A systematic review on the genetics of male infertility in the era of next-generation sequencing

Robay, Amal; Abbasi, Saleha; Akil, Ammira Al‐Shabeeb; Elbardisi, Haitham; Arafa, Mohamed; Crystal, Ronald G.; Fakhro, Khalid

doi:10.1016/j.aju.2017.12.003

Cited by 41 publications

(31 citation statements)

References 68 publications

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“…ale factor infertility is a complex disease with multifactorial etiologies, in which genetic, epigenetic, and nongenic factors interplay in the pathophysiology of the condition (1,2). Considerable attention has been paid to uncovering the role played by a vast number of genes in the control of human spermatogenesis (3,4). However, the role of most of these genes in male factor fertility is still unclear, and their function is driven by a number of underlying regulators, including microRNAs (miRNAs).…”

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confidence: 99%

Differential expression of miR-23a/b-3p and its target genes in male patients with subfertility

Abu‐Halima

Ayesh

Hart

et al. 2019

Fertility and Sterility

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Objective: To elucidate the potential regulatory function of miR-23a/b-3p on spermatogenesis-specific genes. Design: Reverse transcription quantitative polymerase chain reaction (RT-qPCR) validation, Northern blot, dual luciferase assay, and Western blot confirmation. Setting: University research and clinical institutes. Patient(s): A total of 115 men presenting at an infertility clinic. Intervention(s): None. Main Outcome Measure(s): Significant higher abundance levels of miR-23a/b-3p and lower abundance levels of PFKFB4, HMMR, SPATA6, and TEX15 in oligoasthenozoospermic men compared with those in normozoospermic men. Result(s): In oligoasthenozoospermic men, the abundance levels of miR-23a/b-3p were significantly higher when compared with controls as determined by RT-qPCR. After in silico prediction of potential targets of miR-23a/b-3p, PFKFB4, HMMR, SPATA6, and TEX15 have been identified as direct targets by dual luciferase assays. Mutations in the miR-23a/b-3p binding site within the 3 0 UTRs resulted in abrogated responsiveness to miR-23a/b-3p. PFKFB4, HMMR, SPATA6, and TEX15 mRNA and HMMR and SPATA6 protein levels were significantly lower in oligoasthenozoospermic men compared with in normozoospermic men. Correlation analysis showed that the sperm count, motility, and morphology were negatively correlated with miR-23a/b-3p and positively correlated with PFKFB4, HMMR, SPATA6, and TEX15 abundance levels (lower DCt, the higher abundance levels). Conclusion(s): This study establishes a link between up-regulation of miR-23a/b-3p and the coincident down-regulation of four expressed genes in the sperm of men with oligoasthenozoospermia, compared with men with normozoospermia. This study provides a novel insight into some of the mechanisms leading to male subfertility, offering a possible therapeutic target for treatment, or even for male contraception. (Fertil Steril Ò 2019;112:323-35. Ó2019 by American Society for Reproductive Medicine.) El resumen está disponible en Español al final del artículo.

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confidence: 99%

Differential expression of miR-23a/b-3p and its target genes in male patients with subfertility

Abu‐Halima

Ayesh

Hart

et al. 2019

Fertility and Sterility

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“…Within this scenario, the next-generation sequencing (NGS) technique can improve and personalize male infertility diagnosis. In addition, NGS can allow the simultaneous analysis of a large cohorts of infertile patients and the screening of multiple disease-causing variants of many genes [ 27 ]. The use of multigene panels can be a useful tool to improve the diagnostic framework of the patients [ 21 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, NGS can allow the simultaneous analysis of a large cohorts of infertile patients and the screening of multiple disease-causing variants of many genes [ 27 ]. The use of multigene panels can be a useful tool to improve the diagnostic framework of the patients [ 21 , 27 ]. 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 that may support a more accurate management of male infertility.…”

Section: Introductionmentioning

confidence: 99%

Clinical Evaluation of a Custom Gene Panel as a Tool for Precision Male Infertility Diagnosis by Next-Generation Sequencing

Cannarella

Precone²,

Busetto

et al. 2020

Life

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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.

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“…Studies in mice have identified 666 genes that cause male infertility when disrupted (Nagirnaja et al 2018 ). As genomic information continues to accumulate, an increasing number of genetic variations linked to male infertility are expected to be identified, and the search for novel genetic variations that underlie male factor infertility is already underway (Miyamoto et al 2017 ; Robay et al 2018 ; Halder et al 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Genetic mapping of a male factor subfertility locus on mouse chromosome 4

2018

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Male reproductive anomalies are widely distributed among mammals, and male factors are estimated to contribute to approximately 50% of cases of human infertility. The B10.M/Sgn (B10.M) mouse strain exhibits two adverse reproductive phenotypes: severe teratospermia and male subfertility. Although teratospermia is known to be heritable, the relationship between teratospermia and male subfertility has not been well characterized. The fertility of B10.M male mice is considerably lower (~ 30%) than that of standard laboratory mouse strains (~ 70%). To genetically analyze male subfertility, F2 males were produced by intercrossing the F1 progeny of female B10.M and male C3H/HeN mice. The fertility of each F2 male mouse was assessed based on the outcomes of matings with five females. Statistical analysis of correlations between the two reproductive phenotypes (teratospermia and subfertility) in F2 males (n = 177) revealed that teratospermia is not the cause of male subfertility. Quantitative trait loci (QTL) analysis of the male subfertility phenotype (n = 128) using GigaMUGA markers mapped one significant QTL peak to chromosome 4 at 62.9 centimorgans (cM) with a logarithm of odds score of 11.81 (P < 0.05). We named the QTL locus Mfsf1 (male factor subfertility 1). Further genetic analysis using recombinant males restricted the physical area to 1.53 megabasepairs (Mbp), encompassing 22 protein-coding genes. In addition, we found one significant QTL and one indicative QTL on chromosome 5 and 12, respectively, that interacted with the Mfsf1 locus. Our results demonstrate that genetic dissection of male subfertility in the B10.M strain is a useful model for characterizing the complex genetic mechanisms underlying reproduction and infertility.Electronic supplementary materialThe online version of this article (10.1007/s00335-018-9773-4) contains supplementary material, which is available to authorized users.

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A systematic review on the genetics of male infertility in the era of next-generation sequencing

Cited by 41 publications

References 68 publications

Differential expression of miR-23a/b-3p and its target genes in male patients with subfertility

Differential expression of miR-23a/b-3p and its target genes in male patients with subfertility

Clinical Evaluation of a Custom Gene Panel as a Tool for Precision Male Infertility Diagnosis by Next-Generation Sequencing

Genetic mapping of a male factor subfertility locus on mouse chromosome 4

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