorders, including primary spermatogenic failure and central hypogonadism, consisting of 110 genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>After NGS sequencing, variants in pre-diagnostic genes were identified in 10\/12 patients who were negative to a diagnostic test for primary spermatogenic failure (n = 9) or central hypogonadism (n = 1) due to mutations of single genes. Two pathogenic variants of <jats:italic>DNAH5<\/jats:italic> and <jats:italic>CFTR<\/jats:italic> genes and three uncertain significance variants of <jats:italic>DNAI1<\/jats:italic>, <jats:italic>DNAH11<\/jats:italic>, and <jats:italic>CCDC40<\/jats:italic> genes were found. Moreover, three variants with high impact were found in <jats:italic>AMELY<\/jats:italic>, <jats:italic>CATSPER 2<\/jats:italic>, and <jats:italic>ADCY10<\/jats:italic> genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study suggests that searching for pre-diagnostic genes may be of relevance to find the cause of infertility in patients with apparently idiopathic primary spermatogenic failure due to mutations of single genes and central hypogonadism.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2020.605237","type":"journal-article","created":{"date-parts":[[2021,1,26]],"date-time":"2021-01-26T17:02:54Z","timestamp":1611680574000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":33,"title":["Male Infertility Diagnosis: Improvement of Genetic Analysis Performance by the Introduction of Pre-Diagnostic Genes in a Next-Generation Sequencing Custom-Made 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