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Early Somatic Mosaicism Is a Rare Cause of Long-QT Syndrome

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Early Somatic Mosaicism Is a Rare Cause of Long-QT Syndrome Early somatic mosaicism is a rare cause of long-QT syndrome James Rush Priesta,b,c, Charles Gawadb,d,1, Kristopher M. Kahlige, Joseph K. Yuf,g, Thomas O’Haraf, Patrick M. Boylef,g, Sridharan Rajamanie,2, Michael J. Clarkh, Sarah T. K. Garciah,3, Scott Ceresnaka,b,c, Jason Harrish, Sean Boyleh, Frederick E. Deweya,i,4, Lindsey Malloy-Waltona,b,c,5, Kyla Dunna,j, Megan Grovea,i, Marco V. Pereza,i, Norma F. Neffk, Richard Chenh, Katsuhide Maedaa,l, Anne Dubina,b,c, Luiz Belardinellie, John Westh, Christian Antolikm, Daniela Macayam, Thomas Quertermousa,i, Natalia A. Trayanovaf,g, Stephen R. Quakek,n,o,6, and Euan A. Ashleya,b,i,6 aStanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, CA 94305; bChild Health Research Institute, Stanford University School of Medicine, Stanford, CA 94305; cDivision of Pediatric Cardiology, Stanford University School of Medicine, Stanford, CA 94305; dDivision of Pediatric Hematology-Oncology, Stanford University School of Medicine, Stanford, CA 94305; eDepartment of Biology, Cardiovascular Therapeutic Area, Gilead Sciences, Fremont, CA 94555; fDepartment of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218; gInstitute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21218; hPersonalis, Inc., Menlo Park, CA 94025; iDivision of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305; jLucile Packard Children’s Hospital Heart Center, Palo Alto, CA 94304; kDepartment of Bioengineering, Stanford University School of Medicine, Stanford, CA 94305; lDivision of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305; mCardiogenetic Testing Services, GeneDx, Gaithersburg, MD 20877; nDepartment of Applied Physics, Stanford University, Stanford, CA 94305; and oHoward Hughes Medical Research Institute, Stanford University School of Medicine, Stanford, CA 94305 Contributed by Stephen R. Quake, August 19, 2016 (sent for review May 5, 2016; reviewed by Leslie Biesecker and Christopher Semsarian) Somatic mosaicism, the occurrence and propagation of genetic varia- The pathophysiological basis of long-QT syndrome (LQTS) is tion in cell lineages after fertilization, is increasingly recognized to play prolongation of cardiac ventricular repolarization by acquired a causal role in a variety of human diseases. We investigated the case factors such as drug exposure or genetic variation in the proteins of life-threatening arrhythmia in a 10-day-old infant with long QT controlling transmembrane ion-concentration gradients (8, 9); syndrome (LQTS). Rapid genome sequencing suggested a variant in the parental gonadal mosaicism is an infrequently described phe- – sodium channel NaV1.5 encoded by SCN5A, NM_000335:c.5284G > T nomenon in LQTS (10 12). Knowledge of the molecular sub- predicting p.(V1762L), but read depth was insufficient to be diagnostic. typing of disease in LQTS has provided a foundation for Exome sequencing of the trio confirmed read ratios inconsistent with genotype-specific risk stratification and treatment strategies (8, 9, Mendelian inheritance only in the proband. Genotyping of single cir- culating leukocytes demonstrated the mutation in the genomes of 8% Significance of patient cells, and RNA sequencing of cardiac tissue from the infant confirmed the expression of the mutant allele at mosaic ratios. Heter- Most genetic studies and clinical genetic testing do not look ologous expression of the mutant channel revealed significantly for the possibility of mosaic variation. The genetic form of delayed sodium current with a dominant negative effect. To investi- long-QT syndrome (LQTS) can result in life-threatening ar- gate the mechanism by which mosaicism might cause arrhythmia, we rhythmias, but 30% of patients do not have a genetic di- built a finite element simulation model incorporating Purkinje fiber agnosis. We performed deep characterization of a mosaic activation. This model confirmed the pathogenic consequences of car- variant in an infant with perinatal LQTS and developed a diac cellular mosaicism and, under the presenting conditions of this computational model showing how abnormal cellular re- case, recapitulated 2:1 AV block and arrhythmia. To investigate the polarization in only 8% of heart cells may cause arrhythmia. extent to which mosaicism might explain undiagnosed arrhyth- Finally we looked at the prevalence of mosaicism among pa- mia, we studied 7,500 affected probands undergoing commercial tients with LQTS; in a population of 7,500 individuals we gene-panel testing. Four individuals with pathogenic variants found evidence of pathogenic early somatic mosaicism in arising from early somatic mutation events were found. Here approximately 0.17% of LQTS patients without a genetic di- we establish cardiac mosaicism as a causal mechanism for LQTS agnosis. Together these data establish an unreported mech- and present methods by which the general phenomenon, likely to anism for LQTS and other genetic arrhythmias. be relevant for all genetic diseases, can be detected through single- cell analysis and next-generation sequencing. Author contributions: J.R.P., K.M.K., T.O., S.R., S.C., R.C., K.M., A.D., L.B., J.W., D.M., T.Q., and E.A.A. designed research; J.R.P., C.G., K.M.K., J.K.Y., P.M.B., L.M.-W., K.D., M.G., M.V.P., and C.A. performed research; J.K.Y., T.O., P.M.B., F.E.D., N.F.N., D.M., N.A.T., mosaicism | arrhythmia | genomics | computational modeling | single cell and S.R.Q. contributed new reagents/analytic tools; J.R.P., C.G., K.M.K., J.K.Y., P.M.B., M.J.C., S.T.K.G., J.H., S.B., and J.W. analyzed data; and J.R.P., K.M.K., J.K.Y., T.Q., and here is growing recognition that somatic mosaicism, i.e., ge- E.A.A. wrote the paper. Tnetic variation within an individual that arises from errors in Reviewers: L.B., NIH; and C.S., University of Sydney. DNA replication during early development, may play a role in a Conflict of interest statement: At the time of this work K.M.K., S.R., and L.B. were em- variety of human diseases other than cancer (1). However, the ployed by Gilead Sciences. M.J.C., S.T.K.G., S.B., J.W., and R.C. were employed by Person- alis, Inc. J.W. and E.A.A. are founders of Personalis, Inc. which offers clinical genetic extent to which cellular heterogeneity contributes to disease is testing but does not offer Clinical Laboratory Improvement Amendments (CLIA)-certified minimally understood. One report suggests that 6.5% of de novo rapid-turnaround whole-genome sequencing. N.A.T. is a co-founder of CardioSolv LLC. mutations presumed to be germline in origin may instead have Freely available online through the PNAS open access option. arisen from postzygotic mosaic mutation events (2), and recent 1Present address: St. Jude Children’s Research Hospital, Memphis, TN 38105. genetic investigations directly interrogating diseased tissues in 2Present address: Amgen, Inc., South San Francisco, CA 94080. brain malformations, breast cancer, and atrial fibrillation have 3Present address: 10X Genomics, Pleasanton, CA 94556. revealed postzygotic causal mutations absent from germline 4Present address: Regeneron Pharmaceuticals, Tarrytown, NY 10591. – DNA (3 6). Pathogenic mosaic structural variation is also de- 5Mercy Children’s Hospital, Kansas City, MO 64108. tectable in children with neurodevelopmental disorders (7). 6To whom correspondence may be addressed. Email: [email protected] or quake@ However, a consequential category of genetic variation has stanford.edu. not been surveyed systematically in clinical or research studies of This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. MEDICAL SCIENCES other human diseases. 1073/pnas.1607187113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1607187113 PNAS | October 11, 2016 | vol. 113 | no. 41 | 11555–11560 Downloaded by guest on October 1, 2021 13, 14). However, nearly 30% of probands remain undiagnosed using standard commercial gene-panel testing, suggesting there is unrecognized genetic variation (genic, regulatory, or otherwise) yet to be associated with disease (15). In its most severe form, LQTS may occur in the neonatal period with bradycardia and functional 2:1 AV block that occur secondary to a severely prolonged ventricular refractory period greater than the short R–R interval characteristic of a normal heart rate in infancy (16). Patients of all ages presenting with LQTS are predisposed to torsades de pointes (TdP), a life- threatening cardiac arrhythmia, with patients presenting in in- fancy showing particularly poor outcomes (13, 16–18). In this study, we applied rapid-turnaround whole-genome sequencing (WGS) on day of life (DOL) 3 in a premature infant with peri- natal LQTS and life-threatening arrhythmia and investigated the contribution of a discovered mosaic variant to abnormal cardiac electrophysiology at the molecular and tissue levels. Additionally we surveyed 7,500 individuals already tested for genetic ar- rhythmias, allowing us to estimate the prevalence of mosaicism in an unbiased population sample. Results Deep Sequencing Identifies Mosaic Variation in SCN5A in an Infant with a Prolonged QT Interval and Arrhythmia. A near-term 2.5-kg female infant of Asian ancestry with prenatally diagnosed 2:1 AV block was delivered by caesarean section at 36-wk gestation. At 1 h of life the infant developed intermittent 2:1 AV block with multiple episodes of TdP with a corrected QT interval (QTc) of 542 ms (Fig. 1), which were relieved by placement of a dual-chamber epicardial implantable cardioverter/defibrillator (ICD) accompanied by a bi- lateral stellate ganglionectomy. A standard commercially available genetic panel for LQTS was sent on DOL 1 (13, 17), and WGS was performed on DOL 3. At 6 mo of age the patient developed dilated cardiomyopathy and subsequently received an orthotopic heart transplant. WGS yielded a 39.76 mean read depth, and coverage across the coding regions of known LQTS and dilated cardiomyopathy (DCM) genes was 99.93% at 10× or greater (Table S1).
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