{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T21:18:06Z","timestamp":1793395086384,"version":"4.5.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T00:00:00Z","timestamp":1755561600000},"content-version":"vor","delay-in-days":230,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish Ministry of Health Instituto Carlos III-FIS FONDOS FEDER","award":["PI20\/01562"],"award-info":[{"award-number":["PI20\/01562"]}]},{"name":"Spanish Ministry of Health Instituto Carlos III-FIS FONDOS FEDER","award":["PI23\/00425"],"award-info":[{"award-number":["PI23\/00425"]}]},{"name":"Spanish Ministry of Health Instituto Carlos III-FIS FONDOS FEDER","award":["CA20119"],"award-info":[{"award-number":["CA20119"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>STUDY QUESTION<\/jats:title>\n                    <jats:p>What is the diagnostic yield and the pre-testicular sperm extraction (TESE) prognostic value of a non-obstructive azoospermia (NOA)-specific virtual gene panel?<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>SUMMARY ANSWER<\/jats:title>\n                    <jats:p>The diagnostic yield in our cohort was 6.1%, and by combining our data with published literature, we identified 11 genes compatible with testicular sperm production and 19 genes associated with no sperm retrieval in carriers of pathogenic (P) or likely pathogenic (LP) mutations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WHAT IS KNOWN ALREADY<\/jats:title>\n                    <jats:p>Azoospermia, the most severe form of male infertility, affects \u223c1% of the male population, with TESE being the primary treatment option. However, in NOA, TESE fails in nearly 50% of cases and existing clinical parameters are unable to predict TESE failure. Over the past decade, next-generation sequencing (NGS) has identified several candidate NOA genes, but their diagnostic utility and impact on TESE outcomes have not been fully explored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY DESIGN, SIZE AND DURATION<\/jats:title>\n                    <jats:p>A literature search was addressed to identify well-established NOA genes for designing a specific virtual gene panel for NOA. Our retrospective study analysed the diagnostic yield of the NGS-based virtual gene panel, comprising 145 genes, in 571 men affected by idiopathic NOA with known TESE outcomes. Subsequently, a second literature search was performed to identify carriers of LP\/P variants in the genes where we identified mutations, focusing on individuals with known TESE outcomes. This approach allowed us to integrate the published data with our findings and predict a genotype\u2013phenotype correlation between the affected genes and TESE success.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>PARTICIPANTS\/MATERIALS, SETTINGS, METHODS<\/jats:title>\n                    <jats:p>571 NOA patients with known TESE outcomes were recruited in two European and one Middle East centres. Variants were obtained from a whole-exome sequencing dataset and crossed with the 145 genes of the virtual gene panel. After a filtering process, variants were manually assessed and classified according to ACMG guidelines by using two methods: (i) In order to compare our data with previously published studies, we applied ACMG-AMP guidelines along with ClinGen recommendations used by other similar studies. (ii) A new approach was used to optimize ACMG-AMP guidelines with all ClinGen recommendations and incorporated NOA-specific rules addressing phenotypic, locus, and allelic heterogeneity. LP and P variants were confirmed by Sanger sequencing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n                    <jats:p>By using the new variant classification approach adapted for NOA, we identified LP\/P variants in 6.1% of patients, with a higher yield (9.4%) in cases with negative TESE outcomes and maturation arrest (11.7%). By integrating our findings with the literature, we highlight 19 genes recurrently associated with negative TESE outcomes and 11 genes associated with positive sperm retrieval either in the testis or in semen. TESE is recommended for patients with LP or P variants in the 11 specific genes. Notably, six of these genes are located on the X chromosome, therefore, these variants will be obligatorily transmitted to daughters, and potentially increase the risk of NOA-related infertility in male offspring. We observed that nine genes, in which we identified LP\/P variants, have been previously described in individuals with premature ovarian insufficiency (POI). Of these, eight were associated with negative TESE outcomes in men. Furthermore, we propose seven additional genes mutated in our cohort of NOA patients as novel POI candidates. These genes have not yet been considered as POI candidates, but they result in female infertility when knocked out in mouse models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LARGE SCALE DATA<\/jats:title>\n                    <jats:p>LP\/P variants have been submitted to ClinVar (https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n                    <jats:p>NOA is genetically heterogeneous, and our panel excludes those genes which were reported only in a single subject or single family. Although this can limit the diagnostic yield in our study, it ensures that only genes with clear relationship with NOA have been analysed. While in our cohort TESE outcomes are known for all patients, this information is often not available for mutation carriers in the published studies. Consequently, the total number of patients with P variants in the same gene remains relatively low, limiting our final conclusions. However, even if the number of carriers of genes associated with positive sperm retrieval is relatively low, it does not constrain our conclusions regarding TESE prediction. On the other hand, caution is warranted for genes linked to negative TESE outcomes, except for TEX11, SYCE1, and MSH4, each of which have 10 or more reported TESE-negative cases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n                    <jats:p>Our study was performed on the largest available NOA cohort with known TESE outcomes. It not only provides an estimate on the diagnostic potential of a NOA-specific virtual gene panel, but it also advances the understanding of genetic factors influencing TESE outcomes. Half of the genes mutated in our study and presenting TESE-positive outcomes are already informative for clinical decision-making. The observed genotype\u2013phenotype correlations may help in personalized decision-making prior to TESE, in order to undergo the procedure or to avoid unnecessary invasive treatment. It provides valuable insights that can inform clinical management strategies and potentially offer personalized treatments based on genetic profiles. The use of two different variant classification methods highlights that previous studies may have over-estimated the diagnostic yield, underscoring the need for a standardized variant classification approach addressed specifically to male infertility. Our study also emphasizes the overlap between NOA- and POI-associated genes, which has important clinical implications for genetic counselling of female siblings of affected individuals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n                    <jats:p>This work was funded by the Spanish Ministry of Health Instituto Carlos III-FIS FONDOS FEDER (grant numbers PI20\/01562 and PI23\/00425) and the Fanconi Research Fund awarded to C.K. and A.R.-E. This article is based upon work from COST Action CA20119 (ANDRONET), supported by COST (European Cooperation in Science and Technology) (www.cost.eu). C.K., A.R.-E., G.F., M.J.X., M.S.O., C.A., M.S., and E.R.-C. are members of the Action. This research was also supported by the Qatar National Research Fund (QNRF) under grant NPRP12S-0318-190394, and by an Investigator Award in Science from the Wellcome Trust (209451 to J.A.V.). The authors declare no competing interests.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/hropen\/hoaf049","type":"journal-article","created":{"date-parts":[[2025,8,17]],"date-time":"2025-08-17T11:23:49Z","timestamp":1755429829000},"source":"Crossref","is-referenced-by-count":18,"title":["Genetic determinants of testicular sperm extraction outcomes: insights from a large multicentre study of men with non-obstructive azoospermia"],"prefix":"10.1093","volume":"2025","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4485-3094","authenticated-orcid":false,"given":"Antoni","family":"Riera-Escamilla","sequence":"first","affiliation":[{"name":"Department of Andrology, Fundaci\u00f3 Puigvert, Universitat Aut\u00f2noma de Barcelona, Instituto de Investigaciones Biom\u00e9dicas Sant Pau (IIB-Sant Pau) , Barcelona, Catalonia,","place":["Spain"]},{"name":"Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University , Beaverton, OR,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed M","family":"Arafa","sequence":"additional","affiliation":[{"name":"Department of Urology, Hamad Medical Corporation , Doha,","place":["Qatar"]},{"name":"Department of Clinical Urology, Weill Cornell Medicine-Qatar , Doha,","place":["Qatar"]},{"name":"Department of Andrology, Cairo University , Cairo,","place":["Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ginevra","family":"Farnetani","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence , Florence,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0709-7223","authenticated-orcid":false,"given":"Miguel J","family":"Xavier","sequence":"additional","affiliation":[{"name":"Faculty of Medical Sciences, Biosciences Institute, Newcastle University , Newcastle-upon-Tyne,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9513-3030","authenticated-orcid":false,"given":"Manon S","family":"Oud","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboudumc , Nijmegen,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad A","family":"Majzoub","sequence":"additional","affiliation":[{"name":"Department of Urology, Hamad Medical Corporation , Doha,","place":["Qatar"]},{"name":"Department of Clinical Urology, Weill Cornell Medicine-Qatar , Doha,","place":["Qatar"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"Ramos","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Radboud University Medical Centre , Nijmegen, The","place":["Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Abrardo","sequence":"additional","affiliation":[{"name":"Department of Andrology, Fundaci\u00f3 Puigvert, Universitat Aut\u00f2noma de Barcelona, Instituto de Investigaciones Biom\u00e9dicas Sant Pau (IIB-Sant Pau) , Barcelona, Catalonia,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matilde","family":"Spinelli","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence , Florence,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Moreno-Mendoza","sequence":"additional","affiliation":[{"name":"Department of Andrology, Fundaci\u00f3 Puigvert, Universitat Aut\u00f2noma de Barcelona, Instituto de Investigaciones Biom\u00e9dicas Sant Pau (IIB-Sant Pau) , Barcelona, Catalonia,","place":["Spain"]},{"name":"Department of Urology, Hospital Francisco Grande Covi\u00e1n , Arriondas, Asturias,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9356-5224","authenticated-orcid":false,"given":"Giuseppe","family":"Defazio","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence , Florence,","place":["Italy"]},{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro , Bari,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabet","family":"Ars","sequence":"additional","affiliation":[{"name":"Molecular Genetic Laboratory Fundaci\u00f3 Puigvert, Universitat Aut\u00f2noma de Barcelona, Instituto de Investigaciones Biom\u00e9dicas Sant Pau (IIB-Sant Pau) , Barcelona, Catalonia,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Pybus","sequence":"additional","affiliation":[{"name":"Molecular Genetic Laboratory Fundaci\u00f3 Puigvert, Universitat Aut\u00f2noma de Barcelona, Instituto de Investigaciones Biom\u00e9dicas Sant Pau (IIB-Sant Pau) , Barcelona, Catalonia,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josvany R","family":"S\u00e1nchez Curbelo","sequence":"additional","affiliation":[{"name":"Department of Andrology, Fundaci\u00f3 Puigvert, Universitat Aut\u00f2noma de Barcelona, Instituto de Investigaciones Biom\u00e9dicas Sant Pau (IIB-Sant Pau) , Barcelona, Catalonia,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitham T","family":"Elbardisi","sequence":"additional","affiliation":[{"name":"Department of Urology, Hamad Medical Corporation , Doha,","place":["Qatar"]},{"name":"Department of Clinical Urology, Weill Cornell Medicine-Qatar , Doha,","place":["Qatar"]},{"name":"Department of Clinical Urology, College of Medicine, Qatar University , Doha,","place":["Qatar"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoaib","family":"Nawaz","sequence":"additional","affiliation":[{"name":"Laboratory of Reproductive Biology, Sidra Medicine , Doha,","place":["Qatar"]},{"name":"Laboratory of Genomic Medicine, Sidra Medicine , Doha,","place":["Qatar"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Najeeb","family":"Syed","sequence":"additional","affiliation":[{"name":"Laboratory of Genomic Medicine, Sidra Medicine , Doha,","place":["Qatar"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduard","family":"Ruiz-Castan\u00e9","sequence":"additional","affiliation":[{"name":"Department of Andrology, Fundaci\u00f3 Puigvert, Universitat Aut\u00f2noma de Barcelona, Instituto de Investigaciones Biom\u00e9dicas Sant Pau (IIB-Sant Pau) , Barcelona, Catalonia,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Godfried W","family":"van der Heijden","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Radboud University Medical Centre , Nijmegen, The","place":["Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid A","family":"Fakhro","sequence":"additional","affiliation":[{"name":"Laboratory of Genomic Medicine, Sidra Medicine , Doha,","place":["Qatar"]},{"name":"College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU) , Doha,","place":["Qatar"]},{"name":"Department of Genetic Medicine, Weill Cornell Medicine, (WCM-Q) , Doha,","place":["Qatar"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3218-8250","authenticated-orcid":false,"given":"Joris A","family":"Veltman","sequence":"additional","affiliation":[{"name":"Faculty of Medical Sciences, Biosciences Institute, Newcastle University , Newcastle-upon-Tyne,","place":["UK"]},{"name":"Institute of Genetics and Cancer, College of Medicine and Veterinary Medicine, University of Edinburgh , Edinburgh,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6748-8918","authenticated-orcid":false,"given":"Csilla","family":"Krausz","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence , Florence,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"key":"2025082919561475700_hoaf049-B1","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s13073-023-01228-w","article-title":"Genomic architecture of autism spectrum disorder in Qatar: the BARAKA-Qatar Study","volume":"15","author":"Abdi","year":"2023","journal-title":"Genome Med"},{"key":"2025082919561475700_hoaf049-B2","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1007\/s10815-021-02154-9","article-title":"Targeted next-generation sequencing panel screening of 668 Chinese patients with non-obstructive azoospermia","volume":"38","author":"An","year":"2021","journal-title":"J Assist Reprod Genet"},{"key":"2025082919561475700_hoaf049-B3","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1111\/andr.12704","article-title":"Sequence analysis of 37 candidate genes for male infertility: challenges in variant assessment and validating genes","volume":"8","author":"Araujo","year":"2020","journal-title":"Andrology"},{"key":"2025082919561475700_hoaf049-B4","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1080\/14647273.2021.1946173","article-title":"Screening by single-molecule molecular inversion probes targeted sequencing panel of candidate genes of infertility in azoospermic infertile Jordanian males","volume":"25","author":"Batiha","year":"2022","journal-title":"Hum Fertil (Camb)"},{"key":"2025082919561475700_hoaf049-B5","doi-asserted-by":"crossref","first-page":"422","DOI":"10.5534\/wjmh.220009","article-title":"Analysis of 29 targeted genes for non-obstructive azoospermia: the relationship between genetic testing and testicular histology","volume":"41","author":"Cannarella","year":"2023","journal-title":"World J Mens Health"},{"key":"2025082919561475700_hoaf049-B6","doi-asserted-by":"crossref","first-page":"24","DOI":"10.4103\/aja.aja_25_20","article-title":"Next-generation sequencing: toward an increase in the diagnostic yield in patients with apparently idiopathic spermatogenic failure","volume":"23","author":"Cannarella","year":"2021","journal-title":"Asian J Androl"},{"key":"2025082919561475700_hoaf049-B7","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1093\/hmg\/ddaa101","article-title":"Whole-exome sequencing of a large Chinese azoospermia and severe oligospermia cohort identifies novel infertility causative variants and genes","volume":"29","author":"Chen","year":"2020","journal-title":"Hum Mol Genet"},{"key":"2025082919561475700_hoaf049-B8","doi-asserted-by":"crossref","first-page":"e53","DOI":"10.1093\/nar\/gkac039","article-title":"Dysgu: efficient structural variant calling using short or long reads","volume":"50","author":"Cleal","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"2025082919561475700_hoaf049-B9","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1093\/humupd\/dmz028","article-title":"Sperm recovery and ICSI outcomes in men with non-obstructive azoospermia: a systematic review and meta-analysis","volume":"25","author":"Corona","year":"2019","journal-title":"Hum Reprod Update"},{"key":"2025082919561475700_hoaf049-B10","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1038\/gim.2018.10","article-title":"Point-of-care whole-exome sequencing of idiopathic male infertility","volume":"20","author":"Fakhro","year":"2018","journal-title":"Genet Med"},{"key":"2025082919561475700_hoaf049-B11","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.scr.2018.04.009","article-title":"Spermatogonial stem cells and spermatogenesis in mice, monkeys and men","volume":"29","author":"Fayomi","year":"2018","journal-title":"Stem Cell Res"},{"key":"2025082919561475700_hoaf049-B12","doi-asserted-by":"crossref","first-page":"e22700","DOI":"10.1002\/jcla.22700","article-title":"A novel stopgain mutation c.G992A (p.W331X) in TACR3 gene was identified in nonobstructive azoospermia by targeted next-generation sequencing","volume":"33","author":"Geng","year":"2019","journal-title":"J Clin Lab Anal"},{"key":"2025082919561475700_hoaf049-B13","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1177\/0300060518811770","article-title":"Association of single nucleotide polymorphism c.673C&gt;A\/p.Gln225Lys in SEPT12 gene with spermatogenesis failure in male idiopathic infertility in Northeast China","volume":"47","author":"Geng","year":"2019","journal-title":"J Int Med Res"},{"key":"2025082919561475700_hoaf049-B14","doi-asserted-by":"crossref","first-page":"e23139","DOI":"10.1002\/jcla.23139","article-title":"Identification of KISS1R gene mutations in disorders of non-obstructive azoospermia in the northeast population of China","volume":"34","author":"Geng","year":"2020","journal-title":"J Clin Lab Anal"},{"key":"2025082919561475700_hoaf049-B15","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/978-3-540-48461-5_11","article-title":"The comparative genetics of human spermatogenesis: clues from flies and other model organisms","volume":"28","author":"Hochstenbach","year":"2000","journal-title":"Results Probl Cell Differ"},{"key":"2025082919561475700_hoaf049-B16","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1210\/clinem\/dgab777","article-title":"Variations of C14ORF39 and SYCE1 identified in idiopathic premature ovarian insufficiency and nonobstructive azoospermia","volume":"107","author":"Hou","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"key":"2025082919561475700_hoaf049-B17","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/humupd\/dmab030","article-title":"A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene\u2013disease relationships","volume":"28","author":"Houston","year":"2021","journal-title":"Hum Reprod Update"},{"key":"2025082919561475700_hoaf049-B18","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/j.ajhg.2022.01.011","article-title":"Whole-exome sequencing improves the diagnosis and care of men with non-obstructive azoospermia","volume":"109","author":"Kherraf","year":"2022","journal-title":"Am J Hum Genet"},{"key":"2025082919561475700_hoaf049-B19","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1111\/andr.13514","article-title":"EAA\/EMQN best practice guidelines for molecular diagnosis of Y-chromosomal microdeletions: state of the art 2023","volume":"12","author":"Krausz","year":"2024","journal-title":"Andrology"},{"key":"2025082919561475700_hoaf049-B20","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/s41585-018-0003-3","article-title":"Genetics of male infertility","volume":"15","author":"Krausz","year":"2018","journal-title":"Nat Rev Urol"},{"key":"2025082919561475700_hoaf049-B2834530","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/s41436-018-0037-1","article-title":"From exome analysis in idiopathic azoospermia to the identification of a high-risk subgroup for occult Fanconi anemia","volume":"21","author":"Krausz","year":"2019","journal-title":"Genet Med"},{"key":"2025082919561475700_hoaf049-B21","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1038\/s41436-020-0907-1","article-title":"Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men","volume":"22","author":"Krausz","year":"2020","journal-title":"Genet Med"},{"key":"2025082919561475700_hoaf049-B22","doi-asserted-by":"crossref","first-page":"e1372","DOI":"10.1002\/mgg3.1372","article-title":"CHD7 missense variants and clinical characteristics of Chinese males with infertility","volume":"8","author":"Li","year":"2020","journal-title":"Mol Genet Genomic Med"},{"key":"2025082919561475700_hoaf049-B23","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.ajhg.2024.03.013","article-title":"Toward clinical exomes in diagnostics and management of male infertility","volume":"111","author":"Lillepea","year":"2024","journal-title":"Am J Hum Genet"},{"key":"2025082919561475700_hoaf049-B24","first-page":"104","article-title":"First custom next-generation sequencing infertility panel in Latin America: design and first results","volume":"24","author":"Lorenzi","year":"2020","journal-title":"JBRA Assist Reprod"},{"key":"2025082919561475700_hoaf049-B25","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1111\/andr.13637","article-title":"The human infertility single-cell testis atlas (HISTA): an interactive molecular scRNA-Seq reference of the human testis","volume":"13","author":"Mahyari","year":"2025","journal-title":"Andrology"},{"key":"2025082919561475700_hoaf049-B26","doi-asserted-by":"crossref","first-page":"e14303","DOI":"10.1111\/and.14303","article-title":"A systemic review and meta-analysis exploring the predictors of sperm retrieval in patients with non-obstructive azoospermia and chromosomal abnormalities","volume":"54","author":"Majzoub","year":"2022","journal-title":"Andrologia"},{"key":"2025082919561475700_hoaf049-B27","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","article-title":"The Ensembl Variant Effect Predictor","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol"},{"key":"2025082919561475700_hoaf049-B28","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1093\/humrep\/deae057","article-title":"Systematic molecular analyses for 115 karyotypically normal men with isolated non-obstructive azoospermia","volume":"39","author":"Muranishi","year":"2024","journal-title":"Hum Reprod"},{"key":"2025082919561475700_hoaf049-B29","doi-asserted-by":"crossref","first-page":"7953","DOI":"10.1038\/s41467-022-35661-z","article-title":"Diverse monogenic subforms of human spermatogenic failure","volume":"13","author":"Nagirnaja","year":"2022","journal-title":"Nat Commun"},{"key":"2025082919561475700_hoaf049-B30","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1111\/andr.12378","article-title":"Next-generation sequencing for patients with non-obstructive azoospermia: implications for significant roles of monogenic\/oligogenic mutations","volume":"5","author":"Nakamura","year":"2017","journal-title":"Andrology"},{"key":"2025082919561475700_hoaf049-B31","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1111\/andr.13742","article-title":"Innovative all-in-one exome sequencing strategy for diagnostic genetic testing in male infertility: validation and 10-month experience","volume":"13","author":"Oud","year":"2025","journal-title":"Andrology"},{"key":"2025082919561475700_hoaf049-B32","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/s41467-021-27132-8","article-title":"A de novo paradigm for male infertility","volume":"13","author":"Oud","year":"2022","journal-title":"Nat Commun"},{"key":"2025082919561475700_hoaf049-B33","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1093\/humrep\/dez022","article-title":"A systematic review and standardized clinical validity assessment of male infertility genes","volume":"34","author":"Oud","year":"2019","journal-title":"Hum Reprod"},{"key":"2025082919561475700_hoaf049-B34","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1093\/bioinformatics\/bts526","article-title":"A robust model for read count data in exome sequencing experiments and implications for copy number variant calling","volume":"28","author":"Plagnol","year":"2012","journal-title":"Bioinformatics"},{"key":"2025082919561475700_hoaf049-B35","doi-asserted-by":"crossref","first-page":"605237","DOI":"10.3389\/fendo.2020.605237","article-title":"Male infertility diagnosis: improvement of genetic analysis performance by the introduction of pre-diagnostic genes in a next-generation sequencing custom-made panel","volume":"11","author":"Precone","year":"2021","journal-title":"Front Endocrinol"},{"key":"2025082919561475700_hoaf049-B36","doi-asserted-by":"crossref","first-page":"e0288336","DOI":"10.1371\/journal.pone.0288336","article-title":"Whole exome data prioritization unveils the hidden weight of Mendelian causes of male infertility. A report from the first Italian cohort","volume":"18","author":"Quarantani","year":"2023","journal-title":"PLoS One"},{"key":"2025082919561475700_hoaf049-B37","volume-title":"R: A Language and Environment for Statistical Computing","author":"R Core Team","year":"2024"},{"key":"2025082919561475700_hoaf049-B38","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"2025082919561475700_hoaf049-B39","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1093\/humrep\/dez042","article-title":"Sequencing of a \u201cmouse azoospermia\u201d gene panel in azoospermic men: identification of RNF212 and STAG3 mutations as novel genetic causes of meiotic arrest","volume":"34","author":"Riera-Escamilla","year":"2019","journal-title":"Hum Reprod"},{"key":"2025082919561475700_hoaf049-B40","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1111\/andr.13753","article-title":"Utility of exome sequencing in primary spermatogenic disorders: from research to diagnostics","volume":"13","author":"Riera-Escamilla","year":"2025","journal-title":"Andrology"},{"key":"2025082919561475700_hoaf049-B41","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1016\/j.ajhg.2022.06.007","article-title":"Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure","volume":"109","author":"Riera-Escamilla","year":"2022","journal-title":"Am J Hum Genet"},{"key":"2025082919561475700_hoaf049-B42","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/nbt.1754","article-title":"Integrative genomics viewer","volume":"29","author":"Robinson","year":"2011","journal-title":"Nat Biotechnol"},{"key":"2025082919561475700_hoaf049-B43","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1007\/s10815-020-01747-0","article-title":"Development of a novel next-generation sequencing panel for diagnosis of quantitative spermatogenic impairment","volume":"37","author":"Rocca","year":"2020","journal-title":"J Assist Reprod Genet"},{"key":"2025082919561475700_hoaf049-B44","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s41525-021-00170-3","article-title":"Ethnic-specific association of amylase gene copy number with adiposity traits in a large Middle Eastern biobank","volume":"6","author":"Rossi","year":"2021","journal-title":"NPJ Genom Med"},{"key":"2025082919561475700_hoaf049-B45","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: a software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res"},{"key":"2025082919561475700_hoaf049-B46","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1002\/humu.24088","article-title":"Fitting a naturally scaled point system to the ACMG\/AMP variant classification guidelines","volume":"41","author":"Tavtigian","year":"2020","journal-title":"Hum Mutat"},{"key":"2025082919561475700_hoaf049-B47","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1093\/humupd\/dmac044","article-title":"A systematic review and evidence assessment of monogenic gene-disease relationships in human female infertility and differences in sex development","volume":"29","author":"Van Der Kelen","year":"2023","journal-title":"Hum Reprod Update"},{"key":"2025082919561475700_hoaf049-B48","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.eururo.2022.05.011","article-title":"Genetic architecture of azoospermia-time to advance the standard of care","volume":"83","author":"Wyrwoll","year":"2023","journal-title":"Eur Urol"},{"key":"2025082919561475700_hoaf049-B49","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1093\/humrep\/deab230","article-title":"Bi-allelic variants in DNA mismatch repair proteins MutS homolog MSH4 and MSH5 cause infertility in both sexes","volume":"37","author":"Wyrwoll","year":"2021","journal-title":"Hum Reprod"}],"container-title":["Human Reproduction Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hropen\/advance-article-pdf\/doi\/10.1093\/hropen\/hoaf049\/64084921\/hoaf049.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hropen\/article-pdf\/2025\/3\/hoaf049\/64084921\/hoaf049.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hropen\/article-pdf\/2025\/3\/hoaf049\/64084921\/hoaf049.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T23:56:32Z","timestamp":1756511792000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hropen\/article\/doi\/10.1093\/hropen\/hoaf049\/8238160"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025]]},"references-count":50,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,6,7]]}},"URL":"https:\/\/doi.org\/10.1093\/hropen\/hoaf049","relation":{},"ISSN":["2399-3529"],"issn-type":[{"value":"2399-3529","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025]]},"published":{"date-parts":[[2025]]},"article-number":"hoaf049"}}