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We performed whole\u2010exome sequencing of 236 patients with NOA and identified a homozygous pathogenic variant of autophagy\u2010related 4D cysteine peptidase (ATG4D) in two siblings from a consanguineous family and compound heterozygous pathogenic variants of ATG4D in two sporadic cases. The expression of LC3B, a regulator of autophagic activity, was significantly decreased, and the apoptosis rate of spermatogenic cells in testicular tissues was increased. Transfection of GC\u20102spd cells with a\n                    <jats:italic>ATG4D<\/jats:italic>\n                    mutant plasmid (Flag\u2010Atg4d\n                    <jats:sup>mut<\/jats:sup>\n                    ) significantly decreased the expression level of Lc3b and increased the rate of apoptosis. Moreover, a pathogenic variant in X\u2010linked ATG4A and compound heterozygous pathogenic variants of ATG4B were identified in one patient each. All novel variants were segregated by disease phenotype and were predicted to be pathogenic. Our findings revealed that autophagy\u2010related cysteine peptidase family genes may play crucial roles in human spermatogenesis and identified ATG4D as a novel candidate gene for male infertility due to NOA.\n                  <\/jats:p>","DOI":"10.1111\/cge.13995","type":"journal-article","created":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T06:14:33Z","timestamp":1620972873000},"page":"280-291","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Pathogenic variants of\n                    <i>ATG4D<\/i>\n                    in infertile men with non\u2010obstructive azoospermia identified using whole\u2010exome sequencing"],"prefix":"10.1111","volume":"100","author":[{"given":"Yanwei","family":"Sha","sequence":"first","affiliation":[{"name":"Department of Andrology, United Diagnostic and Research Centre for Clinical Genetics School of Public Health &amp; Women and Children's Hospital, Xiamen University  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