Vincenza Precone1, Rossella Cannarella2, Stefano Paolacci3, Gian Maria Busetto4, Tommaso Beccari5, Liborio Stuppia6, Gerolamo Tonini7, Alessandra Zulian3, Giuseppe Marceddu1, Aldo E Calogero2, Matteo Bertelli1,3,8. 1. MAGI EUREGIO, Bolzano, Italy. 2. Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy. 3. MAGI'S LAB, Rovereto, Italy. 4. Department of Urology, "Sapienza" University of Rome, Policlinico Umberto I, Rome, Italy. 5. Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy. 6. Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy. 7. Department of Surgery, Fondazione Poliambulanza, Brescia, Italy. 8. EBTNA-LAB, Rovereto, Italy.
Abstract
Background: 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 "diagnostic" genes, for a wide panel of genes that we have defined as "pre-diagnostic." Methods: 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. Results: 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 DNAH5 and CFTR genes and three uncertain significance variants of DNAI1, DNAH11, and CCDC40 genes were found. Moreover, three variants with high impact were found in AMELY, CATSPER 2, and ADCY10 genes. Conclusion: 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.
Background: 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 infertilepatients negative for a validated panel of "diagnostic" genes, for a wide panel of genes that we have defined as "pre-diagnostic." Methods: 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. Results: 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 DNAH5 and CFTR genes and three uncertain significance variants of DNAI1, DNAH11, and CCDC40 genes were found. Moreover, three variants with high impact were found in AMELY, CATSPER 2, and ADCY10 genes. Conclusion: 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.
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