{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T02:15:47Z","timestamp":1793412947641,"version":"4.5.0"},"reference-count":73,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2024,9,28]],"date-time":"2024-09-28T00:00:00Z","timestamp":1727481600000},"content-version":"vor","delay-in-days":271,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Flemish Fund for Scientific Research","award":["T002223N"],"award-info":[{"award-number":["T002223N"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,10,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>STUDY QUESTION<\/jats:title>\n                    <jats:p>What is the frequency of PLCZ1, ACTL7A, and ACTL9 variants in male patients showing fertilization failure after ICSI, and how effective is assisted oocyte activation (AOA) for them?<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>SUMMARY ANSWER<\/jats:title>\n                    <jats:p>Male patients with fertilization failure after ICSI manifest variants in PLCZ1 (29.09%), ACTL7A (14.81%), and ACTL9 (3.70%), which can be efficiently overcome by AOA treatment with ionomycin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WHAT IS KNOWN ALREADY<\/jats:title>\n                    <jats:p>Genetic variants in PLCZ1, and more recently, in ACTL7A, and ACTL9 male genes, have been associated with total fertilization failure or low fertilization after ICSI. A larger patient cohort is required to understand the frequency at which these variants occur, and to assess their effect on the calcium ion (Ca2+) release during oocyte activation. AOA, using ionomycin, can restore fertilization and pregnancy rates in patients with PLCZ1 variants, but it remains unknown how efficient this is for patients with ACTL7A and ACTL9 variants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY DESIGN, SIZE, DURATION<\/jats:title>\n                    <jats:p>This prospective study involved two patient cohorts. In the first setting, group 1 (N\u2009=\u200928, 2006\u20132020) underwent only PLCZ1 genetic screening, while group 2 (N\u2009=\u200927, 2020\u20132023) underwent PLCZ1, ACTL7A, and ACTL9 genetic screening. Patients were only recruited when they had a mean fertilization rate of \u226433.33% in at least one ICSI cycle with at least four MII oocytes. Patients underwent a mouse oocyte activation test (MOAT) and at least one ICSI\u2013AOA cycle using calcium chloride (CaCl2) injection and double ionomycin exposure at our centre. All patients donated a saliva sample for genetic screening and a sperm sample for further diagnostic tests, including Ca2+ imaging.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n                    <jats:p>Genetic screening was performed via targeted next-generation sequencing. Identified variants were classified by applying the revised ACMG guidelines into a Bayesian framework and were confirmed by bidirectional Sanger sequencing. If variants of uncertain significance or likely pathogenic or pathogenic variants were found, patients underwent additional determination of the sperm Ca2+-releasing pattern in mouse (MOCA) and in IVM human (HOCA) oocytes. Additionally, ACTL7A immunofluorescence and acrosome ultrastructure analyses by transmission electron microscopy (TEM) were performed for patients with ACTL7A and\/or ACTL9 variants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n                    <jats:p>Overall, the frequency rate of PLCZ1 variants was 29.09%. Moreover, 14.81% of patients carried ACTL7A variants and 3.70% carried ACTL9 variants. Seven different PLCZ1 variants were identified (p.Ile74Thr, p.Gln94*, p.Arg141His, p.His233Leu, p.Lys322*, p.Ile379Thr, and p.Ser500Leu), five of which are novel. Interestingly, PLCZ1 variants p.Ser500Leu and p.His233Leu occurred in 14.55% and 9.09% of cases. Five different variants were found in ACTL7A (p.Tyr183His, p.Gly214Ser, p.Val340Met, p.Ser364Glnfs*9, p.Arg373Cys), four of them being identified for the first time. A novel variant in ACTL9 (p.Arg271Pro) was also described. Notably, both heterozygous and homozygous variants were identified.<\/jats:p>\n                    <jats:p>The MOCA and HOCA tests revealed abnormal or absent Ca2+ release during fertilization in all except one patient, including patients with PLCZ1 heterozygous variants. TEM analysis revealed abnormal acrosome ultrastructure in three patients with ACTL7A variants, but only patients with homozygous ACTL7A variants showed reduced fluorescence intensity in comparison to the control.<\/jats:p>\n                    <jats:p>AOA treatment significantly increased the fertilization rate in the 19 patients with detected variants (from 11.24% after conventional ICSI to 61.80% after ICSI\u2013AOA), as well as positive hCG rate (from 10.64% to 60.00%) and live birth rate (from 6.38% to 37.14%), resulting in 13 healthy newborns. In particular, four live births and two ongoing pregnancies were produced using sperm from patients with ACTL7A variants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n                    <jats:p>Genetic screening included exonic and outflanking intronic regions, which implies that deep intronic variants were missed. In addition, other male genes or possible female-related factors affecting the fertilization process remain to be investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n                    <jats:p>Genetic screening of PLCZ1, ACTL7A, and ACTL9 offers a fast, cost-efficient, and easily implementable diagnostic test for total fertilization failure or low fertilization after ICSI, eliminating the need for complex diagnostic tests like MOAT or Ca2+ analysis. Nonetheless, HOCA remains the most sensitive functional test to reveal causality of uncertain significance variants. Interestingly, heterozygous PLCZ1 variants are sufficient to cause inadequate Ca2+ release during ICSI. Most importantly, AOA treatment using CaCl2 injection followed by double ionomycin exposure is highly effective for this patient group, including those with ACTL7A variants, who also display a Ca2+-release deficiency.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n                    <jats:p>This study was supported by the Flemish Fund for Scientific Research (FWO) (TBM-project grant T002223N awarded to B.H.) and by the Special Research Fund (BOF) (starting grant BOF.STG.2021.0042.01 awarded to B.H.). A.C.B., R.R.G., C.C., E.V.D.V., A.R., D.S., L.L., P.C., S.S., A.B., and F.V.M. have nothing to disclose. B.H. reports a research grant from FWO and BOF, and reports being a board member of the Belgian Ethical Committee on embryo research.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>TRIAL REGISTRATION NUMBER<\/jats:title>\n                    <jats:p>N\/A.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/hropen\/hoae057","type":"journal-article","created":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T07:20:54Z","timestamp":1727421654000},"source":"Crossref","is-referenced-by-count":15,"title":["High rate of detected variants in male\n                    <i>PLCZ1<\/i>\n                    and\n                    <i>ACTL7A<\/i>\n                    genes causing failed fertilization after ICSI"],"prefix":"10.1093","volume":"2024","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3136-8946","authenticated-orcid":false,"given":"Arantxa","family":"Cardona Barber\u00e1n","sequence":"first","affiliation":[{"name":"Ghent-Fertility And Stem cell Team (G-FaST), Department for Reproductive Medicine, Ghent University Hospital , Ghent,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramesh","family":"Reddy Guggilla","sequence":"additional","affiliation":[{"name":"Ghent-Fertility And Stem cell Team (G-FaST), Department for Reproductive Medicine, Ghent University Hospital , Ghent,","place":["Belgium"]},{"name":"MedGenome Labs Ltd, Narayana Health City , Bengaluru,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cora","family":"Colenbier","sequence":"additional","affiliation":[{"name":"Ghent-Fertility And Stem cell Team (G-FaST), Department for Reproductive Medicine, Ghent University Hospital , Ghent,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Van der Velden","sequence":"additional","affiliation":[{"name":"Ghent-Fertility And Stem cell Team (G-FaST), Department for Reproductive Medicine, Ghent University Hospital , Ghent,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei","family":"Rybouchkin","sequence":"additional","affiliation":[{"name":"Ghent-Fertility And Stem cell Team (G-FaST), Department for Reproductive Medicine, Ghent University Hospital , Ghent,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic","family":"Stoop","sequence":"additional","affiliation":[{"name":"Ghent-Fertility And Stem cell Team (G-FaST), Department for Reproductive Medicine, Ghent University Hospital , Ghent,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc","family":"Leybaert","sequence":"additional","affiliation":[{"name":"Physiology Group, Department of Basic and Applied Medical Sciences, Ghent University , Ghent,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Coucke","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Medicine, Center for Medical Genetics Ghent (CMGG), Ghent University Hospital , Ghent,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofie","family":"Symoens","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Medicine, Center for Medical Genetics Ghent (CMGG), Ghent University Hospital , Ghent,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3256-7020","authenticated-orcid":false,"given":"Annekatrien","family":"Boel","sequence":"additional","affiliation":[{"name":"Ghent-Fertility And Stem cell Team (G-FaST), Department for Reproductive Medicine, Ghent University Hospital , Ghent,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7681-0179","authenticated-orcid":false,"given":"Frauke","family":"Vanden Meerschaut","sequence":"additional","affiliation":[{"name":"Ghent-Fertility And Stem cell Team (G-FaST), Department for Reproductive Medicine, Ghent University Hospital , Ghent,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0630-8420","authenticated-orcid":false,"given":"Bj\u00f6rn","family":"Heindryckx","sequence":"additional","affiliation":[{"name":"Ghent-Fertility And Stem cell Team (G-FaST), Department for Reproductive Medicine, Ghent University Hospital , Ghent,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,9,28]]},"reference":[{"key":"2024101600013625500_hoae057-B1","doi-asserted-by":"crossref","first-page":"e82249","DOI":"10.1371\/journal.pone.0082249","article-title":"Factors associated with failed treatment: an analysis of 121,744 women embarking on their first IVF cycles","volume":"8","author":"Bhattacharya","year":"2013","journal-title":"PLoS One"},{"key":"2024101600013625500_hoae057-B2","doi-asserted-by":"crossref","first-page":"eabb1723","DOI":"10.1126\/science.abb1723","article-title":"Widespread haploid-biased gene expression enables sperm-level natural selection","volume":"371","author":"Bhutani","year":"2021","journal-title":"Science"},{"key":"2024101600013625500_hoae057-B3","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.fertnstert.2019.04.006","article-title":"Assisted oocyte activation significantly increases fertilization and pregnancy outcome in patients with low and total failed fertilization after intracytoplasmic sperm injection: a 17-year retrospective study","volume":"112","author":"Bonte","year":"2019","journal-title":"Fertil Steril"},{"key":"2024101600013625500_hoae057-B4","doi-asserted-by":"crossref","first-page":"F39","DOI":"10.1530\/REP-21-0387","article-title":"Sperm factors and egg activation: fertilization failure after human ICSI and the clinical potential of PLCZ1","volume":"164","author":"Cardona Barber\u00e1n","year":"2022","journal-title":"Reproduction"},{"key":"2024101600013625500_hoae057-B5","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1093\/humrep\/dead051","article-title":"Assisted oocyte activation does not overcome recurrent embryo developmental problems","volume":"38","author":"Cardona Barber\u00e1n","year":"2023","journal-title":"Hum Reprod"},{"key":"2024101600013625500_hoae057-B6","first-page":"169","article-title":"A homozygous protein-truncating mutation in ACTL7A causes male infertility characterized by fertilization failure","volume":"6","author":"Chen","year":"2022","journal-title":"Reprod Dev Med"},{"key":"2024101600013625500_hoae057-B7","doi-asserted-by":"crossref","first-page":"eadg7492","DOI":"10.1126\/science.adg7492","article-title":"Accurate proteome-wide missense variant effect prediction with AlphaMissense","volume":"381","author":"Cheng","year":"2023","journal-title":"Science"},{"key":"2024101600013625500_hoae057-B8","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.fertnstert.2020.04.044","article-title":"Identification and treatment of men with phospholipase C\u03b6\u2013defective spermatozoa","volume":"114","author":"Cheung","year":"2020","journal-title":"Fertil Steril"},{"key":"2024101600013625500_hoae057-B9","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1093\/humrep\/dead068","article-title":"Characterization of ovarian tissue oocytes from transgender men reveals poor calcium release and embryo development, which might be overcome by spindle transfer","volume":"38","author":"Christodoulaki","year":"2023","journal-title":"Hum Reprod"},{"key":"2024101600013625500_hoae057-B10","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1016\/j.fertnstert.2023.02.008","article-title":"First pilot study of maternal spindle transfer for the treatment of repeated in vitro fertilization failures in couples with idiopathic infertility","volume":"119","author":"Costa-Borges","year":"2023","journal-title":"Fertil Steril"},{"key":"2024101600013625500_hoae057-B12","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1111\/cge.13636","article-title":"Novel homozygous variations in PLCZ1 lead to poor or failed fertilization characterized by abnormal localization patterns of PLC\u03b6 in sperm","volume":"97","author":"Dai","year":"2020","journal-title":"Clin Genet"},{"key":"2024101600013625500_hoae057-B11","doi-asserted-by":"crossref","first-page":"gaac028","DOI":"10.1093\/molehr\/gaac028","article-title":"Pathogenic variant in ACTL7A causes severe teratozoospermia characterized by bubble-shaped acrosomes and male infertility","volume":"28","author":"Dai","year":"2022","journal-title":"Mol Hum Reprod"},{"key":"2024101600013625500_hoae057-B13","doi-asserted-by":"crossref","first-page":"e16501","DOI":"10.15252\/emmm.202216501","article-title":"IQCN disruption causes fertilization failure and male infertility due to manchette assembly defect","volume":"14","author":"Dai","year":"2022","journal-title":"EMBO Mol Med"},{"key":"2024101600013625500_hoae057-B14","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.ajhg.2021.02.004","article-title":"Homozygous pathogenic variants in ACTL9 cause fertilization failure and male infertility in humans and mice","volume":"108","author":"Dai","year":"2021","journal-title":"Am J Hum Genet"},{"key":"2024101600013625500_hoae057-B20","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/j.fertnstert.2021.11.029","article-title":"Machine learning for prediction of euploidy in human embryos: in search of the best-performing model and predictive features","volume":"117","author":"De Gheselle","year":"2022","journal-title":"Fertil Steril"},{"key":"2024101600013625500_hoae057-B15","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1002\/humu.22739","article-title":"Flexible, scalable, and efficient targeted resequencing on a benchtop sequencer for variant detection in clinical practice","volume":"36","author":"De Leeneer","year":"2015","journal-title":"Hum Mutat"},{"key":"2024101600013625500_hoae057-B16","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1177\/1933719114542017","article-title":"Health of children born through artificial oocyte activation","volume":"22","author":"Deemeh","year":"2015","journal-title":"Reprod Sci"},{"key":"2024101600013625500_hoae057-B17","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1093\/hmg\/ddv617","article-title":"Homozygous mutation of PLCZ1 leads to defective human oocyte activation and infertility that is not rescued by the WW-binding protein PAWP","volume":"25","author":"Escoffier","year":"2016","journal-title":"Hum Mol Genet"},{"key":"2024101600013625500_hoae057-B18","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1093\/humrep\/dex376","article-title":"Human oocyte calcium analysis predicts the response to assisted oocyte activation in patients experiencing fertilization failure after ICSI","volume":"33","author":"Ferrer-Buitrago","year":"2018","journal-title":"Hum Reprod"},{"issue":"Suppl 1","key":"2024101600013625500_hoae057-B19","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1093\/humrep\/13.suppl_1.155","article-title":"Fertilization failures and abnormal fertilization after intracytoplasmic sperm injection","volume":"13","author":"Flaherty","year":"1998","journal-title":"Hum Reprod"},{"key":"2024101600013625500_hoae057-B21","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1111\/j.1439-0272.2005.00656.x","article-title":"Mature human spermatozoa do not transcribe novel RNA","volume":"37","author":"Grunewald","year":"2005","journal-title":"Andrologia"},{"key":"2024101600013625500_hoae057-B22","doi-asserted-by":"crossref","first-page":"2914","DOI":"10.1242\/dev.150227","article-title":"PLC\u03b6 is the physiological trigger of the Ca2+ oscillations that induce embryogenesis in mammals but conception can occur in its absence","volume":"144","author":"Hachem","year":"2017","journal-title":"Development"},{"key":"2024101600013625500_hoae057-B23","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/S1472-6483(10)60313-6","article-title":"Efficiency of assisted oocyte activation as a solution for failed intracytoplasmic sperm injection","volume":"17","author":"Heindryckx","year":"2008","journal-title":"Reprod Biomed Online"},{"key":"2024101600013625500_hoae057-B24","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1093\/humrep\/dei029","article-title":"Treatment option for sperm- or oocyte-related fertilization failure: assisted oocyte activation following diagnostic heterologous ICSI","volume":"20","author":"Heindryckx","year":"2005","journal-title":"Hum Reprod"},{"key":"2024101600013625500_hoae057-B25","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.1093\/humrep\/dep207","article-title":"Reduced amounts and abnormal forms of phospholipase C zeta (PLC) in spermatozoa from infertile men","volume":"24","author":"Heytens","year":"2009","journal-title":"Hum Reprod"},{"key":"2024101600013625500_hoae057-B26","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","article-title":"REVEL: an Ensemble method for predicting the pathogenicity of rare missense variants","volume":"99","author":"Ioannidis","year":"2016","journal-title":"Am J Hum Genet"},{"key":"2024101600013625500_hoae057-B27","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1016\/j.jmb.2019.04.009","article-title":"Can predicted protein 3D structures provide reliable insights into whether missense variants are disease associated?","volume":"431","author":"Ittisoponpisan","year":"2019","journal-title":"J Mol Biol"},{"key":"2024101600013625500_hoae057-B28","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.rbmo.2022.08.105","article-title":"Artificial oocyte activation with ionomycin compared with A23187 among patients at risk of failed or impaired fertilization","volume":"46","author":"Jia","year":"2023","journal-title":"Reprod Biomed Online"},{"key":"2024101600013625500_hoae057-B29","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1093\/humupd\/dmq018","article-title":"Oocyte activation, phospholipase C zeta and human infertility","volume":"16","author":"Kashir","year":"2010","journal-title":"Hum Reprod Update"},{"key":"2024101600013625500_hoae057-B30","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1093\/humrep\/der384","article-title":"A maternally inherited autosomal point mutation in human phospholipase C zeta (PLC\u03b6) leads to male infertility","volume":"27","author":"Kashir","year":"2012","journal-title":"Hum Reprod"},{"key":"2024101600013625500_hoae057-B31","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1530\/REP-12-0362","article-title":"Connecting cis-elements and trans-factors with mechanisms of developmental regulation of mRNA translation in meiotic and haploid mammalian spermatogenic cells","volume":"146","author":"Kleene","year":"2013","journal-title":"Reproduction"},{"key":"2024101600013625500_hoae057-B32","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1186\/s12859-017-1809-3","article-title":"High-throughput PCR assay design for targeted resequencing using primerXL","volume":"18","author":"Lefever","year":"2017","journal-title":"BMC Bioinformatics"},{"key":"2024101600013625500_hoae057-B33","doi-asserted-by":"crossref","first-page":"1193248","DOI":"10.3389\/fcell.2023.1193248","article-title":"Novel mutations in PLCZ1 lead to early embryonic arrest as a male factor","volume":"11","author":"Lin","year":"2023","journal-title":"Front Cell Dev Biol"},{"key":"2024101600013625500_hoae057-B766084990","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.1093\/humrep\/dead184","article-title":"Good practice recommendations on add-ons in reproductive medicine\u2020","volume":"38","author":"Lundin","year":"2023","journal-title":"Hum Reprod"},{"key":"2024101600013625500_hoae057-B34","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.rbmo.2020.01.001","article-title":"Artificial oocyte activation to improve reproductive outcomes in couples with various causes of infertility: a retrospective cohort study","volume":"40","author":"Lv","year":"2020","journal-title":"Reprod Biomed Online"},{"key":"2024101600013625500_hoae057-B35","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1007\/s10815-018-1124-6","article-title":"Obstetric and neonatal outcome following ICSI with assisted oocyte activation by calcium ionophore treatment","volume":"35","author":"Mateizel","year":"2018","journal-title":"J Assist Reprod Genet"},{"key":"2024101600013625500_hoae057-B36","doi-asserted-by":"crossref","first-page":"e1589","DOI":"10.1002\/wsbm.1589","article-title":"Human globozoospermia-related genes and their role in acrosome biogenesis","volume":"15","author":"Moreno","year":"2023","journal-title":"WIREs Mech Dis"},{"key":"2024101600013625500_hoae057-B37","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1093\/molehr\/gaaa003","article-title":"The identification of novel mutations in PLCZ1 responsible for human fertilization failure and a therapeutic intervention by artificial oocyte activation","volume":"26","author":"Mu","year":"2020","journal-title":"Mol Hum Reprod"},{"key":"2024101600013625500_hoae057-B38","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1016\/j.fertnstert.2015.11.007","article-title":"Effect of two assisted oocyte activation protocols used to overcome fertilization failure on the activation potential and calcium releasing pattern","volume":"105","author":"Nikiforaki","year":"2016","journal-title":"Fertil Steril"},{"key":"2024101600013625500_hoae057-B39","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1093\/molehr\/gau011","article-title":"Human PLC\u03b6 exhibits superior fertilization potency over mouse PLC\u03b6 in triggering the Ca2+ oscillations required for mammalian oocyte activation","volume":"20","author":"Nomikos","year":"2014","journal-title":"Mol Hum Reprod"},{"key":"2024101600013625500_hoae057-B40","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.fertnstert.2012.08.035","article-title":"Phospholipase C\u03b6 rescues failed oocyte activation in a prototype of male factor infertility","volume":"99","author":"Nomikos","year":"2013","journal-title":"Fertil Steril"},{"key":"2024101600013625500_hoae057-B41","doi-asserted-by":"crossref","first-page":"F93","DOI":"10.1530\/REP-17-0374","article-title":"Intracytoplasmic sperm injection: state of the art in humans","volume":"154","author":"Palermo","year":"2017","journal-title":"Reproduction"},{"key":"2024101600013625500_hoae057-B42","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s10815-022-02670-2","article-title":"Mutations in PLCZ1 induce male infertility associated with polyspermy and fertilization failure","volume":"40","author":"Peng","year":"2023","journal-title":"J Assist Reprod Genet"},{"key":"2024101600013625500_hoae057-B43","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014a visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J Comput Chem"},{"key":"2024101600013625500_hoae057-B44","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":"2024101600013625500_hoae057-B45","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1530\/rep.1.00484","article-title":"Phospholipase Czeta causes Ca2+ oscillations and parthenogenetic activation of human oocytes","volume":"128","author":"Rogers","year":"2004","journal-title":"Reproduction"},{"key":"2024101600013625500_hoae057-B46","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1016\/S0015-0282(97)00378-6","article-title":"Fertilization and pregnancy after assisted oocyte activation and intracytoplasmic sperm injection in a case of round-headed sperm associated with deficient oocyte activation capacity","volume":"68","author":"Rybouchkin","year":"1997","journal-title":"Fertil Steril"},{"key":"2024101600013625500_hoae057-B47","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.ajhg.2018.02.015","article-title":"Homozygous mutations in WEE2 cause fertilization failure and female infertility","volume":"102","author":"Sang","year":"2018","journal-title":"Am J Hum Genet"},{"key":"2024101600013625500_hoae057-B48","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat Methods"},{"key":"2024101600013625500_hoae057-B49","doi-asserted-by":"crossref","first-page":"lnac050","DOI":"10.1093\/lifemedi\/lnac050","article-title":"Biallelic mutations in IQCN, encoding a novel acroplaxome protein, lead to fertilization failure and male infertility with defects in the acrosome and shaping of the spermatid head in humans and mice","volume":"2","author":"Sha","year":"2023","journal-title":"Life Med"},{"key":"2024101600013625500_hoae057-B51","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S1642-431X(12)60055-2","article-title":"Value of quantitative ultramorphological sperm analysis in infertile men","volume":"10","author":"Skowronek","year":"2010","journal-title":"Reprod Biol"},{"key":"2024101600013625500_hoae057-B52","doi-asserted-by":"crossref","first-page":"e20200219","DOI":"10.1590\/1984-3143-ar2020-0219","article-title":"The effects of cryopreservation on the acrosome structure, enzyme activity, motility, and fertility of bovine, ovine, and goat sperm","volume":"17","author":"Sun","year":"2020","journal-title":"Anim Reprod"},{"key":"2024101600013625500_hoae057-B53","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1007\/s10815-022-02401-7","article-title":"Human germline nuclear transfer to overcome mitochondrial disease and failed fertilization after ICSI","volume":"39","author":"Tang","year":"2022","journal-title":"J Assist Reprod Genet"},{"key":"2024101600013625500_hoae057-B54","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1038\/gim.2017.210","article-title":"Modeling the ACMG\/AMP variant classification guidelines as a Bayesian classification framework","volume":"20","author":"Tavtigian","year":"2018","journal-title":"Genet Med"},{"key":"2024101600013625500_hoae057-B55","doi-asserted-by":"crossref","first-page":"F1","DOI":"10.1530\/REP-21-0477","article-title":"Sperm factors and egg activation: the structure and function relationship of sperm PLCZ1","volume":"164","author":"Thanassoulas","year":"2022","journal-title":"Reproduction"},{"key":"2024101600013625500_hoae057-B56","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1093\/humrep\/dez094","article-title":"Novel phospholipase C zeta 1 mutations associated with fertilization failures after ICSI","volume":"34","author":"Torra-Massana","year":"2019","journal-title":"Hum Reprod"},{"key":"2024101600013625500_hoae057-B57","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.rbmo.2013.07.013","article-title":"Neonatal and neurodevelopmental outcome of children aged 3-10 years born following assisted oocyte activation","volume":"28","author":"Vanden Meerschaut","year":"2014","journal-title":"Reprod Biomed Online"},{"key":"2024101600013625500_hoae057-B58","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1093\/humrep\/des368","article-title":"Diagnostic and prognostic value of calcium oscillatory pattern analysis for patients with ICSI fertilization failure","volume":"28","author":"Vanden Meerschaut","year":"2013","journal-title":"Hum Reprod"},{"key":"2024101600013625500_hoae057-B59","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1007\/s10815-020-01719-4","article-title":"A homozygous nonsense mutation of PLCZ1 cause male infertility with oocyte activation deficiency","volume":"37","author":"Wang","year":"2020","journal-title":"J Assist Reprod Genet"},{"key":"2024101600013625500_hoae057-B60","doi-asserted-by":"crossref","first-page":"3161","DOI":"10.1093\/humrep\/deab228","article-title":"Novel bi-allelic variants in ACTL7A are associated with male infertility and total fertilization failure","volume":"36","author":"Wang","year":"2021","journal-title":"Hum Reprod"},{"key":"2024101600013625500_hoae057-B61","doi-asserted-by":"publisher","DOI":"10.1111\/andr.13553","article-title":"Novel ACTL7A variants in males lead to fertilization failure and male infertility","author":"Wang","year":"2023","journal-title":"Andrology"},{"key":"2024101600013625500_hoae057-B62","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1093\/humupd\/dmad026","article-title":"Genetic mechanisms of fertilization failure and early embryonic arrest: a comprehensive review","volume":"30","author":"Wei","year":"2023","journal-title":"Hum Reprod Update"},{"key":"2024101600013625500_hoae057-B63","volume-title":"WHO Laboratory Manual for the Examination and Processing of Human Semen","author":"WHO","year":"2021","edition":"6th edn"},{"key":"2024101600013625500_hoae057-B64","doi-asserted-by":"crossref","first-page":"eaaz4796","DOI":"10.1126\/sciadv.aaz4796","article-title":"Disruption in ACTL7A causes acrosomal ultrastructural defects in human and mouse sperm as a novel male factor inducing early embryonic arrest","volume":"6","author":"Xin","year":"2020","journal-title":"Sci Adv"},{"key":"2024101600013625500_hoae057-B65","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.ceca.2017.03.002","article-title":"The establishment of appropriate methods for egg-activation by human PLCZ1 RNA injection into human oocyte","volume":"65","author":"Yamaguchi","year":"2017","journal-title":"Cell Calcium"},{"key":"2024101600013625500_hoae057-B66","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1093\/humrep\/dez282","article-title":"Novel mutations in PLCZ1 cause male infertility due to fertilization failure or poor fertilization","volume":"35","author":"Yan","year":"2020","journal-title":"Hum Reprod"},{"key":"2024101600013625500_hoae057-B68","doi-asserted-by":"crossref","first-page":"3671","DOI":"10.1172\/JCI36942","article-title":"Human sperm devoid of PLC, zeta 1 fail to induce Ca(2+) release and are unable to initiate the first step of embryo development","volume":"118","author":"Yoon","year":"2008","journal-title":"J Clin Invest"},{"key":"2024101600013625500_hoae057-B69","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1038\/nprot.2007.7","article-title":"Piezo-actuated mouse intracytoplasmic sperm injection (ICSI)","volume":"2","author":"Yoshida","year":"2007","journal-title":"Nat Protoc"},{"key":"2024101600013625500_hoae057-B70","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1093\/humrep\/dez293","article-title":"A novel homozygous mutation of phospholipase C zeta leading to defective human oocyte activation and fertilization failure","volume":"35","author":"Yuan","year":"2020","journal-title":"Hum Reprod"},{"key":"2024101600013625500_hoae057-B71","doi-asserted-by":"crossref","first-page":"e1470","DOI":"10.1002\/mgg3.1470","article-title":"Novel mutations in the PLCZ1 gene associated with human low or failed fertilization","volume":"8","author":"Yuan","year":"2020","journal-title":"Mol Genet Genomic Med"},{"key":"2024101600013625500_hoae057-B73","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1111\/cge.14293","article-title":"Novel variants in ACTL7A and PLCZ1 are associated with male infertility and total fertilization failure","volume":"103","author":"Zhao","year":"2023","journal-title":"Clin Genet"},{"key":"2024101600013625500_hoae057-B74","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.bbrc.2022.07.065","article-title":"Actl7a deficiency in mice leads to male infertility and fertilization failure","volume":"623","author":"Zhou","year":"2022","journal-title":"Biochem Biophys Res Commun"},{"key":"2024101600013625500_hoae057-B75","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s00438-022-01985-0","article-title":"A novel homozygous mutation in ACTL7A leads to male infertility","volume":"298","author":"Zhou","year":"2023","journal-title":"Mol Genet Genomics"}],"container-title":["Human Reproduction Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hropen\/advance-article-pdf\/doi\/10.1093\/hropen\/hoae057\/59419265\/hoae057.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hropen\/article-pdf\/2024\/4\/hoae057\/59765377\/hoae057.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hropen\/article-pdf\/2024\/4\/hoae057\/59765377\/hoae057.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,15]],"date-time":"2024-10-15T20:02:18Z","timestamp":1729022538000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hropen\/article\/doi\/10.1093\/hropen\/hoae057\/7789475"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024]]},"references-count":73,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2024,10,9]]}},"URL":"https:\/\/doi.org\/10.1093\/hropen\/hoae057","relation":{},"ISSN":["2399-3529"],"issn-type":[{"value":"2399-3529","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024]]},"published":{"date-parts":[[2024]]},"article-number":"hoae057"}}