Lack of evidence for a role of PIWIL1 variants in human male infertility

Oud, Manon S; Voložonoka, Ludmila; Friedrich, Corinna; Kliesch, Sabine; Nagirnaja, Liina; Gilissen, Christian; O'Bryan, Moira K; McLachlan, Robert I; Aston, Kenneth I.; Tüttelmann, Frank; Conrad, Don F.; Veltman, Joris A.

doi:10.1016/j.cell.2021.03.001

Cited by 12 publications

(4 citation statements)

References 8 publications

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“…For example, in 2017 variants in the D-box region of PIWIL1 were implicated as a recurrent cause of NOA ( Gou et al , 2017 ). Using WES on 2740 men with NOA or severe oligozoospermia, the IMIGC/GEMINI consortia demonstrated that pathogenic variants in the D-box region of PIWIL1 specifically, and variants elsewhere in the gene, are not a common cause of male infertility ( Oud et al , 2021 ).…”

Section: Discussionmentioning

confidence: 99%

A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene–disease relationships

Houston

Riera-Escamilla

Wyrwoll

et al. 2021

Human Reproduction Update

152

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BACKGROUND Human male infertility has a notable genetic component, including well-established diagnoses such as Klinefelter syndrome, Y-chromosome microdeletions and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a majority (60–70%) remain without a clear diagnosis and are classified as unexplained. This is likely in large part due to a delay in the field adopting next-generation sequencing (NGS) technologies, and the absence of clear statements from field leaders as to what constitutes a validated cause of human male infertility (the current paper aims to address this). Fortunately, there has been a significant increase in the number of male infertility NGS studies. These have revealed a considerable number of novel gene–disease relationships (GDRs), which each require stringent assessment to validate the strength of genotype–phenotype associations. To definitively assess which of these GDRs are clinically relevant, the International Male Infertility Genomics Consortium (IMIGC) has identified the need for a systematic review and a comprehensive overview of known male infertility genes and an assessment of the evidence for reported GDRs. OBJECTIVE AND RATIONALE In 2019, the first standardised clinical validity assessment of monogenic causes of male infertility was published. Here, we provide a comprehensive update of the subsequent 1.5 years, employing the joint expertise of the IMIGC to systematically evaluate all available evidence (as of 1 July 2020) for monogenic causes of isolated or syndromic male infertility, endocrine disorders or reproductive system abnormalities affecting the male sex organs. In addition, we systematically assessed the evidence for all previously reported possible monogenic causes of male infertility, using a framework designed for a more appropriate clinical interpretation of disease genes. SEARCH METHODS We performed a literature search according to the PRISMA guidelines up until 1 July 2020 for publications in English, using search terms related to ‘male infertility’ in combination with the word ‘genetics’ in PubMed. Next, the quality and the extent of all evidence supporting selected genes were assessed using an established and standardised scoring method. We assessed the experimental quality, patient phenotype assessment and functional evidence based on gene expression, mutant in-vitro cell and in-vivo animal model phenotypes. A final score was used to determine the clinical validity of each GDR, across the following five categories: no evidence, limited, moderate, strong or definitive. Variants were also reclassified according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines and were recorded in spreadsheets for each GDR, which are available at imigc.org. OUTCOMES The primary outcome of this review was an overview of all known GDRs for monogenic causes of human male infertility and their clinical validity. We identified a total of 120 genes that were moderately, strongly or definitively linked to 104 infertility phenotypes. WIDER IMPLICATIONS Our systematic review curates all currently available evidence to reveal the strength of GDRs in male infertility. The existing guidelines for genetic testing in male infertility cases are based on studies published 25 years ago, and an update is far overdue. The identification of 104 high-probability ‘human male infertility genes’ is a 33% increase from the number identified in 2019. The insights generated in the current review will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of male infertility genetics. We discuss the relevant international guidelines regarding research related to gene discovery and provide specific recommendations to the field of male infertility. Based on our findings, the IMIGC consortium recommend several updates to the genetic testing standards currently employed in the field of human male infertility, most important being the adoption of exome sequencing, or at least sequencing of the genes validated in this study, and expanding the patient groups for which genetic testing is recommended.

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Section: Discussionmentioning

confidence: 99%

A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene–disease relationships

Houston

Riera-Escamilla

Wyrwoll

et al. 2021

Human Reproduction Update

152

View full text Add to dashboard Cite

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“…Furthermore, no homozygous potentially pathogenic missense variants had yet been reported for TDRD1 and DDX4, both of which are highly intolerant to genetic variation. Of note, the presented homozygous stop-gain variant in PIWIL1 resolves the controversy regarding the causal link between heterozygous human PIWIL1 variants and azoospermia 39,40 and renders this another autosomal recessive disease gene.…”

Section: Discussionmentioning

confidence: 81%

Inherited defects of piRNA biogenesis cause transposon de-repression, impaired spermatogenesis, and human male infertility

Stallmeyer,

Bühlmann,

Stakaitis

et al. 2024

Preprint

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Piwi-interacting RNAs (piRNAs) are crucial for transposon silencing, germ cell maturation, and fertility in male mice. Here, we report on the genetic landscape of piRNA dysfunction in humans and present 39 infertile men carrying biallelic variants in 14 different piRNA pathway genes, including PIWIL1, GTSF1, GPAT2, MAEL, TDRD1, and DDX4 as novel disease genes. The testicular phenotypes repeatedly differ from those of the respective knockout mice and range from complete germ cell loss to the production of a few morphologically abnormal spermatozoa. LINE1 expression in spermatogonia links impaired piRNA biogenesis to transposon de-silencing and serves to classify variants as functionally relevant. Furthermore, an abolished expression of not only the encoded proteins but also of additional piRNA factors reveals co-dependencies within the human pathway. These results establish the disrupted piRNA pathway as a major cause of human spermatogenic failure and provide insights into transposon silencing in human male germ cells.

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“…Additionally, the authors demonstrated in mice that the resulting stabilization and accumulation of PIWI-LIKE 1 induces abnormal chromatin compaction due to an impaired histone–protamine exchange and thus leading to male sterility [ 27 ]. However, recently Oud and colleagues showed in a larger study cohort of 2740 patients with azoospermia or severe oligozoospermia, that HIWI D-box variations are less frequent than proposed by Gou and colleagues, and the that loss of function of PIWI-LIKE 1 is unlikely to cause fertility impairments when haploin-sufficient [ 28 ]. In our study, we did not perform mutational screenings on the PIWI-LIKE genes, therefore statements about the relationship of mutated PIWI-LIKE genes and male infertility cannot be drawn from our experimental setting.…”

Section: Discussionmentioning

confidence: 99%

Lower Spermatozoal PIWI-LIKE 1 and 2 Transcript Levels Are Significantly Associated with Higher Fertilization Rates in IVF

Giebler

Greither

Handke

et al. 2021

IJMS

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The four human PIWI-LIKE gene family members PIWI-LIKE 1–4 play a pivotal role in stem cell maintenance and transposon repression in the human germline. Therefore, dysregulation of these genes negatively influences the genetic stability of the respective germ cell and subsequent development and maturation. Recently, we demonstrated that a lower PIWI-LIKE 2 mRNA expression in ejaculated spermatozoa is more frequent in men with oligozoospermia. In this study, we analysed how PIWI-LIKE 1–4 mRNA expression in ejaculated spermatozoa predicts ART outcome. From 160 IVF or ICSI cycles, portions of swim-up spermatozoa used for fertilization were collected, and the total RNA was isolated. PIWI-LIKE 1–4 mRNA expression was measured by qPCR using TaqMan probes with GAPDH as a reference gene. PIWI-LIKE 1 and 2 transcript levels in the spermatozoa of the swim-up fraction were positively correlated to each other (rS = 0.78; p < 0.001). Moreover, lower PIWI-LIKE 2 mRNA levels, as well as lower PIWI-LIKE 1 mRNA levels, in these spermatozoa were positively associated with a fertilization rate ≥ 50% in the respective ART cycles (p = 0.02 and p = 0.0499, Mann–Whitney U-Test). When separately analysing IVF and ICSI cycles, PIWI-LIKE 1 and 2 transcript levels were only significantly associated to increased fertilization rates in IVF, yet not in ICSI cycles. Spermatozoal PIWI-LIKE 3 and 4 transcript levels were not significantly associated to fertilization rates in ART cycles. In conclusion, lower levels of spermatozoal PIWI-LIKE 1 and 2 mRNA levels are positively associated with a higher fertilization rate in IVF cycles.

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Lack of evidence for a role of PIWIL1 variants in human male infertility

Cited by 12 publications

References 8 publications

A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene–disease relationships

A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene–disease relationships

Inherited defects of piRNA biogenesis cause transposon de-repression, impaired spermatogenesis, and human male infertility

Lower Spermatozoal PIWI-LIKE 1 and 2 Transcript Levels Are Significantly Associated with Higher Fertilization Rates in IVF

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