Truncating variants in the SHANK1 gene are associated with a spectrum of neurodevelopmental disorders

Halie J. May, Jaehoon Jeong, Anya Revah-Politi, Julie S. Cohen, Anna Chassevent, Julia Baptista, Evan H. Baugh, Louise Bier, Armand Bottani, Maria Teresa Maria, Charles Conlon, Joel Fluss, Michel Guipponi, Chong Ae Kim, Naomichi Matsumoto, Richard Person, Michelle Primiano, Julia Rankin, Marwan Shinawi, Constance Smith-HicksAida Telegrafi, Samantha Toy, Yuri Uchiyama, Vimla Aggarwal, David B. Goldstein, Katherine W. Roche, Kwame Anyane-Yeboa

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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.

Original languageEnglish
Pages (from-to)1912-1921
Number of pages10
JournalGenetics in Medicine
Issue number10
StatePublished - Oct 2021


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