Neurodevelopmental disorders caused by de novo variants in KCNB1 genotypes and phenotypes

Carolien G.F. De Kovel, Steffen Syrbe, Eva H. Brilstra, Nienke Verbeek, Bronwyn Kerr, Holly Dubbs, Allan Bayat, Sonal Desai, Sakkubai Naidu, Siddharth Srivastava, Hande Cagaylan, Uluc Yis, Carol Saunders, Martin Rook, Susanna Plugge, Hiltrud Muhle, Zaid Afawi, Karl Martin Klein, Vijayakumar Jayaraman, Ramakrishnan RajagopalanEthan Goldberg, Eric Marsh, Sudha Kessler, Christina Bergqvist, Laura K. Conlin, Bryan L. Krok, Isabelle Thiffault, Manuela Pendziwiat, Ingo Helbig, Tilman Polster, Ingo Borggraefe, Johannes R. Lemke, Marie José Van Den Boogaardt, Rikke S. Møller, Bobby P.C. Koeleman

Research output: Contribution to journalArticle

Abstract

IMPORTANCE: Knowing the range of symptoms seen in patients with a missense or loss-of-function variant in KCNB1 and how these symptoms correlate with the type of variant will help clinicians with diagnosis and prognosis when treating new patients. OBJECTIVES: To investigate the clinical spectrum associated with KCNB1 variants and the genotype-phenotype correlations. DESIGN, SETTING, AND PARTICIPANTS: This study summarized the clinical and genetic information of patients with a presumed pathogenic variant in KCNB1. Patients were identified in research projects or during clinical testing. Information on patients from previously published articles was collected and authors contacted if feasible. All patients were seen at a clinic at one of the participating institutes because of presumed genetic disorder. They were tested in a clinical setting or included in a research project. MAIN OUTCOMES AND MEASURES: The genetic variant and its inheritance and information on the patient's symptoms and characteristics in a predefined format. All variants were identified with massive parallel sequencing and confirmed with Sanger sequencing in the patient. Absence of the variant in the parents could be confirmed with Sanger sequencing in all families except one. RESULTS: Of 26 patients (10 female, 15 male, 1 unknown; mean age at inclusion, 9.8 years; age range, 2-32 years) with developmental delay, 20 (77%) carried a missense variant in the ion channel domain of KCNB1, with a concentration of variants in region S5 to S6. Three variants that led to premature stops were located in the C-terminal and 3 in the ion channel domain. Twenty-one of 25 patients (84%) had seizures, with 9 patients (36%) starting with epileptic spasms between 3 and 18 months of age. All patients had developmental delay, with 17 (65%) experiencing severe developmental delay; 14 (82%) with severe delay had behavioral problems. The developmental delay was milder in 4 of 6 patients with stop variants and in a patient with a variant in the S2 transmembrane element rather than the S4 to S6 region. CONCLUSIONS AND RELEVANCE: De novo KCNB1 missense variants in the ion channel domain and loss-of-function variants in this domain and the C-terminal likely cause neurodevelopmental disorders with or without seizures. Patients with presumed pathogenic variants in KCNB1 have a variable phenotype. However, the type and position of the variants in the protein are (imperfectly) correlated with the severity of the disorder.

Original languageEnglish (US)
Pages (from-to)1228-1236
Number of pages9
JournalJAMA Neurology
Volume74
Issue number10
DOIs
StatePublished - Oct 1 2017

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Genotype
Phenotype
Ion Channels
S 6
Neurodevelopmental Disorders
Seizures
Inborn Genetic Diseases
Spasm
Genetic Association Studies
Research
Parents

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

De Kovel, C. G. F., Syrbe, S., Brilstra, E. H., Verbeek, N., Kerr, B., Dubbs, H., ... Koeleman, B. P. C. (2017). Neurodevelopmental disorders caused by de novo variants in KCNB1 genotypes and phenotypes. JAMA Neurology, 74(10), 1228-1236. https://doi.org/10.1001/jamaneurol.2017.1714

Neurodevelopmental disorders caused by de novo variants in KCNB1 genotypes and phenotypes. / De Kovel, Carolien G.F.; Syrbe, Steffen; Brilstra, Eva H.; Verbeek, Nienke; Kerr, Bronwyn; Dubbs, Holly; Bayat, Allan; Desai, Sonal; Naidu, Sakkubai; Srivastava, Siddharth; Cagaylan, Hande; Yis, Uluc; Saunders, Carol; Rook, Martin; Plugge, Susanna; Muhle, Hiltrud; Afawi, Zaid; Klein, Karl Martin; Jayaraman, Vijayakumar; Rajagopalan, Ramakrishnan; Goldberg, Ethan; Marsh, Eric; Kessler, Sudha; Bergqvist, Christina; Conlin, Laura K.; Krok, Bryan L.; Thiffault, Isabelle; Pendziwiat, Manuela; Helbig, Ingo; Polster, Tilman; Borggraefe, Ingo; Lemke, Johannes R.; Van Den Boogaardt, Marie José; Møller, Rikke S.; Koeleman, Bobby P.C.

In: JAMA Neurology, Vol. 74, No. 10, 01.10.2017, p. 1228-1236.

Research output: Contribution to journalArticle

De Kovel, CGF, Syrbe, S, Brilstra, EH, Verbeek, N, Kerr, B, Dubbs, H, Bayat, A, Desai, S, Naidu, S, Srivastava, S, Cagaylan, H, Yis, U, Saunders, C, Rook, M, Plugge, S, Muhle, H, Afawi, Z, Klein, KM, Jayaraman, V, Rajagopalan, R, Goldberg, E, Marsh, E, Kessler, S, Bergqvist, C, Conlin, LK, Krok, BL, Thiffault, I, Pendziwiat, M, Helbig, I, Polster, T, Borggraefe, I, Lemke, JR, Van Den Boogaardt, MJ, Møller, RS & Koeleman, BPC 2017, 'Neurodevelopmental disorders caused by de novo variants in KCNB1 genotypes and phenotypes', JAMA Neurology, vol. 74, no. 10, pp. 1228-1236. https://doi.org/10.1001/jamaneurol.2017.1714
De Kovel CGF, Syrbe S, Brilstra EH, Verbeek N, Kerr B, Dubbs H et al. Neurodevelopmental disorders caused by de novo variants in KCNB1 genotypes and phenotypes. JAMA Neurology. 2017 Oct 1;74(10):1228-1236. https://doi.org/10.1001/jamaneurol.2017.1714
De Kovel, Carolien G.F. ; Syrbe, Steffen ; Brilstra, Eva H. ; Verbeek, Nienke ; Kerr, Bronwyn ; Dubbs, Holly ; Bayat, Allan ; Desai, Sonal ; Naidu, Sakkubai ; Srivastava, Siddharth ; Cagaylan, Hande ; Yis, Uluc ; Saunders, Carol ; Rook, Martin ; Plugge, Susanna ; Muhle, Hiltrud ; Afawi, Zaid ; Klein, Karl Martin ; Jayaraman, Vijayakumar ; Rajagopalan, Ramakrishnan ; Goldberg, Ethan ; Marsh, Eric ; Kessler, Sudha ; Bergqvist, Christina ; Conlin, Laura K. ; Krok, Bryan L. ; Thiffault, Isabelle ; Pendziwiat, Manuela ; Helbig, Ingo ; Polster, Tilman ; Borggraefe, Ingo ; Lemke, Johannes R. ; Van Den Boogaardt, Marie José ; Møller, Rikke S. ; Koeleman, Bobby P.C. / Neurodevelopmental disorders caused by de novo variants in KCNB1 genotypes and phenotypes. In: JAMA Neurology. 2017 ; Vol. 74, No. 10. pp. 1228-1236.
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T1 - Neurodevelopmental disorders caused by de novo variants in KCNB1 genotypes and phenotypes

AU - De Kovel, Carolien G.F.

AU - Syrbe, Steffen

AU - Brilstra, Eva H.

AU - Verbeek, Nienke

AU - Kerr, Bronwyn

AU - Dubbs, Holly

AU - Bayat, Allan

AU - Desai, Sonal

AU - Naidu, Sakkubai

AU - Srivastava, Siddharth

AU - Cagaylan, Hande

AU - Yis, Uluc

AU - Saunders, Carol

AU - Rook, Martin

AU - Plugge, Susanna

AU - Muhle, Hiltrud

AU - Afawi, Zaid

AU - Klein, Karl Martin

AU - Jayaraman, Vijayakumar

AU - Rajagopalan, Ramakrishnan

AU - Goldberg, Ethan

AU - Marsh, Eric

AU - Kessler, Sudha

AU - Bergqvist, Christina

AU - Conlin, Laura K.

AU - Krok, Bryan L.

AU - Thiffault, Isabelle

AU - Pendziwiat, Manuela

AU - Helbig, Ingo

AU - Polster, Tilman

AU - Borggraefe, Ingo

AU - Lemke, Johannes R.

AU - Van Den Boogaardt, Marie José

AU - Møller, Rikke S.

AU - Koeleman, Bobby P.C.

PY - 2017/10/1

Y1 - 2017/10/1

N2 - IMPORTANCE: Knowing the range of symptoms seen in patients with a missense or loss-of-function variant in KCNB1 and how these symptoms correlate with the type of variant will help clinicians with diagnosis and prognosis when treating new patients. OBJECTIVES: To investigate the clinical spectrum associated with KCNB1 variants and the genotype-phenotype correlations. DESIGN, SETTING, AND PARTICIPANTS: This study summarized the clinical and genetic information of patients with a presumed pathogenic variant in KCNB1. Patients were identified in research projects or during clinical testing. Information on patients from previously published articles was collected and authors contacted if feasible. All patients were seen at a clinic at one of the participating institutes because of presumed genetic disorder. They were tested in a clinical setting or included in a research project. MAIN OUTCOMES AND MEASURES: The genetic variant and its inheritance and information on the patient's symptoms and characteristics in a predefined format. All variants were identified with massive parallel sequencing and confirmed with Sanger sequencing in the patient. Absence of the variant in the parents could be confirmed with Sanger sequencing in all families except one. RESULTS: Of 26 patients (10 female, 15 male, 1 unknown; mean age at inclusion, 9.8 years; age range, 2-32 years) with developmental delay, 20 (77%) carried a missense variant in the ion channel domain of KCNB1, with a concentration of variants in region S5 to S6. Three variants that led to premature stops were located in the C-terminal and 3 in the ion channel domain. Twenty-one of 25 patients (84%) had seizures, with 9 patients (36%) starting with epileptic spasms between 3 and 18 months of age. All patients had developmental delay, with 17 (65%) experiencing severe developmental delay; 14 (82%) with severe delay had behavioral problems. The developmental delay was milder in 4 of 6 patients with stop variants and in a patient with a variant in the S2 transmembrane element rather than the S4 to S6 region. CONCLUSIONS AND RELEVANCE: De novo KCNB1 missense variants in the ion channel domain and loss-of-function variants in this domain and the C-terminal likely cause neurodevelopmental disorders with or without seizures. Patients with presumed pathogenic variants in KCNB1 have a variable phenotype. However, the type and position of the variants in the protein are (imperfectly) correlated with the severity of the disorder.

AB - IMPORTANCE: Knowing the range of symptoms seen in patients with a missense or loss-of-function variant in KCNB1 and how these symptoms correlate with the type of variant will help clinicians with diagnosis and prognosis when treating new patients. OBJECTIVES: To investigate the clinical spectrum associated with KCNB1 variants and the genotype-phenotype correlations. DESIGN, SETTING, AND PARTICIPANTS: This study summarized the clinical and genetic information of patients with a presumed pathogenic variant in KCNB1. Patients were identified in research projects or during clinical testing. Information on patients from previously published articles was collected and authors contacted if feasible. All patients were seen at a clinic at one of the participating institutes because of presumed genetic disorder. They were tested in a clinical setting or included in a research project. MAIN OUTCOMES AND MEASURES: The genetic variant and its inheritance and information on the patient's symptoms and characteristics in a predefined format. All variants were identified with massive parallel sequencing and confirmed with Sanger sequencing in the patient. Absence of the variant in the parents could be confirmed with Sanger sequencing in all families except one. RESULTS: Of 26 patients (10 female, 15 male, 1 unknown; mean age at inclusion, 9.8 years; age range, 2-32 years) with developmental delay, 20 (77%) carried a missense variant in the ion channel domain of KCNB1, with a concentration of variants in region S5 to S6. Three variants that led to premature stops were located in the C-terminal and 3 in the ion channel domain. Twenty-one of 25 patients (84%) had seizures, with 9 patients (36%) starting with epileptic spasms between 3 and 18 months of age. All patients had developmental delay, with 17 (65%) experiencing severe developmental delay; 14 (82%) with severe delay had behavioral problems. The developmental delay was milder in 4 of 6 patients with stop variants and in a patient with a variant in the S2 transmembrane element rather than the S4 to S6 region. CONCLUSIONS AND RELEVANCE: De novo KCNB1 missense variants in the ion channel domain and loss-of-function variants in this domain and the C-terminal likely cause neurodevelopmental disorders with or without seizures. Patients with presumed pathogenic variants in KCNB1 have a variable phenotype. However, the type and position of the variants in the protein are (imperfectly) correlated with the severity of the disorder.

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