Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Populations
2.2. Genetic Sequencing
2.3. Selection of Candidate Genes
2.4. Evaluation of Identified Variants
2.5. Pathway Analysis
2.6. Statistical Analyses
3. Results
3.1. Clinical Characteristics
3.2. Genetic Variation
3.3. Genetic Correlation
3.4. Pathway Analysis
4. Discussion
4.1. Variants in DMD
4.2. Variants in FKTN and PDLIM3
4.3. Atrial Cardiomyopathy
4.4. Treatment Consequences
4.5. Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Early-Onset AF Cohort (n = 527) | Control Cohort (n = 383) | |
---|---|---|
Sex, male, n (%) | 441 (83.6) | 257 (67) |
Age, years, median (IQR) | 30 (24–36) a | 71 (66–76) b |
Height, cm, mean (SD) | 183 (±9) | 172 (±9) |
Weight, kg, mean (SD) | 89 (±17) | 77 (±15) |
BMI, kg/m2, mean (SD) | 26 (±5) | 26 (±5) |
Comorbidities: | ||
Hypertension, n (%) | 0 (0) | 246 (64.2) |
Diabetes, n (%) | 0 (0) | 39 (10.2) |
Heart failure, n (%) | 0 (0) | 0 (0) |
Ischemic heart disease, n (%) | 0 (0) | 0 (0) |
Valvular heart disease, n (%) | 0 (0) | 0 (0) |
Patient | Gene | Variant | RefSNP | Gender | Genotype | Onset of AF (age in years) | AF Type | LVEF (%) | Family History of AF (self-reported) |
---|---|---|---|---|---|---|---|---|---|
I | DMD | p.D615Efs*6 | rs752332058 | Male | Hemizygote | 28 | Persistent | >55 | No |
II | DMD | p.D615Efs*6 | rs752332058 | Male | Hemizygote | 25 | Persistent | >55 | Yes |
III | DMD | c.10262+1G > A | rs145603325 | Male | Hemizygote | 21 | Persistent | >55 | Yes |
IV | DMD | c.10262+1G > A | rs145603325 | Male | Hemizygote | 28 | Persistent | >55 | No |
V | FKTN | Chr9:108358933C > T | NA | Male | Heterozygote | 31 | Paroxysmal | NA | No |
VI | PDLIM3 | Chr4:186425651_186425652del | NA | Female | Heterozygote | 40 | Paroxysmal | >55 | Yes |
Gene | Genomic Position | RefSNP | Transcript | Consequence | Effect | GnomAD MAF (%) |
---|---|---|---|---|---|---|
DMD | ChrX:31140001_31140013del | rs752332058 | ENST00000378723 | p.D615Efs*6 | Frameshift variant | 0.02491 |
DMD | ChrX:31196048C>T | rs145603325 | ENST00000357033 | c.10262+1G>A | Splice donor | 0.02689 |
FKTN | Chr9:108358933C>T | NA | ENST00000223528 | p.Q54* | Nonsense variant | NA |
PDLIM3 | Chr4:186425651_186425652del | NA | ENST00000284771 | p.C246*fs*1 | Frameshift variant | NA |
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Vad, O.B.; Paludan-Müller, C.; Ahlberg, G.; Kalstø, S.M.; Ghouse, J.; Andreasen, L.; Haunsø, S.; Tveit, A.; Sajadieh, A.; Christophersen, I.E.; et al. Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation. J. Clin. Med. 2020, 9, 372. https://doi.org/10.3390/jcm9020372
Vad OB, Paludan-Müller C, Ahlberg G, Kalstø SM, Ghouse J, Andreasen L, Haunsø S, Tveit A, Sajadieh A, Christophersen IE, et al. Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation. Journal of Clinical Medicine. 2020; 9(2):372. https://doi.org/10.3390/jcm9020372
Chicago/Turabian StyleVad, Oliver Bundgaard, Christian Paludan-Müller, Gustav Ahlberg, Silje Madeleine Kalstø, Jonas Ghouse, Laura Andreasen, Stig Haunsø, Arnljot Tveit, Ahmad Sajadieh, Ingrid Elisabeth Christophersen, and et al. 2020. "Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation" Journal of Clinical Medicine 9, no. 2: 372. https://doi.org/10.3390/jcm9020372
APA StyleVad, O. B., Paludan-Müller, C., Ahlberg, G., Kalstø, S. M., Ghouse, J., Andreasen, L., Haunsø, S., Tveit, A., Sajadieh, A., Christophersen, I. E., Svendsen, J. H., & Olesen, M. S. (2020). Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation. Journal of Clinical Medicine, 9(2), 372. https://doi.org/10.3390/jcm9020372