Exome Sequencing Identifies a Novel LMNA Splice-Site Mutation and Multigenic Heterozygosity of Potential Modifiers in a Family with Sick Sinus Syndrome, Dilated Cardiomyopathy, and Sudden Cardiac Death

The goals are to understand the primary genetic mechanisms that cause Sick Sinus Syndrome and to identify potential modifiers that may result in intrafamilial variability within a multigenerational family. The proband is a 63-year-old male with a family history of individuals (>10) with sinus nod...

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Bibliographic Details
Published in:	PloS one Vol. 11; no. 5; p. e0155421
Main Authors:	Zaragoza, Michael V, Fung, Lianna, Jensen, Ember, Oh, Frances, Cung, Katherine, McCarthy, Linda A, Tran, Christine K, Hoang, Van, Hakim, Simin A, Grosberg, Anna
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 16-05-2016 Public Library of Science (PLoS)
Subjects:	Adult Age Alleles Arrhythmia Bioinformatics Biology and Life Sciences Biomarkers Biomedical engineering Bradycardia Cardiac arrhythmia Cardiomyopathy Cardiomyopathy, Dilated - diagnosis Cardiomyopathy, Dilated - genetics Complications and side effects Data processing Death, Sudden, Cardiac - etiology Dilated cardiomyopathy DNA Mutational Analysis DNA sequencing Electrocardiography Exome Family studies Female Gene expression Gene Expression Profiling Gene Frequency Gene sequencing Genes Genetic aspects Genetic Association Studies Genetic Heterogeneity Genetic Predisposition to Disease Genetics Genomics Haploinsufficiency Heart Heart diseases Heart failure Heterozygosity High-Throughput Nucleotide Sequencing Humans Ion channels Ion channels (cyclic nucleotide-gated) Lamin Type A - genetics Male Medical records Medicine and Health Sciences Middle Aged Mutation Pediatrics Pedigree Phenotype Reproducibility of Results Research and analysis methods Risk factors RNA Splice Sites Sequence Analysis, DNA Sick sinus syndrome Sick Sinus Syndrome - diagnosis Sick Sinus Syndrome - genetics Sinuses Studies Ventricle Zygosity United States > US California
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Summary:	The goals are to understand the primary genetic mechanisms that cause Sick Sinus Syndrome and to identify potential modifiers that may result in intrafamilial variability within a multigenerational family. The proband is a 63-year-old male with a family history of individuals (>10) with sinus node dysfunction, ventricular arrhythmia, cardiomyopathy, heart failure, and sudden death. We used exome sequencing of a single individual to identify a novel LMNA mutation and demonstrated the importance of Sanger validation and family studies when evaluating candidates. After initial single-gene studies were negative, we conducted exome sequencing for the proband which produced 9 gigabases of sequencing data. Bioinformatics analysis showed 94% of the reads mapped to the reference and identified 128,563 unique variants with 108,795 (85%) located in 16,319 genes of 19,056 target genes. We discovered multiple variants in known arrhythmia, cardiomyopathy, or ion channel associated genes that may serve as potential modifiers in disease expression. To identify candidate mutations, we focused on ~2,000 variants located in 237 genes of 283 known arrhythmia, cardiomyopathy, or ion channel associated genes. We filtered the candidates to 41 variants in 33 genes using zygosity, protein impact, database searches, and clinical association. Only 21 of 41 (51%) variants were validated by Sanger sequencing. We selected nine confirmed variants with minor allele frequencies <1% for family studies. The results identified LMNA c.357-2A>G, a novel heterozygous splice-site mutation as the primary mutation with rare or novel variants in HCN4, MYBPC3, PKP4, TMPO, TTN, DMPK and KCNJ10 as potential modifiers and a mechanism consistent with haploinsufficiency.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceived and designed the experiments: MVZ LF EJ FO KC. Performed the experiments: MVZ LF EJ FO KC LAM CKT SAH. Analyzed the data: MVZ LF EJ FO KC VH CKT SAH. Contributed reagents/materials/analysis tools: MVZ AG. Wrote the paper: MVZ LF EJ FO AG. Competing Interests: The authors have declared that no competing interests exist.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0155421