@article{cc34eb8d7c7245e59b534fb021575819,
title = "Truncating variants in the SHANK1 gene are associated with a spectrum of neurodevelopmental disorders",
abstract = "Purpose: In this study, we aimed to characterize the clinical phenotype of a SHANK1-related disorder and define the functional consequences of SHANK1 truncating variants. Methods: Exome sequencing (ES) was performed for six individuals who presented with neurodevelopmental disorders. Individuals were ascertained with the use of GeneMatcher and Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER). We evaluated potential nonsense-mediated decay (NMD) of two variants by making knock-in cell lines of endogenous truncated SHANK1, and expressed the truncated SHANK1 complementary DNA (cDNA) in HEK293 cells and cultured hippocampal neurons to examine the proteins. Results: ES detected de novo truncating variants in SHANK1 in six individuals. Evaluation of NMD resulted in stable transcripts, and the truncated SHANK1 completely lost binding with Homer1, a linker protein that binds to the C-terminus of SHANK1. These variants may disrupt protein–protein networks in dendritic spines. Dispersed localization of the truncated SHANK1 variants within the spine and dendritic shaft was also observed when expressed in neurons, indicating impaired synaptic localization of truncated SHANK1. Conclusion: This report expands the clinical spectrum of individuals with truncating SHANK1 variants and describes the impact these variants may have on the pathophysiology of neurodevelopmental disorders.",
author = "May, {Halie J.} and Jaehoon Jeong and Anya Revah-Politi and Cohen, {Julie S.} and Anna Chassevent and Julia Baptista and Baugh, {Evan H.} and Louise Bier and Armand Bottani and Maria, {Maria Teresa} and Charles Conlon and Joel Fluss and Michel Guipponi and Kim, {Chong Ae} and Naomichi Matsumoto and Richard Person and Michelle Primiano and Julia Rankin and Marwan Shinawi and Constance Smith-Hicks and Aida Telegrafi and Samantha Toy and Yuri Uchiyama and Vimla Aggarwal and Goldstein, {David B.} and Roche, {Katherine W.} and Kwame Anyane-Yeboa",
note = "Funding Information: We thank all affected individuals and family members for their participation in this work. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from https:// deciphergenomics.org/about/stats and via email from contact@deciphergenomics. org. Funding for the DECIPHER project was provided by Wellcome. Those who carried out the original analysis and collection of the Data bear no responsibility for the further analysis or interpretation of the data. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/ 284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. This publication was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1TR001873; the Japan Agency for Medical Research and Development (AMED) under grant numbers JP20ek0109486, JP20dm0107090, JP20ek0109301, JP20ek0109348, and JP20kk0205012 (to N.M.); and by JSPS KAKENHI grant numbers JP17H01539 (to N.M.) and JP19K17865 (to Y.U.); the NINDS Intramural Research Program. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.",
year = "2021",
month = oct,
doi = "10.1038/s41436-021-01222-w",
language = "English",
volume = "23",
pages = "1912--1921",
journal = "Genetics in Medicine",
issn = "1098-3600",
number = "10",
}