Comprehensive analysis across SMN2 excludes DNA methylation as an epigenetic biomarker for spinal muscular atrophy

Maria M. Zwartkruis; Joris V. Kortooms; Demi Gommers; Martin G. Elferink; Ilaria Signoria; Joyce van der Sel; Paul J. Hop; Ramona A.J. Zwamborn; Robin Geene; Jared W. Green; Hanneke W.M. van Deutekom; Wouter van Rheenen; Jan H. Veldink; Fay Lynn Asselman; Renske I. Wadman; W. Ludo van der Pol; Gijs W. van Haaften; Ewout J.N. Groen

doi:10.1016/j.isci.2025.112461

Comprehensive analysis across SMN2 excludes DNA methylation as an epigenetic biomarker for spinal muscular atrophy

Maria M. Zwartkruis, Joris V. Kortooms, Demi Gommers, Martin G. Elferink, Ilaria Signoria, Joyce van der Sel, Paul J. Hop, Ramona A.J. Zwamborn, Robin Geene, Jared W. Green, Hanneke W.M. van Deutekom, Wouter van Rheenen, Jan H. Veldink, Fay Lynn Asselman, Renske I. Wadman, W. Ludo van der Pol, Gijs W. van Haaften^*, Ewout J.N. Groen^*

^*Corresponding author for this work

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Abstract

Spinal muscular atrophy (SMA) is a severe neurodegenerative disease caused by defects in the survival motor neuron 1 (SMN1) gene. Although disease severity partially correlates with SMN2 copy number, significant variability in disease severity and treatment response remains unexplained, prompting a search for additional biomarkers. Using native, long-read nanopore and targeted short-read bisulfite sequencing, we analyzed methylation patterns across the 30 kb SMN2 gene. Our long-read analysis of 29 SMA patients identified tissue-specific variation in SMN2 intronic regions and the 3′UTR. Further analysis of blood-derived DNA of 365 SMA patients identified no association between SMN2 methylation and disease severity or treatment response, excluding blood-derived DNA methylation as a predictive biomarker. However, we discovered significant age-associated variation in SMN2 methylation in intron 1 and the 3′UTR, suggesting a possible role in modifying SMN expression during development and aging. This study provides a framework for detailed methylation analysis in complex genetic regions.

Original language	English
Article number	112461
Journal	iScience
Volume	28
Issue number	5
DOIs	https://doi.org/10.1016/j.isci.2025.112461
Publication status	Published - 16 May 2025

Keywords

Health sciences
Internal medicine
Medical specialty
Medicine
Neurology

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Zwartkruis, M. M., Kortooms, J. V., Gommers, D., Elferink, M. G., Signoria, I., van der Sel, J., Hop, P. J., Zwamborn, R. A. J., Geene, R., Green, J. W., van Deutekom, H. W. M., van Rheenen, W., Veldink, J. H., Asselman, F. L., Wadman, R. I., van der Pol, W. L., van Haaften, G. W., & Groen, E. J. N. (2025). Comprehensive analysis across SMN2 excludes DNA methylation as an epigenetic biomarker for spinal muscular atrophy. iScience, 28(5), Article 112461. https://doi.org/10.1016/j.isci.2025.112461

@article{dbb22df6f65a4025b054c32baaf45449,

title = "Comprehensive analysis across SMN2 excludes DNA methylation as an epigenetic biomarker for spinal muscular atrophy",

abstract = "Spinal muscular atrophy (SMA) is a severe neurodegenerative disease caused by defects in the survival motor neuron 1 (SMN1) gene. Although disease severity partially correlates with SMN2 copy number, significant variability in disease severity and treatment response remains unexplained, prompting a search for additional biomarkers. Using native, long-read nanopore and targeted short-read bisulfite sequencing, we analyzed methylation patterns across the 30 kb SMN2 gene. Our long-read analysis of 29 SMA patients identified tissue-specific variation in SMN2 intronic regions and the 3′UTR. Further analysis of blood-derived DNA of 365 SMA patients identified no association between SMN2 methylation and disease severity or treatment response, excluding blood-derived DNA methylation as a predictive biomarker. However, we discovered significant age-associated variation in SMN2 methylation in intron 1 and the 3′UTR, suggesting a possible role in modifying SMN expression during development and aging. This study provides a framework for detailed methylation analysis in complex genetic regions.",

keywords = "Health sciences, Internal medicine, Medical specialty, Medicine, Neurology",

author = "Zwartkruis, {Maria M.} and Kortooms, {Joris V.} and Demi Gommers and Elferink, {Martin G.} and Ilaria Signoria and {van der Sel}, Joyce and Hop, {Paul J.} and Zwamborn, {Ramona A.J.} and Robin Geene and Green, {Jared W.} and {van Deutekom}, {Hanneke W.M.} and {van Rheenen}, Wouter and Veldink, {Jan H.} and Asselman, {Fay Lynn} and Wadman, {Renske I.} and {van der Pol}, {W. Ludo} and {van Haaften}, {Gijs W.} and Groen, {Ewout J.N.}",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

month = may,

day = "16",

doi = "10.1016/j.isci.2025.112461",

language = "English",

volume = "28",

number = "5",

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Zwartkruis, MM, Kortooms, JV, Gommers, D, Elferink, MG, Signoria, I, van der Sel, J, Hop, PJ, Zwamborn, RAJ, Geene, R, Green, JW, van Deutekom, HWM , van Rheenen, W , Veldink, JH, Asselman, FL, Wadman, RI, van der Pol, WL , van Haaften, GW & Groen, EJN 2025, 'Comprehensive analysis across SMN2 excludes DNA methylation as an epigenetic biomarker for spinal muscular atrophy', iScience, vol. 28, no. 5, 112461. https://doi.org/10.1016/j.isci.2025.112461

TY - JOUR

T1 - Comprehensive analysis across SMN2 excludes DNA methylation as an epigenetic biomarker for spinal muscular atrophy

AU - Zwartkruis, Maria M.

AU - Kortooms, Joris V.

AU - Gommers, Demi

AU - Elferink, Martin G.

AU - Signoria, Ilaria

AU - van der Sel, Joyce

AU - Hop, Paul J.

AU - Zwamborn, Ramona A.J.

AU - Geene, Robin

AU - Green, Jared W.

AU - van Deutekom, Hanneke W.M.

AU - van Rheenen, Wouter

AU - Veldink, Jan H.

AU - Asselman, Fay Lynn

AU - Wadman, Renske I.

AU - van der Pol, W. Ludo

AU - van Haaften, Gijs W.

AU - Groen, Ewout J.N.

PY - 2025/5/16

Y1 - 2025/5/16

N2 - Spinal muscular atrophy (SMA) is a severe neurodegenerative disease caused by defects in the survival motor neuron 1 (SMN1) gene. Although disease severity partially correlates with SMN2 copy number, significant variability in disease severity and treatment response remains unexplained, prompting a search for additional biomarkers. Using native, long-read nanopore and targeted short-read bisulfite sequencing, we analyzed methylation patterns across the 30 kb SMN2 gene. Our long-read analysis of 29 SMA patients identified tissue-specific variation in SMN2 intronic regions and the 3′UTR. Further analysis of blood-derived DNA of 365 SMA patients identified no association between SMN2 methylation and disease severity or treatment response, excluding blood-derived DNA methylation as a predictive biomarker. However, we discovered significant age-associated variation in SMN2 methylation in intron 1 and the 3′UTR, suggesting a possible role in modifying SMN expression during development and aging. This study provides a framework for detailed methylation analysis in complex genetic regions.

AB - Spinal muscular atrophy (SMA) is a severe neurodegenerative disease caused by defects in the survival motor neuron 1 (SMN1) gene. Although disease severity partially correlates with SMN2 copy number, significant variability in disease severity and treatment response remains unexplained, prompting a search for additional biomarkers. Using native, long-read nanopore and targeted short-read bisulfite sequencing, we analyzed methylation patterns across the 30 kb SMN2 gene. Our long-read analysis of 29 SMA patients identified tissue-specific variation in SMN2 intronic regions and the 3′UTR. Further analysis of blood-derived DNA of 365 SMA patients identified no association between SMN2 methylation and disease severity or treatment response, excluding blood-derived DNA methylation as a predictive biomarker. However, we discovered significant age-associated variation in SMN2 methylation in intron 1 and the 3′UTR, suggesting a possible role in modifying SMN expression during development and aging. This study provides a framework for detailed methylation analysis in complex genetic regions.

KW - Health sciences

KW - Internal medicine

KW - Medical specialty

KW - Medicine

KW - Neurology

UR - http://www.scopus.com/inward/record.url?scp=105003748802&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2025.112461

DO - 10.1016/j.isci.2025.112461

M3 - Article

AN - SCOPUS:105003748802

VL - 28

JO - iScience

JF - iScience

IS - 5

M1 - 112461

ER -

Comprehensive analysis across SMN2 excludes DNA methylation as an epigenetic biomarker for spinal muscular atrophy

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