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Fortunately, in recent years, gene sequencing has allowed the identification of multiple genetic variants underlying failed ICSI outcomes, but the use of this approach is still far from routine in the fertility clinic. In this systematic review, the genetic variants associated with FF, abnormal fertilization and\/or zygotic arrest after ICSI are compiled and analyzed. Forty-seven studies were included. Data from 141 patients carrying 121 genetic variants affecting 16 genes were recorded and analyzed. In total, 27 variants in<jats:italic>PLCZ1<\/jats:italic>(in 50 men) and 26 variants in<jats:italic>WEE2<\/jats:italic>(in 24 women) are two of the factors related to oocyte activation failure that could explain a high percentage of male-related and female-related FF. Additional variants identified were reported in<jats:italic>WBP2NL<\/jats:italic>,<jats:italic>ACTL9, ACTLA7,<\/jats:italic>and<jats:italic>DNAH17<\/jats:italic>(in men), and<jats:italic>TUBB8<\/jats:italic>,<jats:italic>PATL2<\/jats:italic>,<jats:italic>TLE6<\/jats:italic>,<jats:italic>PADI6<\/jats:italic>,<jats:italic>TRIP13<\/jats:italic>,<jats:italic>BGT4, NLRP5, NLRP7<\/jats:italic>,<jats:italic>CDC20<\/jats:italic>and<jats:italic>ZAR1<\/jats:italic>(in women). Most of these variants are pathogenic or potentially pathogenic (89\/121, 72.9%), as demonstrated by experimental and\/or<jats:italic>in silico<\/jats:italic>approaches. Most individuals carried bi-allelic variants (89\/141, 63.1%), but pathogenic variants in heterozygosity have been identified for<jats:italic>PLCZ1<\/jats:italic>and<jats:italic>TUBB8<\/jats:italic>. Clinical treatment options for affected individuals, such as chemical-assisted oocyte activation (AOA) or<jats:italic>PLCZ1<\/jats:italic>cRNA injection in the oocyte, are still experimental. In conclusion, a genetic study of known pathogenic variants may help in diagnosing recurrent FF and zygotic arrest and guide patient counselling and future research perspectives.<\/jats:p>","DOI":"10.1017\/s096719942300014x","type":"journal-article","created":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T08:32:16Z","timestamp":1684744336000},"page":"316-341","update-policy":"https:\/\/doi.org\/10.1017\/policypage","source":"Crossref","is-referenced-by-count":11,"title":["Exonic genetic variants associated with unexpected fertilization failure and zygotic arrest after ICSI: a systematic 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