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Disease\u2010causing variants in <jats:italic>SYNGAP1<\/jats:italic> typically occur <jats:italic>de novo<\/jats:italic>. This study aims to characterize inherited cases of <jats:italic>SYNGAP1<\/jats:italic>\u2010related disorders.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here we report three families including eight total individuals with inherited, protein\u2010truncating variants in <jats:italic>SYNGAP1<\/jats:italic>, recruited through a natural history study. In two of the families, the proband inherited their pathogenic variant from a heterozygous parent. In the remaining family, the variant was inherited from a mosaic parent. This study additionally reports two families with inherited missense variants classified as variants of uncertain significance, which are not clearly diagnostic at this time.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Phenotypes in affected children and parents included both typical and attenuated <jats:italic>SYNGAP1<\/jats:italic> presentations, including a single individual with a mosaic <jats:italic>SYNGAP1<\/jats:italic> variant who was clinically unaffected. Among the individuals with protein\u2010truncating variants, generalized epilepsy was observed in six individuals, autism spectrum disorder in two individuals, and developmental delay or intellectual disability in all individuals with germline variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>We demonstrate that <jats:italic>SYNGAP1<\/jats:italic>\u2010related disorder can occur in families and that clinical presentations of familial cases are not limited to milder phenotypes. We estimate that 3% of cases of <jats:italic>SYNGAP1\u2010<\/jats:italic>related disorder are inherited. Recognition of familial <jats:italic>SYNGAP1<\/jats:italic>\u2010related disorders delineates edge cases of a relatively common neurodevelopmental disorder and has implications for variant interpretation and clinical practice.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.18469","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T09:59:52Z","timestamp":1747994392000},"page":"3505-3515","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Familial <scp><i>SYNGAP1<\/i><\/scp> variants define the boundaries of a complex neurodevelopmental disorder with epilepsy"],"prefix":"10.1111","volume":"66","author":[{"given":"Alicia G.","family":"Harrison","sequence":"first","affiliation":[{"name":"Division of Neurology Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"The Epilepsy NeuroGenetics Initiative (ENGIN) Children's Hospital of Philadelphia  Philadelphia 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