Many genes encoding synaptic proteins are associated with neurodevelopmental disorders (NDDs) such as autism spectrum disorders (ASDs), intellectual disability (ID), and epilepsy. Here we review recent studies on the synaptic effects of disease-associated rare variants identified in two families of synaptic proteins: NMDA receptors (NMDARs) and the postsynaptic adhesion molecules neuroligins (NLGNs). Many NMDAR subunit genes (GRINs) are highly intolerant to variation, and both gain-of-function (GOF) and loss-of-function (LOF) variants are implicated in disease. NLGN genes are also associated with ASDs, and in some cases, contribute to the male bias identified in these patients. Understanding the molecular basis of synaptic dysfunction of rare variants in these genes will help the design of new therapeutic approaches.

许多编码突触蛋白的基因与神经发育障碍 (NDD) 相关，例如自闭症谱系障碍 (ASD)、智力障碍 (ID) 和癫痫。在这里，我们回顾了最近关于在两个突触蛋白家族中发现的疾病相关罕见变异的突触效应的研究：NMDA 受体 (NMDARs) 和突触后粘附分子神经蛋白 (NLGNs)。许多 NMDAR 亚基基因 ( GRIN ) 对变异高度不耐受，并且功能获得 (GOF) 和功能丧失 (LOF) 变体都与疾病有关。NLGN基因也与 ASD 相关，并且在某些情况下，会导致这些患者中发现的男性偏见。了解这些基因中罕见变异突触功能障碍的分子基础将有助于设计新的治疗方法。