De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders PMID: 35977029

ADC Targets in Oncology

2026-04-10

De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders

Sci Adv. 2022 Aug 19;8(33):eabo7112. doi: 10.1126/sciadv.abo7112.

Xiangbin Jia ¹ , Shujie Zhang ² ³ , Senwei Tan ¹ , Bing Du ¹ , Mei He ¹ ⁴ , Haisong Qin ² , Jia Chen ¹ , Xinyu Duan ⁵ , Jingsi Luo ² , Fei Chen ² , Luping Ouyang ² , Jian Wang ³ , Guodong Chen ¹ , Bin Yu ¹ , Ge Zhang ¹ , Zimin Zhang ¹ , Yongqing Lyu ¹ , Yi Huang ⁶ , Jian Jiao ⁶ , Jin Yun Helen Chen ⁷ , Kathryn J Swoboda ⁸ , Emanuele Agolini ⁹ , Antonio Novelli ⁹ , Chiara Leoni ¹⁰ , Giuseppe Zampino ¹⁰ ¹¹ ¹² ¹³ , Gerarda Cappuccio ¹⁴ ¹⁵ , Nicola Brunetti-Pierri ¹⁴ ¹⁵ , Benedicte Gerard ¹⁶ , Emmanuelle Ginglinger ¹⁷ , Julie Richer ¹⁸ , Hugh McMillan ¹⁹ , Alexandre White-Brown ²⁰ , Kendra Hoekzema ²¹ , Raphael A Bernier ²² , Evangeline C Kurtz-Nelson ²³ , Rachel K Earl ²² , Claartje Meddens ²⁴ ²⁵ , Marielle Alders ²⁶ , Meredith Fuchs ²⁷ , Roseline Caumes ²⁸ , Perrine Brunelle ²⁹ , Thomas Smol ²⁹ , Ryan Kuehl ³⁰ , Debra-Lynn Day-Salvatore ³⁰ , Kristin G Monaghan ³¹ , Michelle M Morrow ³¹ , Evan E Eichler ²¹ ³² , Zhengmao Hu ¹ , Ling Yuan ¹ , Jieqiong Tan ¹ , Kun Xia ¹ ³³ ³⁴ , Yiping Shen ² ³ ³⁵ , Hui Guo ¹ ³⁶

Affiliations

1. Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University; Changsha, Hunan 410078, China.
2. Genetic and Metabolic Central Laboratory, Birth Defects Prevention and Control Institute of Guangxi Zhuang Autonomous Region, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, China.
3. Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200000, China.
4. NHC Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Hunan, China.
5. Department of Pediatrics, Daping Hospital, Army Medical University, Chongqing, China.
6. Mental Health Center, West China Hospital of Sichuan University, Chengdu 610000, China.
7. Massachusetts General Hospital Neurogenetics Unit, Department of Neurology, Massachusetts General Brigham, Boston, MA 02114, USA.
8. Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
9. Laboratory of Medical Genetics, Bambino Gesù Children's Hospital, IRCCS, Rome 00165, Italy.
10. Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome 00168, Italy.
11. Faculty of Medicine and Surgery, Catholic University of the Sacred Heart, Rome 00168, Italy.
12. Fondazione Policlinico Universitario Agostino Gemelli Dipartimento Scienze della Salute della Donna e del Bambino, Rome, Italy.
13. Università Cattolica S. Cuore, Dipartimento Scienze della Vita e Sanità Pubblica, Rome, Italy.
14. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
15. Department of Translational Medicine, Federico II University, Naples, Italy.
16. Institut de Génétique Médicale d'Alsace (IGMA), Laboratoire de Diagnostic Génétique, Hôpitaux universitaires de Strasbourg, Strasbourg, Alsace, France.
17. Service de Génétique, Centre Hospitalier de Mulhouse, Mulhouse, Alsace, France.
18. Department of Medical Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
19. Department of Pediatrics, Neurology and Neurosurgery, Montreal Children's Hospital, McGill University, Montreal, Canada.
20. Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
21. Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
22. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
23. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
24. Amsterdam University Medical Center, Department of Clinical Genetics, Amsterdam, Netherlands.
25. University Medical Center Utrecht, Department of Paediatrics, Utrecht, Netherlands.
26. Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands.
27. Pediatrics and Genetics, Alpharetta, GA 30005, USA.
28. CHU Lille, Clinique de Génétique, Guy Fontaine, F-59000 Lille, France.
29. Institut de Génétique Médicale, Université de Lille, ULR7364 RADEME, CHU Lille, F-59000 Lille, France.
30. Department of Medical Genetics and Genomic Medicine, Saint Peter's University Hospital, New Brunswick, NJ 08901, USA.
31. GeneDx, Gaithersburg, MD 20877, USA.
32. Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
33. CAS Center for Excellence in Brain Science and Intelligences Technology (CEBSIT), Chinese Academy of Sciences, Shanghai 200000, China.
34. Hengyang Medical School, University of South China, Hengyang, China.
35. Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
36. Hunan Key Laboratory of Animal Models for Human Diseases, Changsha, Hunan 410078, China.

Abstract

Stress granules (SGs) are cytoplasmic assemblies in response to a variety of stressors. We report a new neurodevelopmental disorder (NDD) with common features of language problems, intellectual disability, and behavioral issues caused by de novo likely gene-disruptive variants in UBAP2L, which encodes an essential regulator of SG assembly. Ubap2l haploinsufficiency in mouse led to social and cognitive impairments accompanied by disrupted neurogenesis and reduced SG formation during early brain development. On the basis of data from 40,853 individuals with NDDs, we report a nominally significant excess of de novo variants within 29 genes that are not implicated in NDDs, including 3 essential genes (G3BP1, G3BP2, and UBAP2L) in the core SG interaction network. We validated that NDD-related de novo variants in newly implicated and known NDD genes, such as CAPRIN1, disrupt the interaction of the core SG network and interfere with SG formation. Together, our findings suggest the common SG pathology in NDDs.