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ResearchIn-Press PreviewGeneticsNeuroscience Open Access | 10.1172/JCI159806

GIGYF1 disruption associates with autism and impaired IGF-1R signaling

Guodong Chen,1 Bin Yu,1 Senwei Tan,1 Jieqiong Tan,1 Xiangbin Jia,1 Qiumeng Zhang,1 Xiaolei Zhang,1 Qian Jiang,1 Yue Hua,1 Yaoling Han,1 Shengjie Luo,1 Kendra Hoekzema,2 Raphael A. Bernier,3 Rachel K. Earl,3 Evangeline C. Kurtz-Nelson,3 Michaela J. Idleburg,4 Suneeta Madan Khetarpal,4 Rebecca Clark,4 Jessica Sebastian,5 Alberto Fernandez-Jaen,6 Sara Alvarez,7 Staci D. King,8 Luiza L.P. Ramos,9 Mara Lucia S.F. Santos,10 Donna M. Martin,11 Dan Brooks,11 Joseph D. Symonds,13 Ioana Cutcutache,14 Qian Pan,1 Zhengmao Hu,1 Ling Yuan,1 Evan E. Eichler,15 Kun Xia,1 and Hui Guo1

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

Find articles by Chen, G. in: JCI | PubMed | Google Scholar

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

Find articles by Tan, J. in: JCI | PubMed | Google Scholar |

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

Find articles by Zhang, Q. in: JCI | PubMed | Google Scholar

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

Find articles by Jiang, Q. in: JCI | PubMed | Google Scholar

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

Find articles by Hoekzema, K. in: JCI | PubMed | Google Scholar |

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

Find articles by Kurtz-Nelson, E. in: JCI | PubMed | Google Scholar

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

Find articles by Sebastian, J. in: JCI | PubMed | Google Scholar

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

Find articles by Fernandez-Jaen, A. in: JCI | PubMed | Google Scholar |

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

Find articles by Martin, D. in: JCI | PubMed | Google Scholar |

1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

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1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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1Center for Medical Genetics, Central South University, Changsha, China

2Department of Genome Sciences, University of Washington School of Medicine, Seattle, American Samoa

3Department of Psychiatry, University of Washington, Seattle, American Samoa

4Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, American Samoa

5Department of Human Genetics, University of Pittsburgh, Pittsburgh, American Samoa

6Department of Pediatric Neurology, Universidad Europea de Madrid, Madrid, Spain

7Department of Genomics and Medicine, NIMGenetics, Madrid, Spain

8Department of Neurology, Baylor College of Medicine, Houston, American Samoa

9Mendelics Genomic Analysis, Mendelics Genomic Analysis, Sao Paulo, Brazil

10Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Brazil

11Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

12Department of Pediatrics, University of Michigan, Ann Arbor, American Samoa

13Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom

14Translational Medicine, UCB Pharma, Slough, United Kingdom

15Department of Genome Sciences, University of Washington, Seattle, United States of America

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Published August 2, 2022 - More info

J Clin Invest. https://doi.org/10.1172/JCI159806.
Copyright © 2022, Chen 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 August 2, 2022 - Version history
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Abstract

Autism spectrum disorder (ASD) represents a group of neurodevelopmental phenotypes with a strong genetic component. Excess of likely gene-disruptive (LGD) mutations of GIGYF1 was implicated in ASD. Here, we reported that GIGYF1 was the second most mutated gene among known ASD high-confidence risk genes. We investigated the inheritance of 46 GIGYF1 LGD variants, including the highly recurrent mutation, c.333del:p.L111Rfs*234. Inherited GIGYF1 heterozygous LGD variants were 1.8 times more common than de novo mutations. Unlike most high-confidence genes, ASD individuals with GIGYF1 LGD variants were less likely to have cognitive impairments. Using a Gigyf1 conditional knockout mouse model, we showed that haploinsufficiency in the developing brain led to social impairments without significant cognitive impairments. In contrast, homozygous mice showed more severe social disability as well as cognitive impairments. Gigyf1 deficiency in mice led to a reduction of upper layer cortical neurons accompanied by decreased proliferation and increased differentiation of neural progenitor cells. We showed that GIGYF1 regulated the recycling of IGF-1R to cell surface. Knockout of GIGYF1 led to a decreased level of IGF-1R on the cell surface disrupting the IGF-1R/ERK signaling pathway. In summary, our findings showed that GIGYF1 was a regulator of IGF-1R recycling. Haploinsufficiency of GIGYF1 was associated with autistic behaviors likely through interference with IGR-1R/ERK signaling pathway.

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