Bi-allelic variants in the secretory pathway gene SEC16A are associated with a neurodevelopmental disorder.

SEC16A encodes a scaffold protein that organizes the endoplasmic reticulum (ER) exit sites, specialized ER subdomains that mediate export of newly synthesized proteins and regulate early secretory pathway steps. The role of SEC16A in human nervous system diseases has not been established yet. Here, we report six individuals with bi-allelic SEC16A variants who presented with early-onset neurological symptoms, including cognitive impairment, motor delays, and seizures. Using Drosophila, we show the Sec16 ortholog is essential for normal development and that its loss causes early lethality. Neuron-specific knockdown of Sec16 causes neurological phenotypes including locomotor defects, seizure-like bang sensitivity, and impaired synaptic transmission, which can be associated with the clinical features observed in affected individuals. Neurons differentiated from patient-derived induced pluripotent stem cells (iPSCs) carrying SEC16A variants display reduced SEC16A protein, impaired neurite outgrowth and increased excitability, which are rescued in isogenic control neurons when the variants are corrected, consistent with a loss-of-function mechanism. Increased ER stress was observed in both patient iPSC-derived neurons and fly models. In summary, our findings indicate a conserved requirement for SEC16A in neurodevelopment and neuronal function and implicate ER stress as a key cellular phenotype underlying the SEC16A-associated neurodevelopmental disorder.