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-Hicks; Aida Telegrafi; Samantha Toy; Yuri Uchiyama; Vimla Aggarwal; David B. Goldstein; Katherine W. Roche; Kwame Anyane-Yeboa

doi:10.1038/s41436-021-01222-w

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 journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	1912-1921
Number of pages	10
Journal	Genetics in Medicine
Volume	23
Issue number	10
DOIs	https://doi.org/10.1038/s41436-021-01222-w
State	Published - Oct 2021

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May, H. J., Jeong, J., Revah-Politi, A., Cohen, J. S., Chassevent, A., Baptista, J., Baugh, E. H., Bier, L., Bottani, A., Maria, M. T., Conlon, C., Fluss, J., Guipponi, M., Kim, C. A., Matsumoto, N., Person, R., Primiano, M., Rankin, J., Shinawi, M., ... Anyane-Yeboa, K. (2021). Truncating variants in the SHANK1 gene are associated with a spectrum of neurodevelopmental disorders. Genetics in Medicine, 23(10), 1912-1921. https://doi.org/10.1038/s41436-021-01222-w

@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 = "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",

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May, HJ, Jeong, J, Revah-Politi, A, Cohen, JS, Chassevent, A, Baptista, J, Baugh, EH, Bier, L, Bottani, A, Maria, MT, Conlon, C, Fluss, J, Guipponi, M, Kim, CA, Matsumoto, N, Person, R, Primiano, M, Rankin, J, Shinawi, M, Smith-Hicks, C, Telegrafi, A, Toy, S, Uchiyama, Y, Aggarwal, V, Goldstein, DB, Roche, KW & Anyane-Yeboa, K 2021, 'Truncating variants in the SHANK1 gene are associated with a spectrum of neurodevelopmental disorders', Genetics in Medicine, vol. 23, no. 10, pp. 1912-1921. https://doi.org/10.1038/s41436-021-01222-w

TY - JOUR

T1 - Truncating variants in the SHANK1 gene are associated with a spectrum of neurodevelopmental disorders

AU - May, Halie J.

AU - Jeong, Jaehoon

AU - Revah-Politi, Anya

AU - Cohen, Julie S.

AU - Chassevent, Anna

AU - Baptista, Julia

AU - Baugh, Evan H.

AU - Bier, Louise

AU - Bottani, Armand

AU - Maria, Maria Teresa

AU - Conlon, Charles

AU - Fluss, Joel

AU - Guipponi, Michel

AU - Kim, Chong Ae

AU - Matsumoto, Naomichi

AU - Person, Richard

AU - Primiano, Michelle

AU - Rankin, Julia

AU - Shinawi, Marwan

AU - Smith-Hicks, Constance

AU - Telegrafi, Aida

AU - Toy, Samantha

AU - Uchiyama, Yuri

AU - Aggarwal, Vimla

AU - Goldstein, David B.

AU - Roche, Katherine W.

AU - Anyane-Yeboa, Kwame

PY - 2021/10

Y1 - 2021/10

N2 - 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.

AB - 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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U2 - 10.1038/s41436-021-01222-w

DO - 10.1038/s41436-021-01222-w

M3 - Article

C2 - 34113010

AN - SCOPUS:85107503999

SN - 1098-3600

VL - 23

SP - 1912

EP - 1921

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 10

ER -

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

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