Key result
Novel FLNC missense mutation links to familial HCM, alongside a MYLK2 truncating variant in DCM.
Why the study?
Mutations in FLNC are linked to HCM and sudden death, but the presence of multiple causal mutations in cardiomyopathy with different phenotypes requires further investigation.
Case Report (n=5)
The identification of novel FLNC and MYLK2 mutations in a single family highlights the possibility of multiple causal mutations contributing to different cardiomyopathy phenotypes, warranting clinical attention for atypical cases.
May inform genetic counseling in select HCM families; extends FLNC spectrum but leaves causality and screening implications open.
Background: Mutations in the sarcomeric protein filamin C (FLNC) gene have been linked to hypertrophic cardiomyopathy (HCM), in which they increase the risk of ventricular arrhythmia and sudden death. In this study, we identified a novel missense mutation of FLNC in a Chinese family with HCM and interestingly a second novel truncating mutation of MYLK2 in one family member with different phenotype. Methods: We performed whole-exome sequencing in a Chinese family with HCM of unknown cause. To validate the function of a novel mutation of FLNC, we introduced the mutant and wild-type gene into AC16 cells (human cardiomyocytes), and used western blotting to analyze the expression of FLNC in subcellular fractions, and confocal microscope to observe the subcellular distribution of the protein. Results: We identified a novel missense single nucleotide variant (FLNC c.G5935A [p.A1979T]) in the family, which segregates with the disease. FLNC expression levels were equivalent in both wild type and p.A1979T cardiomyocytes. However, expression of the mutant protein resulted in cytoplasmic protein aggregations, in contrast to wild type FLNC, which was distributed in the cytoplasm and did not form aggregates. Unexpectely, a second truncating mutation, NM_033118:exon8:c.G1138T:p.E380X of the MYLK2 gene, was identified in the mother of the proband with dilated cardiomyopathy, but absent in other subjects. Conclusion: We identified the FLNC A1979T mutation as a novel pathogenic variant associated with HCM in a Chinese family, as well as a second causal mutation in a family member with a distinct phenotype. The possibility of more than one causal mutations in cardiomyopathy warrants clinical attention, especially for patients with atypical clinical features.
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Qin et al. (2020) conducted a case report in Hypertrophic cardiomyopathy and dilated cardiomyopathy (n=5). FLNC c.G5935A (p.A1979T) and MYLK2 p.E380X mutations vs. Unaffected family members / wild-type was evaluated on Identification of causal genetic variants and their functional effects. Whole-exome sequencing identified a novel pathogenic FLNC missense mutation (p.A1979T) segregating with hypertrophic cardiomyopathy, and a second MYLK2 truncating mutation (p.E380X) in a family member with dilated cardiomyopathy.
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