The Missing LINC for Genetic Cardiovascular Disease?

As of 2014, cardiovascular disease (CVD) was listed as the underlying cause for 1 of every 3 deaths in the United States. Many forms of CVD have a strong genetic component, and the number of causal genes elucidated greatly depends on the type of CVD under study. Understanding the molecular basis of CVD can guide medical decisions of the practitioner, patient, and family members. Currently, gene panels are used in the clinical setting to screen for disease-causing variation. Panels vary greatly in size depending on the number of genetic causes of the disease in question. There is often a great deal of phenotypic overlap between the inherited CVDs. To accommodate these variable phenotypes, many testing laboratories now use large panels that include >75 genes. Another route that is more commonly being used is the use of whole exome sequencing and whole genome sequencing to identify causal and contributory variants. Whole exome sequencing or whole genome sequencing can begin with focus on rare variants in genes most commonly associated with disease, and, if no attractive candidates are identified, the search is broadened to include genes not currently associated with disease. Such broad searches can lead to the identification of new disease genes; a great benefit in the research context, but a burden in the clinical-setting making disease risk assessment more difficult. It is also an ever-evolving target to determine the amount of validation necessary to deem variants pathogenic and therefore reportable, especially when variants are unique to individuals or to individual families. It can be especially troubling when the disease in question involves sudden death where there is significant risk for surviving family members. It is imperative that new, potential CVD genes continue to be validated using a variety of methods, including family studies, animaland cell-based models, and in vitro techniques. Much is known about the role of sarcomere proteins and ion channels in inherited CVD. However, although proteins of the nuclear envelope (NE) are implicated in CVD, only a handful of the ≈80 proteins of the NE have been exhaustively screened, and more work needs to be done to understand the risk of variants in genes of the NE. See Article by Haskell et al In this issue, Haskell et al present whole exome sequencing data on 55 patients with suspected monogenic CVD, including cardiomyopathy, long QT, thoracic aortic aneurysm, and mitral valve prolapse. Variants were initially filtered using candidate gene panels specific to each subject’s phenotype. Analysis of established disease genes identified pathogenic or likely pathogenic variants in 12 subjects and variants of unknown significance in an additional 19 of 55 subjects resulting in identification of a potentially pathogenic variant in a known candidate gene in 56.4% of the cohort. This left >40% of the cohort negative for diagnostic genetic variants. To identify novel candidate disease genes in the remainder of the cohort, the authors examined variants across the entire captured exome. They examined rare (minor allele frequency <0.001), predicted loss-of-function variants (pLOF), including nonsense, splice site, and frameshifting variants. Four potential candidate variants were identified, all in genes of the NE. The NE separates the functions of the cytoplasm and nucleus and is composed of the inner and outer nuclear membrane separated by the perinuclear space and spanned by the nuclear pore complex (NPC). The nuclear lamina underlies the inner nuclear membrane and is composed of the Aand B-type lamins and their associated proteins. In addition to the mechanical support provided by the nuclear lamina, its other functions involve DNA replication, cell division, chromatin localization, and gene expression. Mutations in genes encoding proteins of the nuclear lamina cause several forms of striated muscle disease. Mutations in the A-type lamins, encoded by the LMNA gene, are responsible for an entire class of diseases, termed the laminopathies, and affecting a diverse group of tissues, including striated muscle, nerves, and adipose tissue. The diseases of striated muscle include Emery–Dreifuss Muscular Dystrophy, a progressive muscle disease that can have a severe cardiac component and dilated cardiomyopathy (DCM) with and without conduction system disease. Of the 4 pLOF variants identified by Haskell et al,5 one was identified in a proband with a severe DCM that required transplant at age 15. The proband’s father also had DCM; neither had a history of skeletal muscle weakness. The pLOF variant identified was in the SYNE1 gene. SYNE1 encodes the giant nesprin-1 protein, a vital component of the LINC complex. The LINC complex (Linker of Nucleoskeleton and Cytoskeleton) spans the NE and is a multiprotein complex composed of the lamins, nesprins, SUN proteins, and a host of other nuclear membrane components (Figure). The LINC complex is thought to transmit mechanical signals from the cytoplasm to the nucleus and plays a role in diverse functions, including moving and shaping the nucleus, signal transduction, and chromatin localization. Mutations in LINC complex components are found in both cardiomyopathy and skeletal (Circ Cardiovasc Genet. 2017;10:e001793. DOI: 10.1161/CIRCGENETICS.117.001793.) © 2017 American Heart Association, Inc.