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Sci Adv. 2019 Sep 25;5(9):eaax2166. doi: 10.1126/sciadv.aax2166. eCollection 2019 Sep.

Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission.

Author information

1
Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
2
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
3
Institute of Life Sciences, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, Jiangsu, China.
4
Department of Neurobiology, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Laboratory of Brain Disorders (Ministry of Science and Technology), Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China.
5
Key Laboratory of Developmental Disorders in Children, Liuzhou Maternity and Child Healthcare Hospital, Liuzhou, Guangxi, China.
6
Division of Human Genetics, Warren Alpert Medical School of Brown University, Hasbro Children's Hospital/Rhode Island Hospital, Providence, RI, USA.
7
Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, Netherlands.
8
Department of Pediatrics, University of Cincinnati College of Medicine, Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, OH, USA.
9
Institute for Human Genetics and Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
10
GeneDx, Gaithersburg, MD, USA.
11
University Medical Center Utrecht, Utrecht, Netherlands.
12
Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China.
13
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
14
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
15
Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands.
16
Goryeb Children's Hospital, Atlantic Health System, Morristown, NJ, USA.
17
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
18
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
19
Department of Neurology, Kennedy Krieger Institute, Baltimore, MD, USA.
20
Program in Human Genetics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
21
Oasi Research Institute-IRCCS, Troina, Italy.
22
School of Medicine and the Robinson Research Institute, University of Adelaide at the Women's and Children's Hospital, Adelaide, South Australia, Australia.
23
Adult Genetics Unit, Royal Adelaide Hospital, and School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
24
Department of Pediatrics, University of South Florida, Tampa, FL, USA.
25
Division of Medical Genetics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
26
Central Washington Genetics Program, Virginia Mason Memorial, Yakima, WA, USA.
27
Children Development Behavior Center of the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
28
Mental Health Institute of the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
29
Baylor Genetics, Houston, TX, USA.
30
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands.
31
Department of Psychiatry, University of Washington, Seattle, WA, USA.
32
Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD, USA.
33
Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
34
Key Laboratory of Medical Information Research, Central South University, Changsha, Hunan, China.
35
CAS Center for Excellence in Brain Science and Intelligences Technology (CEBSIT), Chinese Academy of Sciences, Shanghai 200030, China.
36
Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, Hunan 410078, China.

Abstract

RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neurodevelopmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely gene-disrupting variants in CSDE1 (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITS-CLIP revealed that Csde1-binding targets are enriched in autism-associated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity-related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in Drosophila result in defects in synapse growth and synaptic transmission. Our study defines a new autism-related syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.

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