ArticlePloS one2016
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.
Article in PloS one, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 32 citations in OpenAlex.
- Article
- The Pathogenic Mechanisms of and Novel Therapies for Lamin A/C-Related Dilated Cardiomyopathy Based on Patient-Specific Pluripotent Stem Cell Platforms and Animal Models.Pharmaceuticals (Basel, Switzerland) · 2024Review
- The Influence of a Genetic Variant inInternational journal of molecular sciences · 2024Article
- Primate Model Carrying LMNA Mutation Develops Dilated Cardiomyopathy.JACC. Basic to translational science · 2024Article
- Genetics of sinoatrial node function and heart rate disorders.Disease models & mechanisms · 2023Review
- Sinus node dysfunction: current understanding and future directions.American journal of physiology. Heart and circulatory physiology · 2023Review
- Characterization of cardiac involvement in patients withFrontiers in genetics · 2023Article
- A comprehensive review of computational and image analysis techniques for quantitative evaluation of striated muscle tissue architecture.Biophysics reviews · 2022Review
- A Study of Gene Expression, Structure, and Contractility of iPSC-Derived Cardiac Myocytes from a Family with Heart Disease due to LMNA Mutation.Annals of biomedical engineering · 2021Article
- Review
- Phosphorylation of Lamin A/C at serine 22 modulates NaPhysiological reports · 2021Article
- DNA methylation analysis reveals epimutation hotspots in patients with dilated cardiomyopathy-associated laminopathies.Clinical epigenetics · 2021Article
- Microelectrode Array Recording of Sinoatrial Node Firing Rate to Identify Intrinsic Cardiac Pacemaking Defects in Mice.Journal of visualized experiments : JoVE · 2021Article
- Genetic predictors of sick sinus syndrome.Molecular biology reports · 2021Article
- Genetic Complexity of Sinoatrial Node Dysfunction.Frontiers in genetics · 2021Review
- Gene expression profiling of fibroblasts in a family with LMNA-related cardiomyopathy reveals molecular pathways implicated in disease pathogenesis.BMC medical genetics · 2020Article
- Databases to Efficiently Manage Medium Sized, Low Velocity, Multidimensional Data in Tissue Engineering.Journal of visualized experiments : JoVE · 2019Article
- Nuclear lamina genetic variants, including a truncated LAP2, in twins and siblings with nonalcoholic fatty liver disease.Hepatology (Baltimore, Md.) · 2018Article
- Identification of novel genomic imbalances in Saudi patients with congenital heart disease.Molecular cytogenetics · 2018Article
- Mechanotransduction, nuclear architecture and epigenetics in Emery Dreifuss Muscular Dystrophy: tous pour un, un pour tous.Nucleus (Austin, Tex.) · 2018Review
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
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