{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T05:11:39Z","timestamp":1788757899226,"version":"build-2803163510"},"reference-count":22,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Non-obstructive azoospermia (NOA) with meiotic maturation arrest is a severe form of male infertility for which genetic diagnosis may inform counseling and sperm-retrieval expectations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Whole-exome sequencing was performed in a consanguineous family with NOA, followed by\n                      <jats:italic>SPDYA<\/jats:italic>\n                      variant screening in 31 unrelated NOA patients and 469 men with documented reproductive outcomes. The proband underwent clinical evaluation and microdissection testicular sperm extraction (micro-TESE). Testicular histology, immunofluorescence staining, and meiotic chromosome-spread analysis were used to assess spermatogenic progression. Structural modeling, immunoblotting, co-immunoprecipitation, and exploratory bulk RNA sequencing were performed using testicular material from the proband and a pooled obstructive azoospermia control reference. The three libraries per condition were technical library replicates, not independent biological replicates.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A homozygous\n                      <jats:italic>SPDYA<\/jats:italic>\n                      missense variant (NM_182756.4:c.596G&amp;gt;A; p.R199H) was identified in the proband, and both parents were heterozygous carriers. No additional biallelic deleterious\n                      <jats:italic>SPDYA<\/jats:italic>\n                      variants were detected in the screening cohort. The patient showed NOA, reduced testicular volume, spermatocyte-stage maturation arrest, and failed micro-TESE. Cytological analyses showed absence of post-meiotic germ cells, persistent nuclear \u03b3H2AX, failed XY body formation, and no pachytene or diplotene spermatocytes. Structural modeling and co-immunoprecipitation were compatible with weakened SPDYA-CDK2 association, and immunoblotting showed lower apparent abundance of SPDYA, CDK2, and SUN1 in the patient sample. Exploratory transcriptomic profiling showed fold-change-based tissue-level trends consistent with early meiotic arrest and loss of post-meiotic germ-cell programs, rather than direct transcriptional effects of the variant.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This single case suggests that biallelic\n                      <jats:italic>SPDYA<\/jats:italic>\n                      variants may be associated with poor sperm retrieval outcomes in severe meiotic arrest, but larger multicenter cohorts are strictly required before\n                      <jats:italic>SPDYA<\/jats:italic>\n                      can be used for clinical prediction or surgical decision-making.\n                    <\/jats:p>\n                  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