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Authors: Rafael Valdés-Mas, Ana Gutiérrez-Fernández, Juan Gómez, Eliecer Coto, Aurora Astudillo, Diana A. Puente, Julián R. Reguero, Victoria Álvarez, César Morís, Diego León, María Martín, Xose S. Puente and Carlos López-Otín
Presented by: Maria Gallego-Delgado, MD & Pablo Garcia-Pavia, MD, PhD. Heart Failure and Inherited Cardiac Diseases Unit. Hospital Universitario Puerta de Hierro, Madrid, Spain.
Mutations in different genes encoding sarcomeric proteins are responsible for 50–60% of familial cases of hypertrophic cardiomyopathy (HCM); however, the genetic alterations causing the disease in one-third of patients are still unknown. Whole exome sequencing with NGS could be a useful tool in the identification of new genes associated with this disease. Present work unravels mutations in FLNC gene as a new cause of HCM by using NGS techniques.
The authors performed whole exome sequencing on the index case of a family with several individuals affected by HCM after failing to find mutations in major sarcomeric genes previously associated with HCM. Of the 128 genetic variants found after removing common polymorphisms, one missense mutation in the gene FLNC predicted affection of protein function and had cardiac-specific expression (muscle-specific filamin C, implicated in myocyte differentiation). Investigators confirmed segregation of FLNC p.A1539T with the disease in the family (see pedigree below).
To examine whether FLNC variants were present in other families with HCM, FLNC gene was analyzed in 92 HCM patients who were negative for mutations in 9 sarcomeric genes previously known to cause HCM. Investigators identified 8 unique variants in a total of 9 unrelated subjects with HCM (10%). In addition they observed strong cosegregation of FLNC variants and clinical status among 8 families affected by HCM (combined LINKAGE LOD score=4.1). Authors found that HCM patients with mutations in FLNC had thinner maximal wall thickness than patients without mutations in FLNC (16 vs. 19.2 mm, P<0.05). They also exhibited higher frequency of familial history of HCM (55 vs. 17.8%, P<0.01) and sudden cardiac death (56 vs. 27%, P<0.05). Immunohistochemical staining of 2 patients with FLNC mutatios who underwent heart transplantation showed the presence of filamin C aggregates inside the sarcomere of cardiac myocytes. A functional analysis was performed in neonatal rat cardiac myocites with clones containing four of the mutations found in HCM patients. Three of the four analysed mutants produced insoluble filamin C aggregates. These data support the hypothesis that the mutations in filamin disrupt the structure of this sarcomeric protein, leading to the formation of protein aggregates that might finally impair sarcomere function.
HCM is the most common inherited cardiomyopathy (prevalence 1:500). Currently, the genetic analysis of the major sarcomeric genes can identify the underlying mutations in 50-60% of cases. However, in up to a third of the familal HCM cases, the causal gene remains unknown. New technologies of high throughput sequencing allows studying a large number of genes simultaneously in a short period of time and at a relatively low cost. This is of particular interest in inherited diseases with a large genetic heterogeneity, like cardiomyopathies. This paper shows the usefulness of NGS in the identification of a new gene linked to HCM. Although this technology has not been validated in clinical practice, as Valdes-Mas et al. show, NGS could be very useful in families with multiple members affected and without mutations in known causal genes, because the pathogenicity of the candidate genetic variants found can be confirmed through segregation studies.
FLNC encodes the sarcomeric protein filamin C, a muscle-specific protein involved in myocyte differentiation and muscle function by interacting with proteins of both the Z-disc and the sarcolemma. Mutations in this gene have been related with myofibrillar myopathy and some individuals exhibited also cardiac involvement, mainly in the form of dilated cardiomyopathy. This gene was therefore one of the main candidate genes to become part of the spectrum of sarcomeric genes causing cardiomyopathies. Curiously, in this research some of the mutation carriers had elevated CK levels although none showed signs or symptoms of myopathy which was actively investigated by the authors.
The main limitation of this study is the small size of some families and the lack of multiple affected members in several families. Cardiac phenotype characterization was also not very exhaustive. In fact, it is surprising that some individuals were considered to be affected with septum of only 12 mm without referring other findings suggestive of HCM. Anyway, and although the functional studies were performed in only four of the eight genetic variants found, they also supported the pathogenicity of FLNC mutations. Further studies in patients with HCM and other cardiomyopathies are needed in order to clarify the role of mutations in FLNC in the pathogenesis of inherited cardiomyopathies.
By using exome-capture and next-generation sequencing to identify the putative genetic alterations in one family with HCM and additional genetic analysis of 92 subjects with HCM, authors have identified FLNC as a new causal gene implicated in HCM.
Reference: Nat Commun. 2014 Oct 29;5:5326. doi: 10.1038/ncomms6326.