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Genetic factors are believed to be one of the primary causes contributing to EDA. In this study, we identify four novel compound heterozygous mutations in <jats:italic>TLE6<\/jats:italic> and <jats:italic>NLRP5<\/jats:italic>, in two infertile female patients experiencing recurrent EDA, using whole\u2010exome sequencing. Functional analysis revealed that the two splicing mutations in <jats:italic>TLE6<\/jats:italic> (c.541+2dupT) and <jats:italic>NLRP5<\/jats:italic> (c.2957+4A&gt;G) resulted in aberrant RNA splicing, leading to abnormal truncations of the corresponding proteins. <jats:italic>In vitro<\/jats:italic> experiments further validated that a missense mutation in <jats:italic>NLRP5<\/jats:italic> led to increased mRNA and protein expression levels compared to wild type, when transfected into HEK293T cells. Immunofluorescence analysis confirmed the decay of the expression of TLE6 protein. Additionally, RNA sequencing results revealed significantly higher expression levels of some maternal genes in mutated embryos with <jats:italic>TLE6<\/jats:italic> mutations, possibly suggesting the disrupted clearance of maternal mRNA and the failure of embryo genome activation. These results highlight the role of biallelic recessive effects associated with <jats:italic>TLE6<\/jats:italic> and <jats:italic>NLRP5<\/jats:italic> variants in embryonic development, thereby widening the scope of the genetic landscape.<\/jats:p>","DOI":"10.1155\/2024\/9278518","type":"journal-article","created":{"date-parts":[[2024,6,22]],"date-time":"2024-06-22T04:50:11Z","timestamp":1719031811000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Biallelic Recessive Mutations in <i>TLE6<\/i> and <i>NLRP5<\/i> Cause Female Infertility Characterized by Human Early Embryonic 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