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We evaluated two unrelated women with primary infertility who showed reproducible oocyte abnormalities across in vitro fertilization cycles, and we performed genomic and functional assays to clarify the role of\n                      <jats:italic>LHX8<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Whole exome sequencing identified heterozygous loss-of-function variants in\n                      <jats:italic>LHX8<\/jats:italic>\n                      (NM_001001933.1) in both patients: c.778\u00a0C\u2009&gt;\u2009T (p.Gln260Ter) in family 1 and c.581-1G\u2009&gt;\u2009A in family 2. Both variants met the American College of Medical Genetics and Genomics criteria for likely pathogenicity. The two patients had high proportions of degenerated or immature oocytes and showed consistent morphologic features, including multiple cytoplasmic vacuoles, impaired zona pellucida function with accumulation of sperm in the perivitelline space, and poor embryo development. The splice site variant was inherited from a fertile mother, which indicates incomplete penetrance. A minigene assay confirmed the use of a cryptic acceptor site that produced a one nucleotide deletion and a frameshift, consistent with loss of function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These findings expand the phenotypic spectrum of\n                      <jats:italic>LHX8<\/jats:italic>\n                      related infertility and provide mechanistic evidence that partial reduction of\n                      <jats:italic>LHX8<\/jats:italic>\n                      activity compromises oocyte quality. Recognition of the characteristic morphology may guide genetic testing and counseling in cases of unexplained infertility.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13048-026-01978-2","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T13:05:03Z","timestamp":1769000703000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel LHX8 variants associated with distinctive oocyte morphological abnormalities and maturation arrest in primary infertility"],"prefix":"10.1186","volume":"19","author":[{"given":"Yusuke","family":"Sako","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidehito","family":"Inagaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Yanagihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Kinoshita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaname","family":"Nakayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuyuki","family":"Mio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keitaro","family":"Yumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rei","family":"Hirata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiro","family":"Habara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruki","family":"Nishizawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Kurahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,21]]},"reference":[{"key":"1978_CR1","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1093\/humrep\/deae292","volume":"40","author":"Y Liang","year":"2025","unstructured":"Liang Y, Huang J, Zhao Q, Mo H, Su Z, Feng S, et al. 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Written informed consent was obtained from both participants prior to their inclusion in this study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"61"}}