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Objective: Non-obstructive azoospermia(NOA),a severe form of male infertility,is often suspected to be linked to currently undefined genetic abnormalities.The objective of the study is to explore the genetic basis of this condition.Methods: We successfully sequenced~650 infertilityrelated genes in 757 NOA patients and 709 fertile males.We evaluated the contributions of rare variants to the etiology of NOA by identifying individual genes showing nominal associations and testing the genetic burden of a given biological process as a whole.Results: We found a significant excess of rare,non-silent variants in genes that are key epigenetic regulators of spermatogenesis,such as BRWD1,DNMT1,DNMT3B,RNF17,UBR2,USP1 and USP26,in NOA patients(P=5.5x10-7),corresponding to a carrier frequency of 22.5%of patients and 13.7%of controls(P=1.4×10-5).An accumulation of low-frequency variants was also identified in additional epigenetic genes(BRDT and MTHFR).Conclusions: Our study suggested the potential associations of genetic defects in genes that are epigenetic regulators with spermatogenic failure in human and proved the novel concept that some epigenetic regulators might be promising targets for the diagnosis and treatment of male infertility,as well as male contraception.