Abstract
Background: Up to 15% of couples are infertile and male factor infertility accounts for approximately 50% of these cases. Male infertility is a multifactorial pathological condition. The genetic of male infertility is very complex and at least 2000 genes are involved in its etiology. Genetic testing by next-generation sequencing (NGS) technologies can be relevant for its diagnostic value in male infertile patients. Therefore, the aim of this study was to implement the diagnostic offer with the use of an NGS panel for the identification of genetic variants. Methods: We developed an NGS gene panel that we used in 22 male infertile patients. The panel consisted of 110 genes exploring the genetic causes of male infertility; namely spermatogenesis failure due to single-gene mutations, central hypogonadism, androgen insensitivity syndrome, congenital hypopituitarism, and primary ciliary dyskinesia. Results: NGS and a subsequent sequencing of the positive pathogenic or likely pathogenic variants, 5 patients (23%) were found to have a molecular defect. In particular, pathogenic variants were identified in TEX11, CCDC39, CHD7, and NR5A1 genes. Moreover, 14 variants of unknown significance and 7 novel variants were found that require further functional studies and family segregation. Conclusion: This extended NGS-based diagnostic approach may represent a useful tool for the diagnosis of male infertility. The development of a custom-made gene panel by NGS seems capable of reducing the proportion of male idiopathic infertility.
Highlights
It is estimated that about 48.5 million couples worldwide are affected by infertility [1,2,3].Epidemiological data have addressed to the male factor an etiologic role, alone or in combination, in the half of cases of couple’s infertility [4]
The diagnostic suspects, made matching data coming from anamnesis, physical examination, hormone values, scrotal ultrasound, and/or sperm analysis, were primary spermatogenic defects (n = 16), central hypogonadism (n = 3), androgen insensitivity (n = 1), congenital hypopituitarism (n = 1), and primary ciliary dyskinesia (n = 1)
Additional genetic anomalies contributing to male infertility are constantly identified
Summary
It is estimated that about 48.5 million couples worldwide are affected by infertility [1,2,3].Epidemiological data have addressed to the male factor an etiologic role, alone or in combination, in the half of cases of couple’s infertility [4]. The secondary male infertility is due to systemic or syndromic genetic defects [6]. Genetic analysis is of relevance since about 15–30% of male infertility cases may recognize a genetic factor [14,15,16]. The genetic of male infertility is very complex and at least 2000 genes are involved in its etiology. Genetic testing by next-generation sequencing (NGS) technologies can be relevant for its diagnostic value in male infertile patients. Methods: We developed an NGS gene panel that we used in 22 male infertile patients. The panel consisted of 110 genes exploring the genetic causes of male infertility; namely spermatogenesis failure due to single-gene mutations, central hypogonadism, androgen insensitivity syndrome, congenital hypopituitarism, and primary ciliary dyskinesia. The development of a custom-made gene panel by NGS seems capable of reducing the proportion of male idiopathic infertility
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