Bi-allelic variants in the secretory pathway gene <i>SEC16A</i> are associated with a neurodevelopmental disorder

Mengqi Ma; Xiaowei Lei; Juan Li; Yiming Zheng; Yu Yuan; Yohei Nitta; Xiao Mao; Zhenming Guo; Shenzhao Lu; Mingxi Deng; Xueyang Pan; Oguz Kanca; Shiyi Liu; Hua Wang; Bo Xiao; Rachel Schot; Serwet Demirdas; Yolande van Bever; Marjon van Slegtenhorst; Tahsin Stefan Barakat; Shan Bian; Hugo J. Bellen; Lili Long

doi:10.1172/JCI199882

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

²Institute for Regenerative Medicine, Medical Innovation Centre and State Key Laboratory of Cardiovascular Diseases, Shanghai East Hospital, National Stem Cell Translational Resource Centre & Resource , Shanghai, China

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by Ma, M. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by Lei, X. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

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¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by Zheng, Y. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by Yuan, Y. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by Nitta, Y. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by Mao, X. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by Guo, Z. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by Lu, S. in: PubMed | Google Scholar |

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by Deng, M. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by Pan, X. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by Kanca, O. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by Liu, S. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by Wang, H. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by Xiao, B. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by Schot, R. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by Demirdas, S. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by van Bever, Y. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by van Slegtenhorst, M. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by Barakat, T. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by Bian, S. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by Bellen, H. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

³Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

⁴National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China

⁵Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China

⁶Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Find articles by Long, L. in: PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI199882.
Copyright © 2026, Ma et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published October 13, 2026 - Version history

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.

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

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