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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,8,4]]},"abstract":"<jats:p>\n                    Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social communication and repetitive behaviors, with genetic studies implicating widespread synaptic dysfunction. However, the contribution of presynaptic vesicle trafficking mechanisms to ASD pathogenesis remains incompletely understood. Here, we identify synaptotagmin-like protein 4 (SYTL4), a RAB27A effector previously characterized in secretory cells, as a regulator of presynaptic function in the mammalian brain. We report a recurrent hemizygous missense variant, R126H, located within the Rab-binding domain of\n                    <jats:italic toggle=\"yes\">SYTL4<\/jats:italic>\n                    in four unrelated male individuals, consistent with an X-linked recessive mode of ASD, and additionally identify a de novo missense variant in\n                    <jats:italic toggle=\"yes\">RAB27A<\/jats:italic>\n                    (T41A) in an independent ASD family that affects a domain mediating interactions with downstream effectors. Using a R126H knock-in mouse model, we show that R126H knock-in male mice exhibit ASD-relevant behavioral abnormalities accompanied by synaptic deficits in the medial prefrontal cortex. At the molecular level, ASD-associated\n                    <jats:italic toggle=\"yes\">SYTL4<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">RAB27A<\/jats:italic>\n                    variants interfere with the interaction between SYTL4 and RAB27A, providing a mechanistic link between human genetic variation and synaptic dysfunction. Together, these findings implicate disrupted SYTL4\u2013RAB27A-dependent vesicle trafficking in ASD pathogenesis and identify\n                    <jats:italic toggle=\"yes\">SYTL4<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">RAB27A<\/jats:italic>\n                    as previously unrecognized contributors to autism-associated synaptic deficits and behavior.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2605483123","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:58:09Z","timestamp":1785427089000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["X-linked\n                    <i>SYTL4<\/i>\n                    missense variant disrupts RAB27A-dependent vesicle trafficking and synaptic transmission in autism"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4069-1700","authenticated-orcid":false,"given":"Yang","family":"Liao","sequence":"first","affiliation":[{"name":"Hunan Key Laboratory of Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, Ministry of Education Key Laboratory of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University","place":["Changsha, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuju","family":"Zhang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03e207173","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medical Genetics, The Affiliated Children\u2019s Hospital of Xiangya School of Medicine (Hunan Children\u2019s Hospital), Central South University","place":["Changsh, 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