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Article

Unpredicted Aberrant Splicing Products Identified in Postmortem Sudden Cardiac Death Samples

by
Monica Coll
1,
Anna Fernandez-Falgueras
2,
Anna Iglesias
1,
Bernat del Olmo
1,
Laia Nogue-Navarro
3,
Adria Simon
1,
Alexandra Perez Serra
1,
Marta Puigmule
1,4,
Laura Lopez
1,
Ferran Pico
1,
Monica Corona
1,
Marta Vallverdu-Prats
1,
Coloma Tiron
2,4,
Oscar Campuzano
1,4,5,
Josep Castella
6,
Ramon Brugada
1,2,4,5,* and
Mireia Alcalde
1,*
1
Cardiovascular Genetics Center, Institut d’Investigació Biomèdica de Girona (IdIBGi), 17190 Salt, Spain
2
Cardiology Service, Hospital Dr. Josep Trueta, University of Girona, 17007 Girona, Spain
3
Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), Can Baumann, 08500 Vic, Spain
4
Centro Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
5
Medical Science Department, School of Medicine, University of Girona, 17004 Girona, Spain
6
Forensic Pathology Service, Institut de Medicina Legal i Ciències Forenses de Catalunya (IMLCFC), 08075 Barcelona, Spain
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(20), 12640; https://doi.org/10.3390/ijms232012640
Submission received: 31 August 2022 / Revised: 14 October 2022 / Accepted: 18 October 2022 / Published: 20 October 2022
(This article belongs to the Special Issue Molecular Study of Cardiac Death)
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Abstract

Molecular screening for pathogenic mutations in sudden cardiac death (SCD)-related genes is common practice for SCD cases. However, test results may lead to uncertainty because of the identification of variants of unknown significance (VUS) occurring in up to 70% of total identified variants due to a lack of experimental studies. Genetic variants affecting potential splice site variants are among the most difficult to interpret. The aim of this study was to examine rare intronic variants identified in the exonic flanking sequence to meet two main objectives: first, to validate that canonical intronic variants produce aberrant splicing; second, to determine whether rare intronic variants predicted as VUS may affect the splicing product. To achieve these objectives, 28 heart samples of cases of SCD carrying rare intronic variants were studied. Samples were analyzed using 85 SCD genes in custom panel sequencing. Our results showed that rare intronic variants affecting the most canonical splice sites displayed in 100% of cases that they would affect the splicing product, possibly causing aberrant isoforms. However, 25% of these cases (1/4) showed normal splicing, contradicting the in silico results. On the contrary, in silico results predicted an effect in 0% of cases, and experimental results showed >20% (3/14) unpredicted aberrant splicing. Thus, deep intron variants are likely predicted to not have an effect, which, based on our results, might be an underestimation of their effect and, therefore, of their pathogenicity classification and family members’ follow-up.
Keywords: sudden death; intronic variants; splicing; genetics sudden death; intronic variants; splicing; genetics

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MDPI and ACS Style

Coll, M.; Fernandez-Falgueras, A.; Iglesias, A.; del Olmo, B.; Nogue-Navarro, L.; Simon, A.; Perez Serra, A.; Puigmule, M.; Lopez, L.; Pico, F.; et al. Unpredicted Aberrant Splicing Products Identified in Postmortem Sudden Cardiac Death Samples. Int. J. Mol. Sci. 2022, 23, 12640. https://doi.org/10.3390/ijms232012640

AMA Style

Coll M, Fernandez-Falgueras A, Iglesias A, del Olmo B, Nogue-Navarro L, Simon A, Perez Serra A, Puigmule M, Lopez L, Pico F, et al. Unpredicted Aberrant Splicing Products Identified in Postmortem Sudden Cardiac Death Samples. International Journal of Molecular Sciences. 2022; 23(20):12640. https://doi.org/10.3390/ijms232012640

Chicago/Turabian Style

Coll, Monica, Anna Fernandez-Falgueras, Anna Iglesias, Bernat del Olmo, Laia Nogue-Navarro, Adria Simon, Alexandra Perez Serra, Marta Puigmule, Laura Lopez, Ferran Pico, and et al. 2022. "Unpredicted Aberrant Splicing Products Identified in Postmortem Sudden Cardiac Death Samples" International Journal of Molecular Sciences 23, no. 20: 12640. https://doi.org/10.3390/ijms232012640

APA Style

Coll, M., Fernandez-Falgueras, A., Iglesias, A., del Olmo, B., Nogue-Navarro, L., Simon, A., Perez Serra, A., Puigmule, M., Lopez, L., Pico, F., Corona, M., Vallverdu-Prats, M., Tiron, C., Campuzano, O., Castella, J., Brugada, R., & Alcalde, M. (2022). Unpredicted Aberrant Splicing Products Identified in Postmortem Sudden Cardiac Death Samples. International Journal of Molecular Sciences, 23(20), 12640. https://doi.org/10.3390/ijms232012640

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