Sequence variants in muscle tissue-related genes may determine the severity of muscle contractures in cerebral palsy

Jessica Pingel; Jeppe Dyrberg Andersen; Sofie Lindgren Christiansen; Claus Børsting; Niels Morling; Jakob Lorentzen; Henrik Kirk; Simon Doessing; Christian Wong; Jens Bo Nielsen

doi:10.1002/ajmg.b.32693

Sequence variants in muscle tissue-related genes may determine the severity of muscle contractures in cerebral palsy

Jessica Pingel, Jeppe Dyrberg Andersen, Sofie Lindgren Christiansen, Claus Børsting, Niels Morling, Jakob Lorentzen, Henrik Kirk, Simon Doessing, Christian Wong, Jens Bo Nielsen

2 Citations (Scopus)

Abstract

Muscle contractures are a common complication to cerebral palsy (CP). The purpose of this study was to evaluate whether individuals with CP carry specific gene variants of important structural genes that might explain the severity of muscle contractures. Next-generation-sequencing (NGS) of 96 candidate genes associated with muscle structure and metabolism were analyzed in 43 individuals with CP (Gross Motor Function classification system [GMFCS] I, n=10; GMFCS II, n=14; GMFCS III, n=19) and four control participants. In silico analysis of the identified variants was performed. The variants were classified into four categories ranging from likely benign (VUS0) to highly likely functional effect (VUS3). All individuals with CP were classified and grouped according to their GMFCS level: Statistical comparisons were made between GMFCS groups. Kruskal-Wallis tests showed significantly more VUS2 variants in the genes COL4 (GMFCS I-III; 1, 1, 5, respectively [p < .04]), COL5 (GMFCS I-III; 1, 1, 5 [p < .04]), COL6 (GMFCS I-III; 0, 4, 7 [p < .003]), and COL9 (GMFCS I-III; 1, 1, 5 [p < .04]), in individuals with CP within GMFCS Level III when compared to the other GMFCS levels. Furthermore, significantly more VUS3 variants in COL6 (GMFCS I-III; 0, 5, 2 [p < .01]) and COL7 (GMFCS I-III; 0, 3, 0 [p < .04]) were identified in the GMFCS II level when compared to the other GMFCS levels. The present results highlight several candidate gene variants in different collagen types with likely functional effects in individuals with CP.

Original language	English
Journal	American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics
Volume	180
Issue number	1
Pages (from-to)	12-24
ISSN	1552-4841
DOIs	https://doi.org/10.1002/ajmg.b.32693
Publication status	Published - Jan 2019

Keywords

cerebral palsy
contracture
DNA
muscle
next-generation sequencing

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10.1002/ajmg.b.32693

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Pingel, J., Andersen, J. D., Christiansen, S. L., Børsting, C., Morling, N., Lorentzen, J., Kirk, H., Doessing, S., Wong, C., & Nielsen, J. B. (2019). Sequence variants in muscle tissue-related genes may determine the severity of muscle contractures in cerebral palsy. American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics, 180(1), 12-24. https://doi.org/10.1002/ajmg.b.32693

Sequence variants in muscle tissue-related genes may determine the severity of muscle contractures in cerebral palsy. / Pingel, Jessica ; Andersen, Jeppe Dyrberg; Christiansen, Sofie Lindgren et al.
In: American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics, Vol. 180, No. 1, 01.2019, p. 12-24.

Research output: Contribution to journal › Journal article › Research › peer-review

Pingel, J , Andersen, JD, Christiansen, SL, Børsting, C , Morling, N, Lorentzen, J, Kirk, H, Doessing, S, Wong, C & Nielsen, JB 2019, 'Sequence variants in muscle tissue-related genes may determine the severity of muscle contractures in cerebral palsy', American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics, vol. 180, no. 1, pp. 12-24. https://doi.org/10.1002/ajmg.b.32693

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title = "Sequence variants in muscle tissue-related genes may determine the severity of muscle contractures in cerebral palsy",

abstract = "Muscle contractures are a common complication to cerebral palsy (CP). The purpose of this study was to evaluate whether individuals with CP carry specific gene variants of important structural genes that might explain the severity of muscle contractures. Next-generation-sequencing (NGS) of 96 candidate genes associated with muscle structure and metabolism were analyzed in 43 individuals with CP (Gross Motor Function classification system [GMFCS] I, n=10; GMFCS II, n=14; GMFCS III, n=19) and four control participants. In silico analysis of the identified variants was performed. The variants were classified into four categories ranging from likely benign (VUS0) to highly likely functional effect (VUS3). All individuals with CP were classified and grouped according to their GMFCS level: Statistical comparisons were made between GMFCS groups. Kruskal-Wallis tests showed significantly more VUS2 variants in the genes COL4 (GMFCS I-III; 1, 1, 5, respectively [p < .04]), COL5 (GMFCS I-III; 1, 1, 5 [p < .04]), COL6 (GMFCS I-III; 0, 4, 7 [p < .003]), and COL9 (GMFCS I-III; 1, 1, 5 [p < .04]), in individuals with CP within GMFCS Level III when compared to the other GMFCS levels. Furthermore, significantly more VUS3 variants in COL6 (GMFCS I-III; 0, 5, 2 [p < .01]) and COL7 (GMFCS I-III; 0, 3, 0 [p < .04]) were identified in the GMFCS II level when compared to the other GMFCS levels. The present results highlight several candidate gene variants in different collagen types with likely functional effects in individuals with CP.",

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AU - Pingel, Jessica

AU - Andersen, Jeppe Dyrberg

AU - Christiansen, Sofie Lindgren

AU - Børsting, Claus

AU - Morling, Niels

AU - Lorentzen, Jakob

AU - Kirk, Henrik

AU - Doessing, Simon

AU - Wong, Christian

AU - Nielsen, Jens Bo

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N2 - Muscle contractures are a common complication to cerebral palsy (CP). The purpose of this study was to evaluate whether individuals with CP carry specific gene variants of important structural genes that might explain the severity of muscle contractures. Next-generation-sequencing (NGS) of 96 candidate genes associated with muscle structure and metabolism were analyzed in 43 individuals with CP (Gross Motor Function classification system [GMFCS] I, n=10; GMFCS II, n=14; GMFCS III, n=19) and four control participants. In silico analysis of the identified variants was performed. The variants were classified into four categories ranging from likely benign (VUS0) to highly likely functional effect (VUS3). All individuals with CP were classified and grouped according to their GMFCS level: Statistical comparisons were made between GMFCS groups. Kruskal-Wallis tests showed significantly more VUS2 variants in the genes COL4 (GMFCS I-III; 1, 1, 5, respectively [p < .04]), COL5 (GMFCS I-III; 1, 1, 5 [p < .04]), COL6 (GMFCS I-III; 0, 4, 7 [p < .003]), and COL9 (GMFCS I-III; 1, 1, 5 [p < .04]), in individuals with CP within GMFCS Level III when compared to the other GMFCS levels. Furthermore, significantly more VUS3 variants in COL6 (GMFCS I-III; 0, 5, 2 [p < .01]) and COL7 (GMFCS I-III; 0, 3, 0 [p < .04]) were identified in the GMFCS II level when compared to the other GMFCS levels. The present results highlight several candidate gene variants in different collagen types with likely functional effects in individuals with CP.

AB - Muscle contractures are a common complication to cerebral palsy (CP). The purpose of this study was to evaluate whether individuals with CP carry specific gene variants of important structural genes that might explain the severity of muscle contractures. Next-generation-sequencing (NGS) of 96 candidate genes associated with muscle structure and metabolism were analyzed in 43 individuals with CP (Gross Motor Function classification system [GMFCS] I, n=10; GMFCS II, n=14; GMFCS III, n=19) and four control participants. In silico analysis of the identified variants was performed. The variants were classified into four categories ranging from likely benign (VUS0) to highly likely functional effect (VUS3). All individuals with CP were classified and grouped according to their GMFCS level: Statistical comparisons were made between GMFCS groups. Kruskal-Wallis tests showed significantly more VUS2 variants in the genes COL4 (GMFCS I-III; 1, 1, 5, respectively [p < .04]), COL5 (GMFCS I-III; 1, 1, 5 [p < .04]), COL6 (GMFCS I-III; 0, 4, 7 [p < .003]), and COL9 (GMFCS I-III; 1, 1, 5 [p < .04]), in individuals with CP within GMFCS Level III when compared to the other GMFCS levels. Furthermore, significantly more VUS3 variants in COL6 (GMFCS I-III; 0, 5, 2 [p < .01]) and COL7 (GMFCS I-III; 0, 3, 0 [p < .04]) were identified in the GMFCS II level when compared to the other GMFCS levels. The present results highlight several candidate gene variants in different collagen types with likely functional effects in individuals with CP.

KW - cerebral palsy

KW - contracture

KW - DNA

KW - muscle

KW - next-generation sequencing

U2 - 10.1002/ajmg.b.32693

DO - 10.1002/ajmg.b.32693

M3 - Journal article

C2 - 30467950

SN - 1552-4841

VL - 180

SP - 12

EP - 24

JO - American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics

JF - American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics

IS - 1

ER -

Sequence variants in muscle tissue-related genes may determine the severity of muscle contractures in cerebral palsy

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Keywords

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