Early somatic mosaicism is a rare cause of long-QT syndrome
| Autor: | Thomas O'Hara, James R. Priest, Jason B. Harris, Marco V Perez, Luiz Belardinelli, Kristopher M. Kahlig, Thomas Quertermous, John A. West, Scott R. Ceresnak, Joseph K. Yu, Patrick M. Boyle, Daniela Macaya, Sean Michael Boyle, Euan A. Ashley, Megan E. Grove, Michael J. Clark, Charles Gawad, Sarah Garcia, Sridharan Rajamani, Stephen R. Quake, Natalia A. Trayanova, Katsuhide Maeda, Richard Chen, Lindsey Malloy-Walton, Christian Antolik, Kyla Dunn, Norma F. Neff, Anne M. Dubin, Frederick E. Dewey |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Proband Genotyping Techniques Action Potentials Germline mosaicism 030204 cardiovascular system & hematology Bioinformatics medicine.disease_cause NAV1.5 Voltage-Gated Sodium Channel Diffusion Electrocardiography 0302 clinical medicine Gene Frequency Myocytes Cardiac Exome sequencing Genes Dominant Genetics Mutation Multidisciplinary Mosaicism High-Throughput Nucleotide Sequencing Biological Sciences Long QT Syndrome Phenotype symbols Single-Cell Analysis Ion Channel Gating Cardiomyopathy Dilated congenital hereditary and neonatal diseases and abnormalities Long QT syndrome Biology Models Biological DNA sequencing 03 medical and health sciences symbols.namesake Germline mutation Heart Conduction System medicine Humans Computer Simulation Genetic Predisposition to Disease cardiovascular diseases Base Sequence Infant Arrhythmias Cardiac medicine.disease 030104 developmental biology Genetic Loci Mendelian inheritance |
| Zdroj: | Proceedings of the National Academy of Sciences. 113:11555-11560 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1607187113 |
| Popis: | Somatic mosaicism, the occurrence and propagation of genetic variation in cell lineages after fertilization, is increasingly recognized to play a causal role in a variety of human diseases. We investigated the case of life-threatening arrhythmia in a 10-day-old infant with long QT syndrome (LQTS). Rapid genome sequencing suggested a variant in the sodium channel NaV1.5 encoded by SCN5A, NM_000335:c.5284G > T predicting p.(V1762L), but read depth was insufficient to be diagnostic. Exome sequencing of the trio confirmed read ratios inconsistent with Mendelian inheritance only in the proband. Genotyping of single circulating leukocytes demonstrated the mutation in the genomes of 8% of patient cells, and RNA sequencing of cardiac tissue from the infant confirmed the expression of the mutant allele at mosaic ratios. Heterologous expression of the mutant channel revealed significantly delayed sodium current with a dominant negative effect. To investigate the mechanism by which mosaicism might cause arrhythmia, we built a finite element simulation model incorporating Purkinje fiber activation. This model confirmed the pathogenic consequences of cardiac cellular mosaicism and, under the presenting conditions of this case, recapitulated 2:1 AV block and arrhythmia. To investigate the extent to which mosaicism might explain undiagnosed arrhythmia, we studied 7,500 affected probands undergoing commercial gene-panel testing. Four individuals with pathogenic variants arising from early somatic mutation events were found. Here we establish cardiac mosaicism as a causal mechanism for LQTS and present methods by which the general phenomenon, likely to be relevant for all genetic diseases, can be detected through single-cell analysis and next-generation sequencing. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|