{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T18:56:49Z","timestamp":1787770609082,"version":"build-2784847793"},"reference-count":19,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T00:00:00Z","timestamp":1752019200000},"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. Genet."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p><jats:italic>PATL2<\/jats:italic> deficiency is a significant cause of female infertility. Although multiple <jats:italic>PATL2<\/jats:italic> missense variants have been reported in prior studies, a number of these variants remain classified as variants of uncertain significance (VUS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We present a patient of primary infertility characterized by oocyte maturation disorders and fertilization failure. Comprehensive genetic analysis was conducted through whole-exome sequencing (WES) to identify pathogenic variants, followed by Sanger sequencing for familial co-segregation analysis. Reverse transcription (RT-PCR), cDNA sequencing and quantitative RT-PCR were performed to validate the effect of the variant on pre-mRNA splicing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified compound heterozygous variants in the <jats:italic>PATL2<\/jats:italic> gene by WES: a pathogenic splice-site splicing variant (c.223-14_223-2del) and a missense variant (c.877G&amp;gt;T) initially classified as a VUS. Sanger sequencing confirmed that the proband carried biallelic variants, whereas her sisters with either wild-type genotypes or a single heterozygous variant exhibited normal fertility, supporting the co-segregation of the identified variants. Critically, RNA assays demonstrated that the missense variant c.877G&amp;gt;T disrupts canonical splicing of <jats:italic>PATL2<\/jats:italic>, resulting in exon 12 skipping.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study provides the first experimental evidence that a <jats:italic>PATL2<\/jats:italic> missense variant (c.877G&amp;gt;T) can exert its pathogenicity through aberrant splicing, supporting its pathogenic reclassification and elucidating a genotype-phenotype correlation for <jats:italic>PATL2<\/jats:italic> missense variants through functional assays.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fgene.2025.1611138","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T05:46:46Z","timestamp":1752126406000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of a PATL2 missense variant (c.877G&gt;T) disrupting canonical splicing and contributing to female infertility"],"prefix":"10.3389","volume":"16","author":[{"given":"Hongyan","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weixu","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingfeng","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yankun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuming","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoqun","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2507","DOI":"10.1016\/j.fertnstert.2010.02.037","article-title":"Oocyte maturation failure: a syndrome of bad eggs","volume":"94","author":"Beall","year":"2010","journal-title":"Fertil. 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