Genomic study of dilated cardiomyopathy in a group of Mexican patients using site‐directed next generation sequencing

Carnevale, Alessandra; Rosas-Madrigal, Sandra; Rosendo-Gutiérrez, Rigoberto; López-Mora, Enrique; Romero‐Hidalgo, Sandra; Avila-Vazzini, Nydia; Jacobo-Albavera, Leonor; Domínguez‐Pérez, Mayra; Vargas‐Alarcón, Gilberto; Pérez-Villatoro, Fernando; Navarrete-Martínez, J.I.; Villarreal-Molina, María Teresa

doi:10.1002/mgg3.1504

Cited by 11 publications

(10 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies with patients fulfilling DCM diagnostic criteria have observed an overall diagnostic yield of 19%–47% ( 11 , 12 , 15 , 20 ). In the recent ESC EURObservational Research Programme (EORP) Cardiomyopathy Registry study 33% of the patients had a diagnostic variant ( 13 ).…”

Section: Discussionmentioning

confidence: 96%

Diagnostic yield of genetic testing in a multinational heterogeneous cohort of 2088 DCM patients

Heliö,

Cicerchia,

Hathaway

et al. 2023

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

BackgroundFamilial dilated cardiomyopathy (DCM) causes heart failure and may lead to heart transplantation. DCM is typically a monogenic disorder with autosomal dominant inheritance. Currently disease-causing variants have been reported in over 60 genes that encode proteins in sarcomeres, nuclear lamina, desmosomes, cytoskeleton, and mitochondria. Over half of the patients undergoing comprehensive genetic testing are left without a molecular diagnosis even when patient selection follows strict DCM criteria.Methods and resultsThis study was a retrospective review of patients referred for genetic testing at Blueprint Genetics due to suspected inherited DCM. Next generation sequencing panels included 23–316 genes associated with cardiomyopathies and other monogenic cardiac diseases. Variants were considered diagnostic if classified as pathogenic (P) or likely pathogenic (LP). Of the 2,088 patients 514 (24.6%) obtained a molecular diagnosis; 534 LP/P variants were observed across 45 genes, 2.7% (14/514) had two diagnostic variants in dominant genes. Nine copy number variants were identified: two multigene and seven intragenic. Diagnostic variants were observed most often in TTN (45.3%), DSP (6.7%), LMNA (6.7%), and MYH7 (5.2%). Clinical characteristics independently associated with molecular diagnosis were: a lower age at diagnosis, family history of DCM, paroxysmal atrial fibrillation, absence of left bundle branch block, and the presence of an implantable cardioverter-defibrillator.ConclusionsPanel testing provides good diagnostic yield in patients with clinically suspected DCM. Causative variants were identified in 45 genes. In minority, two diagnostic variants were observed in dominant genes. Our results support the use of genetic panels in clinical settings in DCM patients with suspected genetic etiology.

show abstract

Section: Discussionmentioning

confidence: 96%

Diagnostic yield of genetic testing in a multinational heterogeneous cohort of 2088 DCM patients

Heliö,

Cicerchia,

Hathaway

et al. 2023

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

show abstract

“…53 47 ) with mutations in ACTC1. Of the hundreds of individuals described with ACTA1associated myopathy, only twelve (nine unique variants) [57][58][59][60][61][62][63][64][65] have been reported to also have a cardiac abnormality (Table S1), either in conjunction with a skeletal myopathy (N=10) or alone (N=2). Rare variants in ACTC1 resulting in congenital contractures in a small fraction of persons with ACTC1 variants appears to be the corollary.…”

Section: Discussionmentioning

confidence: 99%

Variants inACTC1underlie distal arthrogryposis accompanied by congenital heart defects

Chong

Childers

Marvin

et al. 2023

Preprint

View full text Add to dashboard Cite

Contraction of the human sarcomere is the result of interactions between myosin cross-bridges and actin filaments. Pathogenic variants in genes such as MYH7, TPM1, and TNNI3 that encode parts of the cardiac sarcomere cause muscle diseases that affect the heart, such as dilated cardiomyopathy and hypertrophic cardiomyopathy. In contrast, pathogenic variants in homologous genes MYH2, TPM2, and TNNI2, that encode parts of the skeletal muscle sarcomere, cause muscle diseases affecting skeletal muscle, such as the distal arthrogryposis (DA) syndromes and skeletal myopathies. To date, there have been few reports of genes (e.g., MYH7) encoding sarcomeric proteins in which the same pathogenic variant affects both skeletal and cardiac muscle. Moreover, none of the known genes underlying DA have been found to contain mutations that also cause cardiac abnormalities. We report five families with DA due to heterozygous missense variants in the gene actin, alpha, cardiac muscle 1 (ACTC1). ACTC1 encodes a highly conserved actin that binds to myosin in both cardiac and skeletal muscle. Mutations in ACTC1 have previously been found to underlie atrial septal defect, dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction. Our discovery delineates a new DA condition due to mutations in ACTC1 and suggests that some functions of actin, alpha, cardiac muscle 1 are shared in cardiac and skeletal muscle.

show abstract

“…One HCM case was associated with congenital myopathy with the core, whereas for another, the myopathy was unclassified (Kaindl et al, 2004 ). Likewise, two cases were associated with DCM alone (Carnevale et al, 2020 ; Reza et al, 2018 ). Genotype–phenotype correlation has not been elucidated; however, 327–328 AA and 336–338 AA residues in the ACTA1 sequence might accumulate mutations related to cardiomyopathy (Figure 2b,c ).…”

Section: Discussionmentioning

confidence: 99%

A case of congenital fiber‐type disproportion syndrome presenting dilated cardiomyopathy with ACTA1 mutation

Matsumoto

Tsuda

Furui

et al. 2022

Molec Gen & Gen Med

View full text Add to dashboard Cite

Background: Actin, alpha, skeletal muscle 1 (ACTA1) is one of the causative genes of nemaline myopathy (NM) and congenital fiber-type disproportion (CFTD). CFTD is characterized by type 1 fiber atrophy and distinguished from NM in the absence of rods. Eight patients with CFTD, including one patient with dilated cardiomyopathy (DCM), have previously been reported. Herein, we report the case of a 10-year-old boy presenting with CFTD and DCM. Methods:We performed exome sequencing and analyzed the effect of Met327Lys mutations on cultured C2C12 muscle cells compared with that seen in the wild type (WT, ACTA1) and previously identified Asp294Val mutations associated with a severe phenotype of CFTD without cardiomyopathy.Results: Exome sequencing revealed a de novo mutation, c.980 T > A, p.(Met327Lys), in ACTA1 (NM_001100.4). C2C12 cells transfected with the WT plasmid expressed ACTA1 in the nucleus and cytoplasm. Cells with the Asp294Val mutant showed needle-like structures in the cytoplasm, whereas the expression of the Met327Lys mutant resulted in few aggregations but many apoptotic cells. Conclusion: Apoptosis induced in Met327Lys-transfected muscle cells supports the pathogenicity of the mutation and can be implicated as one of the histopathological features associated with CFTD, as in NM.

show abstract

Genomic study of dilated cardiomyopathy in a group of Mexican patients using site‐directed next generation sequencing

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 11 publications

References 40 publications

Diagnostic yield of genetic testing in a multinational heterogeneous cohort of 2088 DCM patients

Diagnostic yield of genetic testing in a multinational heterogeneous cohort of 2088 DCM patients

Variants inACTC1underlie distal arthrogryposis accompanied by congenital heart defects

A case of congenital fiber‐type disproportion syndrome presenting dilated cardiomyopathy with ACTA1 mutation

Contact Info

Product

Resources

About