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Previous reports have demonstrated the causal role of biallelic pathogenic variants in the Subcortical Maternal Complex (SCMC) genes in female reproductive failure with some leading to infertility, early embryonic loss, and molar pregnancies, while others are compatible with live birth with and without multilocus imprinting disorders (MLID). Here, we report two deleterious protein\u2010truncating variants, c.1326delG, p.Leu443Phefs*78 and c.2802_2803del, p.Arg935Metfs*15, in heterozygous state in the <jats:italic>NLRP2<\/jats:italic> gene of a patient with primary infertility, four early miscarriages, and one failed attempt of intracytoplasmic sperm injection. We show that the two variants mediate mRNA decay in EBV\u2010transformed lymphoblastoid cells from the patient, lead to decreased NLRP2 protein levels, and alter NLRP2 interactions with other members of the SCMC in\u00a0vitro. This study emphasizes the importance of performing clinical exomes for patients with recurrent reproductive failure and reporting their variants and reproductive histories to improve patient counseling.<\/jats:p>","DOI":"10.1111\/cge.14718","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T01:44:06Z","timestamp":1738719846000},"page":"179-183","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Two Novel Protein\u2010Truncating Variants in <i>NLRP2<\/i> and Their Functional Impacts on the Subcortical Maternal Complex"],"prefix":"10.1111","volume":"108","author":[{"given":"Zeynep","family":"Yalcin","sequence":"first","affiliation":[{"name":"Department of Human Genetics McGill University Health Centre  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, Guangdong\u2010Hong Kong\u2010Macao Greater Bay Area Higher Education Joint Laboratory of Maternal\u2010Fetal Medicine The Third Affiliated Hospital of Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim M.","family":"Abdelrazek","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Medical Research Institute Alexandria University  Alexandria Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Bareke","sequence":"additional","affiliation":[{"name":"Department of Human Genetics McGill University Health Centre  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacek","family":"Majewski","sequence":"additional","affiliation":[{"name":"Department of Human Genetics McGill University Health Centre  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ebtesam","family":"Abdalla","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Medical Research Institute Alexandria University  Alexandria Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seang\u2010Lin","family":"Tan","sequence":"additional","affiliation":[{"name":"OriginElle Fertility Clinic  Montreal Quebec Canada"},{"name":"Department of Obstetrics and Gynecology McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Key Laboratory of Organ Regeneration and Reconstruction, Beijing Institute of Stem Cell and Regenerative Medicine, IOZ\/CAS University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4060-2159","authenticated-orcid":false,"given":"Rima","family":"Slim","sequence":"additional","affiliation":[{"name":"Department of Human Genetics McGill University Health Centre  Montreal Quebec Canada"},{"name":"Department of Obstetrics and Gynecology McGill University  Montreal Quebec Canada"},{"name":"Research Institute of the McGill University Health Centre  Montreal Qu\u00e9bec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,4]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"World Health Organization \u201cInfertility \u201d 2024 https:\/\/www.who.int\/news\u2010room\/fact\u2010sheets\/detail\/infertility."},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1530\/REP\u201021\u20100486"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10815\u2010024\u201003248\u2010w"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty897"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2890"},{"key":"e_1_2_9_7_1","unstructured":"Z.Hu C.Yau andA. A.Ahmed \u201cmasonmd: Making Sense of Nonsense\u2010Mediated Decay \u201d 2016 https:\/\/github.com\/zhiyhu\/masonmd?tab=readme\u2010ov\u2010file https:\/\/doi.org\/10.5281\/zenodo.546698."},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556\u2010022\u201000869\u20100"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41594\u2010024\u201001396\u20102"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.039487"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13148\u2010022\u201001262\u20102"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073\u2010019\u20100694\u2010y"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.111.093583"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.666136"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13148\u2010022\u201001259\u2010x"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.14718","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T04:00:18Z","timestamp":1752638418000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.14718"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,4]]},"references-count":14,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1111\/cge.14718"],"URL":"https:\/\/doi.org\/10.1111\/cge.14718","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,4]]},"assertion":[{"value":"2024-11-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}