Human exocyst complex is an evolutionary conserved multimeric complex composed of proteins encoded by eight genes EXOC1-EXOC8. It is known that the exocyst complex plays a role in ciliogenesis, cytokinesis, cell migration, autophagy, and fusion of secretory vesicles. Recently, loss of function variants in EXOC7 and EXOC8 has been associated with abnormalities of cerebral cortical development leading to a neurodevelopmental phenotype. Neurodevelopmental disorders are a huge group of clinically and genetically heterogeneous disorders. In the present study, we recruited a large consanguineous family segregating a neurodevelopmental disorder in an autosomal recessive form. We performed clinical phenotyping by imaging the patient’s brain followed by whole exome sequencing examining DNA from two affected individuals. The clinical phenotypes of the disease were suggestive of brain atrophy. Clinical examination revealed intellectual impairment with hypertonia and brisk reflexes. WES followed by Sanger sequencing revealed a novel homozygous nonsense mutation [EXOC8; NM_175876.5; c.1714G > T; p.(Glu572Ter)] in the DNA of affected individuals. Both parents of the patients were heterozygous for the identified mutation. All the pathogenicity prediction softwares predicted the identified variant as disease causing. This study reports a second protein-truncating variant in EXOC8. The findings confirm that loss of function variants in EXOC8 underlies a neurodevelopmental disorder. The identification of a protein-truncating variant in EXOC8 in the current study can be helpful in establishing genotype–phenotype correlations. Our results also provide new insights into genetic counseling and clinical management for the affected individuals.

人类外囊复合物是一种进化保守的多聚体复合物，由八个基因EXOC1-EXOC8编码的蛋白质组成。已知外囊复合物在纤毛发生、胞质分裂、细胞迁移、自噬和分泌囊泡融合中起作用。最近，EXOC7和EXOC8中的功能缺失变体与导致神经发育表型的大脑皮质发育异常有关。神经发育障碍是一大类临床和遗传异质性疾病。在本研究中，我们招募了一个以常染色体隐性形式分离神经发育障碍的大型近亲家庭。我们通过对患者的大脑进行成像，然后对来自两个受影响个体的 DNA 进行全外显子组测序来进行临床表型分析。该疾病的临床表型提示脑萎缩。临床检查显示智力障碍伴肌张力亢进和反应敏捷。WES 和 Sanger 测序揭示了一种新的纯合无义突变 [ EXOC8; NM_175876.5；c.1714G > T；p.(Glu572Ter)] 在受影响个体的 DNA 中。患者的父母双方都是已鉴定突变的杂合子。所有的致病性预测软件都将识别出的变异预测为致病。该研究报告了EXOC8中的第二种蛋白质截断变体。研究结果证实，EXOC8中功能变体的丧失是神经发育障碍的基础。在当前研究中鉴定 EXOC8中的蛋白质截断变体有助于建立基因型 - 表型相关性。我们的结果还为受影响个体的遗传咨询和临床管理提供了新的见解。