Targeted next-generation sequencing of candidate genes reveals novel mutations in patients with dilated cardiomyopathy

Abstract

Dilated cardiomyopathy (DCM) is a major cause of sudden cardiac death and heart failure, and it is characterized by genetic and clinical heterogeneity, even for some patients with a very poor clinical prognosis; in the majority of cases, DCM necessitates a heart transplant. Genetic mutations have long been considered to be associated with this disease. At present, mutations in over 50 genes related to DCM have been documented. This study was carried out to elucidate the characteristics of gene mutations in patients with DCM. The candidate genes that may cause DCM include MYBPC3, MYH6, MYH7, LMNA, TNNT2, TNNI3, MYPN, MYL3, TPM1, SCN5A, DES, ACTC1 and RBM20. Using next-generation sequencing (NGS) and subsequent mutation confirmation with traditional capillary Sanger sequencing analysis, possible causative non-synonymous mutations were identified in ~57% (12/21) of patients with DCM. As a result, 7 novel mutations (MYPN, p.E630K; TNNT2, p.G180A; MYH6, p.R1047C; TNNC1, p.D3V; DES, p.R386H; MYBPC3, p.C1124F; and MYL3, p.D126G), 3 variants of uncertain significance (RBM20, p.R1182H; MYH6, p.T1253M; and VCL, p.M209L), and 2 known mutations (MYH7, p.A26V and MYBPC3, p.R160W) were revealed to be associated with DCM. The mutations were most frequently found in the sarcomere (MYH6, MYBPC3, MYH7, TNNC1, TNNT2 and MYL3) and cytoskeletal (MYPN, DES and VCL) genes. As genetic testing is a useful tool in the clinical management of disease, testing for pathogenic mutations is beneficial to the treatment of patients with DCM and may assist in predicting disease risk for their family members before the onset of symptoms.

Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy

“…8,[10][11][12][13][14][15][16][17][18][19][20] Although we made a genetic analysis of several cardiac core transcriptional factor genes in the two mutation carriers with DCM, including GATA4, GATA5, GATA6, TBX5, TBX20, and HAND1, as described previously, [22][23][24][25][26][27][28][29][30][31] and found no mutations, we cannot rule out the possibility that the genetic variants in other genes may also contribute to DCM in these two patients. Genome sequencing analysis may help to explain the possibility for these patients.…”

“…8,9) At present, an increasing number of causative mutations in > 50 genes have been causally linked to idiopathic DCM. 8,[10][11][12][13][14][15][16][17][18][19][20] Among these well established DCM-associated genes, most encode contractile sarcomeric proteins as well as cytoskeletal/sarcolemmal and nuclear envelope proteins. 8) Nevertheless, these DCM-causing genes can explain only about one-third of patients and for most genes, the mutational frequency is low, with genetic mutation occurring in < 1% of DCM patients.…”

Letter to editor: Genetic basis of dilated cardiomyopathy

“…In this review, the authors held a view that "EMD has been recently reported as a causal gene in DCM" and cited a reference to prove it [2]. However, we cannot find any evidence about the association with DCM and EMD mutation in this reference.…”

Structural basis of UCUU RNA motif recognition by splicing factor RBM20

“…RBM20 was itself first identified in a search for a familial genetic basis of DCM in human patients (Brauch et al, 2009). Subsequent investigation has identified additional patients and mutations involving RBM20 related to DCM (Zhao et al, 2015b;Long et al, 2017;Wells et al, 2013;Waldmüller et al, 2015;Chami et al, 2014;Refaat et al, 2012;Rampersaud et al, 2011;Millat et al, 2011;Li et al, 2010;Robyns et al, 2019), as well as cardiac arrhythmia (Nielsen et al, 2018;Parikh et al, 2019), pediatric restrictive cardiomyopathy (Rindler et al, 2017) and left-ventricular non-compaction . Although representing only 3 % of idiopathic cases, patients with DCM that have mutant RBM20 correlate with earlier disease onset, high penetrance, and requirement for heart transplantation (Brauch et al, 2009;Li et al, 2010;Kayvanpour et al, 2017;Wells et al, 2013;Hey et al, 2019).…”