Halie J May1, Jaehoon Jeong2, Anya Revah-Politi3,4, Julie S Cohen5,6, Anna Chassevent5, Julia Baptista7,8, Evan H Baugh3, Louise Bier3, Armand Bottani9, Maria Teresa Carminho A Rodrigues9, Charles Conlon5, Joel Fluss10, Michel Guipponi9, Chong Ae Kim11, Naomichi Matsumoto12, Richard Person13, Michelle Primiano14, Julia Rankin15, Marwan Shinawi16, Constance Smith-Hicks5,6, Aida Telegrafi13, Samantha Toy16, Yuri Uchiyama12,17, Vimla Aggarwal4, David B Goldstein3, Katherine W Roche2, Kwame Anyane-Yeboa18,19. 1. Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA. hh2742@cumc.columbia.edu. 2. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. 3. Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA. 4. Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA. 5. Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD, USA. 6. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 7. Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK. 8. Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, UK. 9. Division of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland. 10. Pediatric Neurology Unit, Pediatrics Subspecialties Service, Geneva Children's Hospital, Geneva, Switzerland. 11. Genetics Unit, Instituto da Crianca, Hospital das Clinicas, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil. 12. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. 13. Clinical Genomics Program, GeneDx, Gaithersburg, MD, USA. 14. Division of Clinical Genetics, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA. 15. Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK. 16. Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University in St. Louis, St. Louis, MO, USA. 17. Department of Rare Disease Genomics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. 18. Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA. ka8@cumc.columbia.edu. 19. Division of Clinical Genetics, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA. ka8@cumc.columbia.edu.
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.
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.
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