Cardiac somatic mosaicism was established as a rare causal mechanism for long-QT syndrome, with pathogenic variants arising from early somatic mutation events found in 4 of 7,500 affected probands.
Observational (n=7,500)
Is early somatic mosaicism a causal mechanism for long-QT syndrome?
Early somatic mosaicism is established as a rare but causal mechanism for long-QT syndrome, detectable through single-cell analysis and next-generation sequencing.
5 encoded by SCN5A, NM₀00335: 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.
Priest et al. (2016) conducted an observational in Long-QT syndrome (n=7,500). Next-generation sequencing and single-cell analysis was evaluated on Pathogenic variants arising from early somatic mutation events. Cardiac somatic mosaicism was established as a rare causal mechanism for long-QT syndrome, with pathogenic variants arising from early somatic mutation events found in 4 of 7,500 affected probands.