Percorrer por autor "Lopes, Alexandra M."
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- Actionable secondary findings following exome sequencing of 836 non-obstructive azoospermia cases and their value in patient managementPublication . Kasak, Laura; Lillepea, Kristiina; Nagirnaja, Liina; Aston, Kenneth I.; Schlegel, Peter N.; Gonçalves, João; Carvalho, Filipa; Moreno-Mendoza, Daniel; Almstrup, Kristian; Eisenberg, Michael L.; Jarvi, Keith A.; O’Bryan, Moira K.; Lopes, Alexandra M.; Conrad, Donald F.; Nagirnaja, Liina; Aston, Kenneth I.; Carrell, Douglas T.; Hotaling, James M.; Jenkins, Timothy G.; McLachlan, Rob; O’Bryan, Moira K.; Schlegel, Peter N.; Eisenberg, Michael L.; Sandlow, Jay I.; Jungheim, Emily S.; Omurtag, Kenan R.; Lopes, Alexandra M.; Seixas, Susana; Carvalho, Filipa; Fernandes, Susana; Barros, Alberto; Laan, Maris; Punab, Margus; Rajpert-De Meyts, Ewa; Jørgensen, Niels; Almstrup, Kristian; Krausz, Csilla G.; Jarvi, Keith A.; Punab, Margus; Laan, MarisStudy question: What is the load, distribution and added clinical value of secondary findings (SFs) identified in exome sequencing (ES) of patients with non-obstructive azoospermia (NOA)? Summary answer: One in 28 NOA cases carried an identifiable, medically actionable SF. What is known already: In addition to molecular diagnostics, ES allows assessment of clinically actionable disease-related gene variants that are not connected to the patient's primary diagnosis, but the knowledge of which may allow the prevention, delay or amelioration of late-onset monogenic conditions. Data on SFs in specific clinical patient groups, including reproductive failure, are currently limited. Study design, size, duration: The study group was a retrospective cohort of patients with NOA recruited in 10 clinics across six countries and formed in the framework of the international GEMINI (The GEnetics of Male INfertility Initiative) study. Participants/materials, setting, methods: ES data of 836 patients with NOA were exploited to analyze SFs in 85 genes recommended by the American College of Medical Genetics and Genomics (ACMG), Geisinger's MyCode, and Clinical Genome Resource. The identified 6374 exonic variants were annotated with ANNOVAR and filtered for allele frequency, retaining 1381 rare or novel missense and loss-of-function variants. After automatic assessment of pathogenicity with ClinVar and InterVar, 87 variants were manually curated. The final list of confident disease-causing SFs was communicated to the corresponding GEMINI centers. When patient consent had been given, available family health history and non-andrological medical data were retrospectively assessed. Main results and the role of chance: We found a 3.6% total frequency of SFs, 3.3% from the 59 ACMG SF v2.0 genes. One in 70 patients carried SFs in genes linked to familial cancer syndromes, whereas 1 in 60 cases was predisposed to congenital heart disease or other cardiovascular conditions. Retrospective assessment confirmed clinico-molecular diagnoses in several cases. Notably, 37% (11/30) of patients with SFs carried variants in genes linked to male infertility in mice, suggesting that some SFs may have a co-contributing role in spermatogenic impairment. Further studies are needed to determine whether these observations represent chance findings or the profile of SFs in NOA patients is indeed different from the general population. Limitations, reasons for caution: One limitation of our cohort was the low proportion of non-Caucasian ethnicities (9%). Additionally, as comprehensive clinical data were not available retrospectively for all men with SFs, we were not able to confirm a clinico-molecular diagnosis and assess the penetrance of the specific variants. Wider implications of the findings: For the first time, this study analyzed medically actionable SFs in men with spermatogenic failure. With the evolving process to incorporate ES into routine andrology practice for molecular diagnostic purposes, additional assessment of SFs can inform about future significant health concerns for infertility patients. Timely detection of SFs and respective genetic counseling will broaden options for disease prevention and early treatment, as well as inform choices and opportunities regarding family planning. A notable fraction of SFs was detected in genes implicated in maintaining genome integrity, essential in both mitosis and meiosis. Thus, potential genetic pleiotropy may exist between certain adult-onset monogenic diseases and NOA.
- Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male InfertilityPublication . Wyrwoll, Margot J.; Temel, Şehime G.; Nagirnaja, Liina; Oud, Manon S.; Lopes, Alexandra M.; van der Heijden, Godfried W.; Heald, James S.; Rotte, Nadja; Wistuba, Joachim; Wöste, Marius; Ledig, Susanne; Krenz, Henrike; Smits, Roos M.; Carvalho, Filipa; Gonçalves, João; Fietz, Daniela; Türkgenç, Burcu; Ergören, Mahmut C.; Çetinkaya, Murat; Başar, Murad; Kahraman, Semra; McEleny, Kevin; Xavier, Miguel J.; Turner, Helen; Pilatz, Adrian; Röpke, Albrecht; Dugas, Martin; Kliesch, Sabine; Neuhaus, Nina; Aston, Kenneth I.; Conrad, Donald F.; Veltman, Joris A.; Friedrich, Corinna; Tüttelmann, FrankMale infertility affects ∼7% of men, but its causes remain poorly understood. The most severe form is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis. So far, only a few validated disease-associated genes have been reported. To address this gap, we performed whole-exome sequencing in 58 men with unexplained meiotic arrest and identified the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 associated protein, in three unrelated men. This variant most likely results in a truncated protein as shown in vitro by heterologous expression of mutant M1AP. Next, we screened four large cohorts of infertile men and identified three additional individuals carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP. Moreover, a homozygous missense variant, c.1166C>T (p.Pro389Leu), segregated with infertility in five men from a consanguineous Turkish family. The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed. A similar phenotype has been described for mice with disruption of M1ap. Collectively, these findings demonstrate that mutations in M1AP are a relatively frequent cause of autosomal recessive severe spermatogenic failure and male infertility with strong clinical validity.
- Common Variation in the PIN1 Locus Increases the Genetic Risk to Suffer from Sertoli Cell-Only SyndromePublication . Cerván-Martín, Miriam; Bossini-Castillo, Lara; Guzmán-Jimenez, Andrea; Rivera-Egea, Rocío; Garrido, Nicolás; Luján, Saturnino; Romeu, Gema; Santos-Ribeiro, Samuel; Castilla, José A.; Gonzalvo, M. Carmen; Clavero, Ana; Vicente, F. Javier; Maldonado, Vicente; González-Muñoz, Sara; Rodríguez-Martín, Inmaculada; Burgos, Miguel; Jiménez, Rafael; Pinto, Maria Graça; Pereira, Isabel; Nunes, Joaquim; Sánchez-Curbelo, Josvany; López-Rodrigo, Olga; Pereira-Caetano, Iris; Marques, Patricia Isabel; Carvalho, Filipa; Barros, Alberto; Bassas, Lluís; Seixas, Susana; Gonçalves, João; Larriba, Sara; Lopes, Alexandra M.; Carmona, F. David; Palomino-Morales, Rogelio J.We aimed to analyze the role of the common genetic variants located in the PIN1 locus, a relevant prolyl isomerase required to control the proliferation of spermatogonial stem cells and the integrity of the blood-testis barrier, in the genetic risk of developing male infertility due to a severe spermatogenic failure (SPGF). Genotyping was performed using TaqMan genotyping assays for three PIN1 taggers (rs2287839, rs2233678 and rs62105751). The study cohort included 715 males diagnosed with SPGF and classified as suffering from non-obstructive azoospermia (NOA, n = 505) or severe oligospermia (SO, n = 210), and 1058 controls from the Iberian Peninsula. The allelic frequency differences between cases and controls were analyzed by the means of logistic regression models. A subtype specific genetic association with the subset of NOA patients classified as suffering from the Sertoli cell-only (SCO) syndrome was observed with the minor alleles showing strong risk effects for this subset (ORaddrs2287839 = 1.85 (1.17-2.93), ORaddrs2233678 = 1.62 (1.11-2.36), ORaddrs62105751 = 1.43 (1.06-1.93)). The causal variants were predicted to affect the binding of key transcription factors and to produce an altered PIN1 gene expression and isoform balance. In conclusion, common non-coding single-nucleotide polymorphisms located in PIN1 increase the genetic risk to develop SCO.
- Contribution of TEX15 genetic variants to the risk of developing severe non-obstructive oligozoospermiaPublication . Guzmán-Jiménez, Andrea; González-Muñoz, Sara; Cerván-Martín, Miriam; Rivera-Egea, Rocío; Garrido, Nicolás; Luján, Saturnino; Santos-Ribeiro, Samuel; Castilla, José A.; Gonzalvo, M. Carmen; Clavero, Ana; Vicente, F. Javier; Maldonado, Vicente; Villegas-Salmerón, Javier; Burgos, Miguel; Jiménez, Rafael; Pinto, Maria Graça; Pereira, Isabel; Nunes, Joaquim; Sánchez-Curbelo, Josvany; López-Rodrigo, Olga; Pereira-Caetano, Iris; Marques, Patricia Isabel; Carvalho, Filipa; Barros, Alberto; Bassas, Lluís; Seixas, Susana; Gonçalves, João; Lopes, Alexandra M.; Larriba, Sara; Palomino-Morales, Rogelio J.; Carmona, F. David; Bossini-Castillo, LaraBackground: Severe spermatogenic failure (SPGF) represents one of the most relevant causes of male infertility. This pathological condition can lead to extreme abnormalities in the seminal sperm count, such as severe oligozoospermia (SO) or non-obstructive azoospermia (NOA). Most cases of SPGF have an unknown aetiology, and it is known that this idiopathic form of male infertility represents a complex condition. In this study, we aimed to evaluate whether common genetic variation in TEX15, which encodes a key player in spermatogenesis, is involved in the susceptibility to idiopathic SPGF. Materials and Methods: We designed a genetic association study comprising a total of 727 SPGF cases (including 527 NOA and 200 SO) and 1,058 unaffected men from the Iberian Peninsula. Following a tagging strategy, three tag single-nucleotide polymorphisms (SNPs) of TEX15 (rs1362912, rs323342, and rs323346) were selected for genotyping using TaqMan probes. Case-control association tests were then performed by logistic regression models. In silico analyses were also carried out to shed light into the putative functional implications of the studied variants. Results: A significant increase in TEX15-rs1362912 minor allele frequency (MAF) was observed in the group of SO patients (MAF = 0.0842) compared to either the control cohort (MAF = 0.0468, OR = 1.90, p = 7.47E-03) or the NOA group (MAF = 0.0472, OR = 1.83, p = 1.23E-02). The genotype distribution of the SO population was also different from those of both control (p = 1.14E-02) and NOA groups (p = 4.33–02). The analysis of functional annotations of the human genome suggested that the effect of the SO-associated TEX15 variants is likely exerted by alteration of the binding affinity of crucial transcription factors for spermatogenesis. Conclusion: Our results suggest that common variation in TEX15 is involved in the genetic predisposition to SO, thus supporting the notion of idiopathic SPGF as a complex trait.
- A de novo paradigm for male infertilityPublication . Oud, M.S.; Smits, R.M.; Smith, H.E.; Mastrorosa, F.K.; Holt, G.S.; Houston, B.J.; de Vries, P.F.; Alobaidi, B.K.S.; Batty, L.E.; Ismail, H.; Greenwood, J.; Sheth, H.; Mikulasova, A.; Astuti, G.D.N.; Gilissen, C.; McEleny, K.; Turner, H.; Coxhead, J.; Cockell, S.; Braat, D.D.M.; Fleischer, K.; D’Hauwers, K.W.M.; Schaafsma, E.; Conrad, Donald F.; Nagirnaja, Liina; Aston, Kenneth I.; Carrell, Douglas T.; Hotaling, James M.; Jenkins, Timothy G.; McLachlan, Rob; O’Bryan, Moira K.; Schlegel, Peter N.; Eisenberg, Michael L.; Sandlow, Jay I.; Jungheim, Emily S.; Omurtag, Kenan R.; Lopes, Alexandra M.; Seixas, Susana; Carvalho, Filipa; Fernandes, Susana; Barros, Alberto; Gonçalves, João; Caetano, Iris; Pinto, Graça; Correia, Sónia; Laan, Maris; Punab, Margus; Meyts, Ewa Rajpert-De; Jørgensen, Niels; Almstrup, Kristian; Krausz, Csilla G.; Jarvi, Keith A.; Nagirnaja, L.; Conrad, D.F.; Friedrich, C.; Kliesch, S.; Aston, K.I.; Riera-Escamilla, A.; Krausz, C.; Gonzaga-Jauregui, C.; Santibanez-Koref, M.; Elliott, D. J.; Vissers, L.E.L.M.; Tüttelmann, F.; O’Bryan, M.K.; Ramos, L.; Xavier, M.J.; van der Heijden, G.W.; Veltman, J.A.De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10−5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10−4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.
- Diminished DNA binding affinity of DMRT1 caused by heterozygous DM domain mutations is a cause of male infertilityPublication . Marić, Tihana; Castillo-Madeen, Helen; Klarić, Monika Logara; Barišić, Antun; Trgovec-Greif, Lovro; Murphy, Mark W.; Juchnewitsch, Anna-Grete; Lillepea, Kristiina; Dutta, Avirup; Žunić, Lucija; Stendahl, Alexandra M.; Punab, Margus; Pomm, Kristjan; Mendoza, Daniel M.; Lopes, Alexandra M.; Šorgić, Ana Merkler; Vugrek, Oliver; Gonçalves, João; Almstrup, Kristian; Aston, Kenneth I.; Belužić, Robert; Ježek, Davor; Bertoša, Branimir; Laan, Maris; Bojanac, Ana Katušić; Conrad, Donald F.; Barbalić, MajaThe most severe form of male infertility is idiopathic non-obstructive azoospermia (NOA), a complete sperm absence in the ejaculate. We performed exome sequencing in the Croatian infertile brothers with NOA and found a variant in DMRT1 (Doublesex and mab-3 related transcription factor 1) gene that was further assessed by the EMSA assay and molecular dynamic simulations. We additionally screened for DMRT1 mutations in 1940 infertile men diagnosed with spermatogenic failure, 644 normozoospermic controls, and 105 females with primary ovarian insufficiency (POI) recruited to the GEnetics of Male INfertility Initiative (GEMINI) or Estonian Andrology (ESTAND) cohorts. DMRT1 p.Pro74Leu (chr9:g.842059C > T) variant was detected in infertile brothers in the highly conserved position within the DNA binding DM domain of the protein. EMSA assay showed reduced DNA binding of DMRT1P74L and molecular dynamic simulations showed differences in structural and dynamical properties between the wild type protein and DMRT1P74L. Plausible disease-causing DMRT1 variants were only identified in infertile men (13/1940; 0.67%), and none in 639 fertile controls. Burden testing showed an excess of rare deleterious DM domain mutations in the infertility cohort compared to gnomAD v.4.0 population-based controls (Fisher’s exact test, p = 1.44 x 10−5). Three rare deleterious variants in DMRT1 were found in 104 cases of POI. The findings of this study strengthen the evidence of DMRT1 variants being a causal factor for male infertility and provide the distribution of likely pathogenic variants across the gene. This is also the first study to suggest that DMRT1 variants may also be linked to POI.
- Disruption of human meiotic telomere complex genes TERB1, TERB2 and MAJIN in men with non-obstructive azoospermiaPublication . Salas-Huetos, Albert; Tüttelmann, Frank; Wyrwoll, Margot J.; Kliesch, Sabine; Lopes, Alexandra M.; Gonçalves, João; Boyden, Steven E.; Wöste, Marius; Hotaling, James M.; GEMINI Consortium; Nagirnaja, Liina; Conrad, Donald F.; Carrell, Douglas T.; Aston, Kenneth I.Non-obstructive azoospermia (NOA), the lack of spermatozoa in semen due to impaired spermatogenesis affects nearly 1% of men. In about half of cases, an underlying cause for NOA cannot be identified. This study aimed to identify novel variants associated with idiopathic NOA. We identified a nonconsanguineous family in which multiple sons displayed the NOA phenotype. We performed whole-exome sequencing in three affected brothers with NOA, their two unaffected brothers and their father, and identified compound heterozygous frameshift variants (one novel and one extremely rare) in Telomere Repeat Binding Bouquet Formation Protein 2 (TERB2) that segregated perfectly with NOA. TERB2 interacts with TERB1 and Membrane Anchored Junction Protein (MAJIN) to form the tripartite meiotic telomere complex (MTC), which has been shown in mouse models to be necessary for the completion of meiosis and both male and female fertility. Given our novel findings of TERB2 variants in NOA men, along with the integral role of the three MTC proteins in spermatogenesis, we subsequently explored exome sequence data from 1495 NOA men to investigate the role of MTC gene variants in spermatogenic impairment. Remarkably, we identified two NOA patients with likely damaging rare homozygous stop and missense variants in TERB1 and one NOA patient with a rare homozygous missense variant in MAJIN. Available testis histology data from three of the NOA patients indicate germ cell maturation arrest, consistent with mouse phenotypes. These findings suggest that variants in MTC genes may be an important cause of NOA in both consanguineous and outbred populations.
- Diverse monogenic subforms of human spermatogenic failurePublication . Nagirnaja, Liina; Lopes, Alexandra M.; Charng, Wu-Lin; Miller, Brian; Stakaitis, Rytis; Golubickaite, Ieva; Stendahl, Alexandra; Luan, Tianpengcheng; Friedrich, Corinna; Mahyari, Eisa; Fadial, Eloise; Kasak, Laura; Vigh-Conrad, Katinka; Oud, Manon S.; Xavier, Miguel J.; Cheers, Samuel R.; James, Emma R.; Guo, Jingtao; Jenkins, Timothy G.; Riera-Escamilla, Antoni; Barros, Alberto; Carvalho, Filipa; Fernandes, Susana; Gonçalves, João; Gurnett, Christina A.; Jørgensen, Niels; Jezek, Davor; Jungheim, Emily S.; Kliesch, Sabine; McLachlan, Robert I.; Omurtag, Kenan R.; Pilatz, Adrian; Sandlow, Jay I.; Smith, James; Eisenberg, Michael L.; Hotaling, James M.; Jarvi, Keith A.; Punab, Margus; Rajpert-De Meyts, Ewa; Carrell, Douglas T.; Krausz, Csilla; Laan, Maris; O’Bryan, Moira K.; Schlegel, Peter N.; Tüttelmann, Frank; Veltman, Joris A.; Almstrup, Kristian; Aston, Kenneth I.; Conrad, Donald F.Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven chal lenging, and the most advanced classification of NOA subforms is not based on genetics, but simple description of testis histology. In this study, we exome sequenced over 1000 clinically diagnosed NOA cases and identified a plausible recessive Mendelian cause in 20%. We find further support for 21 genes in a 2-stage burden test with 2072 cases and 11,587 fertile controls. The disrupted genes are primarily on the autosomes, enriched for undescribed human “knockouts”, and, for the most part, have yet to be linked to a Mendelian trait. Integration with single-cell RNA sequencing data shows that azoospermia genes can be grouped into molecular subforms with synchronized expression patterns, and analogs of these subforms exist in mice. This analysis framework identifies groups of genes with known roles in spermatogenesis but also reveals unrecognized subforms, such as a set of genes expressed across mitotic divisions of differentiating spermatogonia. Our findings highlight NOA as an understudied Mendelian disorder and provide a conceptual structure for organizing the complex genetics of male infertility, which may provide a rational basis for disease classification
- Evaluation of Male Fertility-Associated Loci in a European Population of Patients with Severe Spermatogenic ImpairmentPublication . Cerván-Martín, Miriam; Bossini-Castillo, Lara; Rivera-Egea, Rocío; Garrido, Nicolás; Luján, Saturnino; Romeu, Gema; Santos-Ribeiro, Samuel; Castilla, José A.; Gonzalvo, M. Carmen; Clavero, Ana; Vicente, F. Javier; Guzmán-Jiménez, Andrea; Costa, Cláudia; Llinares-Burguet, Inés; Khantham, Chiranan; Burgos, Miguel; Barrionuevo, Francisco J.; Jiménez, Rafael; Sánchez-Curbelo, Josvany; López-Rodrigo, Olga; Peraza, M. Fernanda; Pereira-Caetano, Iris; Marques, Patricia I.; Carvalho, Filipa; Barros, Alberto; Bassas, Lluís; Seixas, Susana; Gonçalves, João; Larriba, Sara; Lopes, Alexandra M.; Palomino-Morales, Rogelio J.; Carmona, F. DavidInfertility is a growing concern in developed societies. Two extreme phenotypes of male infertility are non-obstructive azoospermia (NOA) and severe oligospermia (SO), which are characterized by severe spermatogenic failure (SpF). We designed a genetic association study comprising 725 Iberian infertile men as a consequence of SpF and 1058 unaffected controls to evaluate whether five single-nucleotide polymorphisms (SNPs), previously associated with reduced fertility in Hutterites, are also involved in the genetic susceptibility to idiopathic SpF and specific clinical entities. A significant difference in the allele frequencies of USP8-rs7174015 was observed under the recessive model between the NOA group and both the control group (p = 0.0226, OR = 1.33) and the SO group (p = 0.0048, OR = 1.78). Other genetic associations for EPSTI1-rs12870438 and PSAT1-rs7867029 with SO and between TUSC1-rs10966811 and testicular sperm extraction (TESE) success in the context of NOA were observed. In silico analysis of functional annotations demonstrated cis-eQTL effects of such SNPs likely due to the modification of binding motif sites for relevant transcription factors of the spermatogenic process. The findings reported here shed light on the molecular mechanisms leading to severe phenotypes of idiopathic male infertility, and may help to better understand the contribution of the common genetic variation to the development of these conditions.
- A genetic variant in the 3′-UTR of PIWIL4 confers risk for extreme phenotypes of male infertility by altering miR-215 and miR-136 binding affinityPublication . González-Muñoz, Sara; Cerván-Martín, Miriam; Guzmán-Jiménez, Andrea; Rodríguez-Martín, Ana Isabel; Garrido, Nicolás; Castilla, José A.; Gonzalvo, M. Carmen; Clavero, Ana; Molina, Marta; Vilches, Miguel Ángel; Espuch-Oliver, Andrea; Maldonado, Vicente; García-Peña, María Luisa; Galiano-Gutiérrez, Noelia; Santamaría, Esther; González, Cristina; Quintana-Ferraz, Fernando; Gómez, Susana; Amorós, David; Martínez-Granados, Luis; Ortega-González, Yanira; Burgos, Miguel; Pereira-Caetano, Iris; Pinto, Graça S.; Aguiar, Ana; Pereira, Isabel S.; López-Rodrigo, Olga; Bassas, Lluís; Seixas, Susana; Gonçalves, João; Lopes, Alexandra M.; Larriba, Sara; Bossini-Castillo, Lara; Carmona, F. David; Palomino-Morales, Rogelio J.Study question: What is the functional impact of the rs508485 genetic polymorphism, located in the 3'-untranslated region (UTR) region of the PIWIL4 gene, on non-obstructive azoospermia (NOA)? Summary answer: The rs508485 genetic variant contributes to the pathogenesis of extreme patterns of NOA by modulating PIWIL4 expression through microRNA (miRNA) interactions. What is known already: Male infertility represents a significant global health challenge with profound societal and economic consequences. One of the most severe forms of male infertility is NOA, which is characterized by severe spermatogenic failure (SPGF) of idiopathic origin in most cases. Cumulating knowledge increasingly suggests that this idiopathic form of NOA may represent a multifactorial condition involving complex interactions between genetic and environmental factors. The PIWI protein subfamily, particularly PIWIL4, plays a pivotal role in spermatogenesis by processing PIWI-interacting RNAs, which silence retrotransposons to protect genomic integrity. Genetic variations in this gene have been found to be associated with susceptibility to NOA. Study design, size, duration: A case-control study was conducted in a European cohort including 1516 infertile men with SPGF and 2451 fertile controls. Logistic regression and functional assays were employed to investigate the functional role of the rs508485 polymorphism in PIWIL4. Participants/materials, setting, methods: Participants were genotyped for the rs508485 polymorphism. Associations between the polymorphism and NOA phenotypes, including Sertoli cell-only (SCO) syndrome and testicular sperm extraction (TESE) outcomes, were assessed. In silico tools predicted miRNA binding effects, which were subsequently validated using luciferase reporter assays. Main results and the role of chance: The T allele of rs508485 was significantly associated with the SCO phenotype (P = 2.69E-03, OR = 1.34) and unfavourable TESE outcomes (P = 1.09E-03, OR = 1.54). In silico analyses predicted that the rs508485 variant might alter binding sites in the 3'-UTR region of PIWIL4 for different miRNAs, such as hsa-miR-215-3p and hsa-miR-136-3p. Functional validation using luciferase assays confirmed that these miRNAs differentially bind to the T and C alleles of this polymorphism, influencing PIWIL4 regulation. Large scale data: N/A. Limitations, reasons for caution: The study is limited to a single genetic polymorphism and functional assays were performed in vitro. Additional studies are required to validate these findings across diverse populations and explore additional genetic interactions. Wider implications of the findings: These findings highlight the critical role of miRNA regulation in extreme forms of male infertility by influencing the expression of essential spermatogenesis genes, such as PIWIL4. Our study sheds light on the genetic mechanisms underlying spermatogenesis and suggests potential therapeutic targets for NOA.