Early somatic mosaicism is a rare cause of long-QT syndrome.
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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, CA 94305; Child Health Research Institute, Stanford University School of Medicine, Stanford, CA 94305; Division of Pediatric Cardiology, Stanford University School of Medicine, Stanford, CA 94305.
James Rush
JR
Priest
Child Health Research Institute, Stanford University School of Medicine, Stanford, CA 94305; Division of Pediatric Hematology-Oncology, Stanford University School of Medicine, Stanford, CA 94305.
Charles
C
Gawad
Department of Biology, Cardiovascular Therapeutic Area, Gilead Sciences, Fremont, CA 94555.
Kristopher M
KM
Kahlig
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218; Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21218.
Joseph K
JK
Yu
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218.
Thomas
T
O'Hara
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218; Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21218.
Patrick M
0000-0001-9048-1239
PM
Boyle
Department of Biology, Cardiovascular Therapeutic Area, Gilead Sciences, Fremont, CA 94555.
Sridharan
S
Rajamani
Personalis, Inc., Menlo Park, CA 94025.
Michael J
MJ
Clark
Personalis, Inc., Menlo Park, CA 94025.
Sarah T K
ST
Garcia
Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, CA 94305; Child Health Research Institute, Stanford University School of Medicine, Stanford, CA 94305; Division of Pediatric Cardiology, Stanford University School of Medicine, Stanford, CA 94305.
Scott
S
Ceresnak
Personalis, Inc., Menlo Park, CA 94025.
Jason
J
Harris
Personalis, Inc., Menlo Park, CA 94025.
Sean
S
Boyle
Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, CA 94305; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305.
Frederick E
FE
Dewey
Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, CA 94305; Child Health Research Institute, Stanford University School of Medicine, Stanford, CA 94305; Division of Pediatric Cardiology, Stanford University School of Medicine, Stanford, CA 94305.
Lindsey
L
Malloy-Walton
Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, CA 94305; Lucile Packard Children's Hospital Heart Center, Palo Alto, CA 94304.
Kyla
K
Dunn
Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, CA 94305; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305.
Megan
M
Grove
Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, CA 94305; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305.
Marco V
0000-0003-2746-0202
MV
Perez
Department of Bioengineering, Stanford University School of Medicine, Stanford, CA 94305.
Norma F
NF
Neff
Personalis, Inc., Menlo Park, CA 94025.
Richard
R
Chen
Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, CA 94305; Division of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305.
Katsuhide
K
Maeda
Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, CA 94305; Child Health Research Institute, Stanford University School of Medicine, Stanford, CA 94305; Division of Pediatric Cardiology, Stanford University School of Medicine, Stanford, CA 94305.
Anne
A
Dubin
Department of Biology, Cardiovascular Therapeutic Area, Gilead Sciences, Fremont, CA 94555.
Luiz
L
Belardinelli
Personalis, Inc., Menlo Park, CA 94025.
John
J
West
Cardiogenetic Testing Services, GeneDx, Gaithersburg, MD 20877.
Christian
C
Antolik
Cardiogenetic Testing Services, GeneDx, Gaithersburg, MD 20877.
Daniela
D
Macaya
Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, CA 94305; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305.
Thomas
T
Quertermous
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218; Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21218.
Natalia A
NA
Trayanova
Department of Bioengineering, Stanford University School of Medicine, Stanford, CA 94305; Department of Applied Physics, Stanford University, Stanford, CA 94305; Howard Hughes Medical Research Institute, Stanford University School of Medicine, Stanford, CA 94305 euan@stanford.edu quake@stanford.edu.
Stephen R
SR
Quake
Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, CA 94305; Child Health Research Institute, Stanford University School of Medicine, Stanford, CA 94305; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305; euan@stanford.edu quake@stanford.edu.
Euan A
EA
Ashley
D000200:Action Potentials; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D001483:Base Sequence; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D003198:Computer Simulation; D004058:Diffusion; D004562:Electrocardiography; D005787:Gene Frequency / Q000235:genetics; D005799:Genes, Dominant; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006329:Heart Conduction System / Q000503:physiopathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D015640:Ion Channel Gating / Q000235:genetics; D008133:Long QT Syndrome / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D008954:Models, Biological; D009030:Mosaicism; D009154:Mutation / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics; D010641:Phenotype; D059010:Single-Cell Analysis
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human
arrhythmia; computational modeling; genomics; mosaicism; single cell
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