Further delineation of phenotypic spectrum of SCN2A-related disorder
Further delineation of phenotypic spectrum of SCN2A-related disorder
SCN2A-related disorders include intellectual disability, autism spectrum disorder, seizures, episodic ataxia, and schizophrenia. In this study, the phenotype–genotype association in SCN2A-related disorders was further delineated by collecting detailed clinical and molecular characteristics. Using previously proposed genotype–phenotype hypotheses based on variant function and position, the potential of phenotype prediction from the variants found was examined. Patients were identified through the Deciphering Developmental Disorders study and gene matching strategies. Phenotypic information and variant interpretation evidence were collated. Seventeen previously unreported patients and five patients who had been previously reported (but with minimal phenotypic and segregation data) were included (10 males, 12 females; median age 10.5 years). All patients had developmental delays and the majority had intellectual disabilities. Seizures were reported in 15 of 22 (68.2%), four of 22 (18.2%) had autism spectrum disorder and no patients were reported with episodic ataxia. The majority of variants were de novo. One family had presumed gonadal mosaicism. The correlation of the use of sodium channel-blocking antiepileptic drugs with phenotype or genotype was variable. These data suggest that variant type and position alone can provide some predictive information about the phenotype in a proportion of cases, but more precise assessment of variant function is needed for meaningful phenotype prediction.
SCN2A, autism spectrum disorder, developmental delay, episodic ataxia, intellectual disability
867-877
Richardson, R.
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Baralle, Diana
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Bennett, C.
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Briggs, T
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Bijlsma, E.K.
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Clayton-Smith, J.
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Constantinou, P.
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Foulds, Nicola
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Jarvis, J.
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Jewell, R.
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Johnson, D.S.
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McEntagart, M.
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Parker, M.J.
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Radley, J.A.
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Robertson, L.
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Ruivenkamp, C.A.L.
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Rutten, J.
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Tellez, J
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Turnpenny, P.
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Wilson, V
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Wright, M.
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Balasubramanian, M.
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1 March 2022
Richardson, R.
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Baralle, Diana
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Bennett, C.
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Briggs, T
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Bijlsma, E.K.
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Clayton-Smith, J.
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Constantinou, P.
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Foulds, Nicola
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Jarvis, J.
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Jewell, R.
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Johnson, D.S.
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McEntagart, M.
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Parker, M.J.
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Radley, J.A.
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Robertson, L.
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Ruivenkamp, C.A.L.
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Rutten, J.
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Tellez, J
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Turnpenny, P.
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Wilson, V
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Wright, M.
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Balasubramanian, M.
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Richardson, R., Baralle, Diana, Bennett, C., Briggs, T, Bijlsma, E.K., Clayton-Smith, J., Constantinou, P., Foulds, Nicola, Jarvis, J., Jewell, R., Johnson, D.S., McEntagart, M., Parker, M.J., Radley, J.A., Robertson, L., Ruivenkamp, C.A.L., Rutten, J., Tellez, J, Turnpenny, P., Wilson, V, Wright, M. and Balasubramanian, M.
(2022)
Further delineation of phenotypic spectrum of SCN2A-related disorder.
American Journal of Medical Genetics: Part A, 188 (3), .
(doi:10.1002/ajmg.a.62595).
Abstract
SCN2A-related disorders include intellectual disability, autism spectrum disorder, seizures, episodic ataxia, and schizophrenia. In this study, the phenotype–genotype association in SCN2A-related disorders was further delineated by collecting detailed clinical and molecular characteristics. Using previously proposed genotype–phenotype hypotheses based on variant function and position, the potential of phenotype prediction from the variants found was examined. Patients were identified through the Deciphering Developmental Disorders study and gene matching strategies. Phenotypic information and variant interpretation evidence were collated. Seventeen previously unreported patients and five patients who had been previously reported (but with minimal phenotypic and segregation data) were included (10 males, 12 females; median age 10.5 years). All patients had developmental delays and the majority had intellectual disabilities. Seizures were reported in 15 of 22 (68.2%), four of 22 (18.2%) had autism spectrum disorder and no patients were reported with episodic ataxia. The majority of variants were de novo. One family had presumed gonadal mosaicism. The correlation of the use of sodium channel-blocking antiepileptic drugs with phenotype or genotype was variable. These data suggest that variant type and position alone can provide some predictive information about the phenotype in a proportion of cases, but more precise assessment of variant function is needed for meaningful phenotype prediction.
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More information
Accepted/In Press date: 20 November 2021
e-pub ahead of print date: 11 December 2021
Published date: 1 March 2022
Additional Information:
Funding Information:
We are grateful to the patients and their families for their cooperation. Co‐author DB is supported by NIHR Research Professorship RP‐2016‐07‐011. 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. 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 study makes use of DECIPHER ( http://decipher.sanger.ac.uk ), which is funded by the Wellcome.
Funding Information:
Co‐author DB is supported by NIHR Research Professorship, Grant/Award Number: RP‐2016‐07‐011; DDD Study funding: Health Innovation Challenge Fund, Grant/Award Number: HICF‐1009‐003; DDD Study Funding: Wellcome Sanger Institute, Grant/Award Number: WT098051 Funding information
Funding Information:
We are grateful to the patients and their families for their cooperation. Co-author DB is supported by NIHR Research Professorship RP-2016-07-011. 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. 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 study makes use of DECIPHER (http://decipher.sanger.ac.uk), which is funded by the Wellcome.
Publisher Copyright:
© 2021 Wiley Periodicals LLC.
Copyright:
Copyright 2022 Elsevier B.V., All rights reserved.
Keywords:
SCN2A, autism spectrum disorder, developmental delay, episodic ataxia, intellectual disability
Identifiers
Local EPrints ID: 453141
URI: http://eprints.soton.ac.uk/id/eprint/453141
ISSN: 1552-4825
PURE UUID: 1e420dce-5df6-421c-b279-87de6d68cab9
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Date deposited: 08 Jan 2022 22:33
Last modified: 17 Mar 2024 06:58
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Contributors
Author:
R. Richardson
Author:
C. Bennett
Author:
T Briggs
Author:
E.K. Bijlsma
Author:
J. Clayton-Smith
Author:
P. Constantinou
Author:
Nicola Foulds
Author:
J. Jarvis
Author:
R. Jewell
Author:
D.S. Johnson
Author:
M. McEntagart
Author:
M.J. Parker
Author:
J.A. Radley
Author:
L. Robertson
Author:
C.A.L. Ruivenkamp
Author:
J. Rutten
Author:
J Tellez
Author:
P. Turnpenny
Author:
V Wilson
Author:
M. Wright
Author:
M. Balasubramanian
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