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The pathophysiology of ASD is complex due to genetic and environmental heterogeneity, complicating the development of therapies and making diagnosis challenging. Growing genetic evidence supports a role of disrupted Ca<jats:sup>2+<\/jats:sup> signaling in ASD. Here, we report that patient-derived fibroblasts from three monogenic models of ASD\u2014fragile X and tuberous sclerosis TSC1 and TSC2 syndromes\u2014display depressed Ca<jats:sup>2+<\/jats:sup> release through inositol trisphosphate receptors (IP<jats:sub>3<\/jats:sub>Rs). This was apparent in Ca<jats:sup>2+<\/jats:sup> signals evoked by G protein-coupled receptors and by photoreleased IP<jats:sub>3<\/jats:sub> at the levels of both global and local elementary Ca<jats:sup>2+<\/jats:sup> events, suggesting fundamental defects in IP<jats:sub>3<\/jats:sub>R channel activity in ASD. Given the ubiquitous involvement of IP<jats:sub>3<\/jats:sub>R-mediated Ca<jats:sup>2+<\/jats:sup> signaling in neuronal excitability, synaptic plasticity, gene expression and neurodevelopment, we propose dysregulated IP<jats:sub>3<\/jats:sub>R signaling as a nexus where genes altered in ASD converge to exert their deleterious effect. These findings highlight potential pharmaceutical targets, and identify Ca<jats:sup>2+<\/jats:sup> screening in skin fibroblasts as a promising technique for early detection of individuals susceptible to ASD.<\/jats:p>","DOI":"10.1038\/tp.2015.123","type":"journal-article","created":{"date-parts":[[2015,9,22]],"date-time":"2015-09-22T14:34:35Z","timestamp":1442932475000},"page":"e643-e643","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Shared functional defect in IP3R-mediated calcium signaling in diverse monogenic autism syndromes"],"prefix":"10.1038","volume":"5","author":[{"given":"G","family":"Schmunk","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B J","family":"Boubion","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I F","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I","family":"Parker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J J","family":"Gargus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,9,22]]},"reference":[{"key":"BFtp2015123_CR1","first-page":"1","volume":"65","author":"SJ Blumberg","year":"2013","unstructured":"Blumberg SJ, Bramlett MD, Kogan MD, Schieve LA, Jones JR, Lu MC . 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