SYNGAP1 loss-of-function variants are causally associated with intellectual disability, severe epilepsy, autism spectrum disorder and schizophrenia. While there are hundreds of genetic risk factors for neurodevelopmental disorders (NDDs), this gene is somewhat unique because of the frequency and penetrance of loss-of-function variants found in patients combined with the range of brain disorders associated with SYNGAP1 pathogenicity. These clinical findings indicate that SYNGAP1 regulates fundamental neurodevelopmental processes that are necessary for brain development. Here, we describe four phenotypic domains that are controlled by Syngap1 expression across vertebrate species. Two domains, the maturation of cognitive functions and maintenance of excitatory-inhibitory balance, are defined exclusively through a review of the current literature. Two additional domains are defined by integrating the current literature with new data indicating that SYNGAP1/Syngap1 regulates innate survival behaviors and brain structure. These four phenotypic domains are commonly disrupted in NDDs, suggesting that a deeper understanding of developmental Syngap1 functions will be generalizable to other NDDs of known or unknown etiology. Therefore, we discuss the known molecular and cellular functions of Syngap1 and consider how these functions may contribute to the emergence of disease-relevant phenotypes. Finally, we identify major unexplored areas of Syngap1 neurobiology and discuss how a deeper understanding of this gene may uncover general principles of NDD pathobiology.

SYNGAP1功能丧失的变异与智力障碍，严重的癫痫症，自闭症谱系障碍和精神分裂症有因果关系。尽管存在数百种神经发育障碍（NDD）的遗传危险因素，但该基因在某种程度上是独一无二的，因为在患者中发现的功能丧失变异的频率和穿透性与与SYNGAP1致病性相关的一系列脑部疾病相结合。这些临床发现表明，SYNGAP1调节大脑发育所必需的基本神经发育过程。在这里，我们描述了由Syngap1控制的四个表型域跨脊椎动物物种的表达。认知功能的成熟和维持兴奋性-抑制性平衡的两个领域仅通过对当前文献的回顾来定义。通过将当前文献与新数据集成来定义两个其他域，这些新数据指示SYNGAP1 / Syngap1调节先天生存行为和大脑结构。这四个表型结构域通常在NDD中被破坏，这表明对发育Syngap1功能的更深入了解将可推广到其他已知或未知病因的NDD。因此，我们讨论了Syngap1的已知分子和细胞功能并考虑这些功能如何促进与疾病相关的表型的出现。最后，我们确定了Syngap1神经生物学的主要未开发领域，并讨论了对该基因的更深入了解如何揭示NDD病理生物学的一般原理。