Abstract
BackgroundInfertility 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.”MethodsWe 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.ResultsAfter 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.ConclusionThis 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.
Highlights
The increasing knowledge of male reproduction physiology, of fertilization, and the advent of increasingly effective assisted reproductive techniques, have led to a profound change in the management of male infertility
Over 200 genetic disorders related to male infertility are reported in the Online Mendelian Inheritance in Man (OMIM) database [7, 8]
The genetic of male infertility is greatly complex because semen and testis histological phenotypes are very heterogeneous and up to 2,300 genes are involved in spermatogenesis [1, 9]
Summary
The increasing knowledge of male reproduction physiology, of fertilization, and the advent of increasingly effective assisted reproductive techniques, have led to a profound change in the management of male infertility. The diagnostic workflow offered to male infertile patients includes medical history collection and physical examination, followed by a combination of laboratory testing tailored to each case, including an in-depth genetic laboratory analysis [1,2,3]. Genetic factors are found in about 15% of male infertile patients. They include chromosomal abnormalities or singlegene mutations [5, 6]. The genetic of male infertility is greatly complex because semen and testis histological phenotypes are very heterogeneous and up to 2,300 genes are involved in spermatogenesis [1, 9]. 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.”
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