Genetic Basis of Male and Female Infertility

Mallepaly, Rathika; Butler, Peter R.; Herati, Amin S.; Lamb, Dolores J.

doi:10.1159/000477275

Cited by 23 publications

(28 citation statements)

References 110 publications

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“…Male infertility can be the result of non-genetic or genetic factors, and it is often multifactorial and/or polygenic [ 32 ]. Hundreds of genes implicated in the development and function of the male reproductive system and in spermatogenesis can be involved [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…The pathogenic variants identified in these genes were reported in NCBI and their causal role has been shown by functional studies [ 29 , 30 , 31 , 32 ]. In particular, two of these variants in homozygosis were identified in TEX11 gene in case 1 (c.2288T > C and c.776C > T), of which one pathogenic and another likely benign.…”

Section: Discussionmentioning

confidence: 99%

“…This variant was reported in a patient with bilateral anorchia, in a functional study that demonstrates its reduced transcriptional activity. Furthermore, a segregation study showed that it was also present in the healthy relatives, suggesting a possible effect of incomplete penetrance [ 32 ]. Instead, the variation c.1063G > A identified in the case 5 affects a conserved protein residue but not altering its nature.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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“…We present a comprehensive genetic test based on NGS that covers the main infertility indications [ 6 , 12 ]: the female panel analyzes genes associated with increased risks for female infertility, including primary ovarian insufficiency, polycystic ovary syndrome, sex chromosome aneuploidy, ovarian hyperstimulation syndrome, and thrombophilia-related pregnancy loss (Fig. 1 ).…”

Section: Discussionmentioning

confidence: 99%

“…While genetics clearly play a role, these effects are mostly polygenic, making it difficult to define a single genetic cause. The two most common female factor conditions, ovulatory dysfunction (25%) and endometriosis (15%), have familial predisposition, suggesting a genetic basis [ 12 ]. In addition, sex chromosome alterations [ 13 ] and several single gene mutations have been described impacting female fertility [ 14 , 15 ], causing conditions like hypogonadotropic hypogonadism, premature ovarian insufficiency, endometriosis, and polycystic ovarian syndrome (reviewed in [ 12 ]).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive genetic testing for female and male infertility using next-generation sequencing

Patel¹,

Parets²,

Akana³

et al. 2018

J Assist Reprod Genet

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PurposeTo develop a comprehensive genetic test for female and male infertility in support of medical decisions during assisted reproductive technology (ART) protocols.MethodsWe developed a next-generation sequencing (NGS) gene panel consisting of 87 genes including promoters, 5′ and 3′ untranslated regions, exons, and selected introns. In addition, sex chromosome aneuploidies and Y chromosome microdeletions were analyzed concomitantly using the same panel.ResultsThe NGS panel was analytically validated by retrospective analysis of 118 genomic DNA samples with known variants in loci representative of female and male infertility. Our results showed analytical accuracy of > 99%, with > 98% sensitivity for single-nucleotide variants (SNVs) and > 91% sensitivity for insertions/deletions (indels). Clinical sensitivity was assessed with samples containing variants representative of male and female infertility, and it was 100% for SNVs/indels, CFTR IVS8-5T variants, sex chromosome aneuploidies, and copy number variants (CNVs) and > 93% for Y chromosome microdeletions. Cost analysis shows potential savings when comparing this single NGS assay with the standard approach, which includes multiple assays.ConclusionsA single, comprehensive, NGS panel can simplify the ordering process for healthcare providers, reduce turnaround time, and lower the overall cost of testing for genetic assessment of infertility in females and males, while maintaining accuracy.Electronic supplementary materialThe online version of this article (10.1007/s10815-018-1204-7) contains supplementary material, which is available to authorized users.

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Genetic Disorders of Human Infertility

Vogt

2017

Encyclopedia of Life Sciences

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Diagnostic identification of human genetic disorders causing male or female infertility is of paramount interest in each infertility clinic dealing with the term ‘idiopathic infertility’, which means ‘no reason found for observed infertility pathology’. In such cases, if there is a genetic disorder behind (in about 30%), there is usually a high risk of transfer of this genetic lesion to the offspring by the applied fertilisation protocol. Such genetic‐based infertility disorders can be unbalanced chromosome aberrations including aneuploidies and/or specific gene mutations, respectively. As comparative genomic hybridisation (CGH) and next‐generation sequencing (NGS) tools have now shown that the normal human genome can have a highly variable sequence composition, thus also in men and women with normal fertility, it has become a major challenge for the clinicians to then identify only those genome/gene mutations which may indeed cause the observed infertility pathology. Key Concepts Genetic disorders can cause about 30% male and female infertility. Analysis of chromosome aberrations (aneuploidies) is mandatory before ART application in ‘idiopathic’ male and female infertility. Artificial insemination protocols such as ICSI can increase genetic disorders causing infertility in offspring. Genes causing male or female infertility can have pleiotropic somatic genetic disorders such as cystic fibrosis. Genes on the Y chromosome causing male infertility (AZF genes) are inherited by ICSI to male offsprings with 100%.

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Genetic Basis of Male and Female Infertility

Cited by 23 publications

References 110 publications

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

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

Comprehensive genetic testing for female and male infertility using next-generation sequencing

Genetic Disorders of Human Infertility

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