In this study, we aimed to characterize the clinical phenotype of a SHANK1-related disorder and define the functional consequences of SHANK1 truncating variants.
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.
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.
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.
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The data sets supporting the current study have not been deposited in a public repository but are available from the corresponding author on request.
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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 email@example.com. 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.
This study has approval through institutional review board–approved research studies at the Institute for Genomic Medicine at Columbia University (protocol AAAO8410) and UK Research Ethics Committee (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). Written informed consent was obtained for patients 1 and 5 as required by the IRB and REC, and data was de-identified. Written informed consent was obtained for patients 2, 3, 4, and 6 as required by their respective healthcare institutions as well as by the labs that performed their clinical testing. Data were de-identified before being used for the purposes of this study.
A.T. and R.P. are employees of GeneDx, Inc. D.B.G. is a founder of and holds equity in Q State Biosciences and Praxis Therapeutics; holds equity in Apostle Inc.; and serves as a consultant to AstraZeneca, Gilead Sciences, GoldFinch Bio, and Gossamer Bio. The other authors declare no competing interests. Web resources ClinVar browser: http://www.ncbi.nlm.nih.gov/clinvar/. Consensus Coding Sequence (CCDS): https://www.ncbi.nlm.nih.gov/CCDS/. Ensembl genome assembly GRCh37: http://grch37.ensembl.org/Homo_sapiens/Info/Index. Ensembl Variant Effect Predictor (VEP): http://grch37.ensembl.org/Homo_sapiens/Tools/VEP. GenBank: https://www.ncbi.nlm.nih.gov/genbank/. gnomAD: https://gnomad.broadinstitute.org/. OMIM: http://www.omim.org/. PubMed: https://www.ncbi.nlm.nih.gov/pubmed. The Human Gene Mutation Database (HGMD): http://www.hgmd.cf.ac.uk/ac/index.php.
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May, H.J., Jeong, J., Revah-Politi, A. et al. Truncating variants in the SHANK1 gene are associated with a spectrum of neurodevelopmental disorders. Genet Med (2021). https://doi.org/10.1038/s41436-021-01222-w