Targeted panel sequencing in adult patients with left ventricular non-compaction reveals a large genetic heterogeneity

Richard, Pascale; Ader, Flavie; Roux, M; Donal, Erwan; Eicher, Jean‐Christophe; Aoutil, Nadia; Huttin, Olivier; Coisne, D.; Jondeau, Guillaume; Damy, Thibaud; Mansencal, Nicolas; Casalta, Anne-Claire; Michel, Nicolas; Haentjens, Julie; Faivre, Laurence; Lavoûte, Cécile; Nguyen, Karine; Trégouët, David‐Alexandre; Habib, Gilbert; Charron, Philippe

doi:10.1016/j.acvdsp.2019.01.016

Cited by 17 publications

(32 citation statements)

References 13 publications

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“…This was further questioned after the study by Weir-McCall et al [20] who demonstrated a 1.3-14.8% prevalence of LVNC in the general population, with the spread depending on the MRI criteria used [10]. Regardless of the unique pathomechanism of abnormal embryonic development, the genetic spectrum of LVNC substantially overlaps with that of other cardiomyopathies, and includes sarcomeric, structural, ionchannel, and metabolic-related genes as demonstrated in several recent studies [7,8,21,22]. However, most of these studies included groups of adults only.…”

Section: Discussionmentioning

confidence: 99%

“…It is generally assumed that the genetic spectrum of LVNC overlaps with other cardiomyopathies and a predominance of sarcomeric gene mutations. However, mutations in cytoskeletal and ion channel-encoding genes as well as in genes encoding for transcriptional factors are also associated with LVNC cardiomyopathy [6,7]. A recent study including 327 adult and paediatric patients with LVNC detected pathogenic and likely pathogenic variants in 32% of the patients.…”

Section: Introductionmentioning

confidence: 99%

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Genetic Spectrum of Left Ventricular Non-Compaction in Paediatric Patients

et al. 2020

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Introduction: Left ventricular non-compaction (LVNC) represents a genetically heterogeneous cardiomyopathy which occurs in both children and adults. Its genetic spectrum overlaps with other types of cardiomyopathy. However, LVNC phenotypes in different age groups can have distinct genetic aetiologies. The aim of the study was to decipher the genetic spectrum of LVNC presented in childhood. Patient Group and Methods: Twenty patients under the age of 18 years diagnosed with LVNC were enrolled in the study. Target sequencing and whole-exome sequencing were performed using a panel of 108 cardiomyopathy-associated genes. Pathogenic, likely pathogenic, and variants of unknown significance found in genes highly expressed in cardiomyocytes were considered as variants of interest for further analysis. Results: The median age at presentation was 8.0 (0.1–17) years, with 6 patients presenting before 1 year of age. Twelve (60%) patients demonstrated reduced ejection fraction. Right ventricular (RV) dilation was registered in 6 (30%), often in combination with reduced RV contractility (25%). Almost half (45%) of the patients demonstrated biventricular involvement already at disease presentation. For pathogenic and likely pathogenic variants, the positive genotyping rate was 45%, and these variants were found mainly in non-contractile structural sarcomeric genes (ACTN2, MYPN, and TTN) or in metabolic and signal transduction genes (BRAF and TAZ). Likely pathogenic TAZ variants were detected in all 5 patients suspected of having Barth syndrome. No pathogenic or likely pathogenic variants were found in genes encoding for sarcomeric contractile proteins, but variants of unknown significance were detected in 3 out of 20 patients (MYH6, MYH7, and MYLK2). In 4 patients, variants of unknown significance in ion-channel genes were detected. Conclusion: We detected a low burden of contractile sarcomeric variants in LVNC patients presenting below the age of 18 years, with the major number of variants residing in non-contractile structural sarcomeric genes. The identification of the variants in ion-channel and related genes not previously associated with LVNC in paediatric patients requires further examination of their functional role.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic Spectrum of Left Ventricular Non-Compaction in Paediatric Patients

et al. 2020

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“…NGS analysis to detect single‐nucleotide and copy‐number variants were performed as previously described, 12 using a specific custom‐designed panel of 54 genes (Table S1). Paired‐end sequencing was performed on a 250 cycle Flow Cell (Illumina, Santa Cruz, CA) and the Illumina MiSeq platform.…”

Section: Methodsmentioning

confidence: 99%

A new congenital multicore titinopathy associated with fast myosin heavy chain deficiency

Perrin

Métay

Villanova³

et al. 2020

Ann Clin Transl Neurol

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Congenital titinopathies are myopathies with variable phenotypes and inheritance modes. Here, we fully characterized, using an integrated approach (deep phenotyping, muscle morphology, mRNA and protein evaluation in muscle biopsies), two siblings with congenital multicore myopathy harboring three TTN variants predicted to affect titin stability and titin-myosin interactions. Muscle biopsies showed multicores, type 1 fiber uniformity and sarcomeric structure disruption with some thick filament loss. Immunohistochemistry and Western blotting revealed a marked reduction of fast myosin heavy chain isoforms. This is the first observation of a titinopathy suggesting that titin defect leads to secondary loss of fast myosin heavy chain isoforms. 846

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“…While no enrichment occurred outside of the transmembrane region (p=0.87), a significant excess was observed for variants within the transmembrane region (3.3% vs 0.1%, p=4.8E-09). Of the HCN4 carriers described in the constituent studies of this meta-analysis, a patient with the p.Tyr481His variant initially presented with bradycardia (although this patient also had two other variants classified as pathogenic -FKTN:p.Tyr371Cys and RBM20:p.Tyr283Glnfs*14) 12 while 3/5 proband carriers of HCN4 variants in the French study were reported to have bradycardia, as did four carriers of the p.Gly480Cys variant in one family 13 (Table S7). In contrast, the Italian LVNC patient with the only non-transmembrane HCN4 variant detected in this study (p.Gly1077Ser) had a normal ECG, suggesting this variant is unlikely to be disease-causing.…”

Section: Variants In Arrhythmia-associated Genes -Ryr2 and Hcn4mentioning

confidence: 92%

The genetic architecture of left ventricular non-compaction reveals both substantial overlap with other cardiomyopathies and a distinct aetiology in a subset of cases

Mazzarotto

Hawley

Beltrami

et al. 2020

Preprint

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Background: Left ventricular non-compaction (LVNC) is a condition characterised by trabeculations in the myocardial wall and is the subject of considerable conjecture as to whether it represents a distinct pathology or a secondary phenotype associated with other cardiac diseases, particularly cardiomyopathies. We sought to investigate the genetic architecture of LVNC by identifying genes and variant classes robustly associated with disease and comparing these to other genetically characterised cardiomyopathies. Methods: We performed rare variant association analysis using six different LVNC cohorts comprising 840 cases together with 125,748 gnomAD population controls and compared results to similar analyses with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) cases. Results: We observed substantial overlap in genes and variant classes enriched in LVNC and DCM/HCM, indicating that in many cases LVNC belongs to a spectrum of more established cardiomyopathies, with non-compaction representing a phenotypic variation in patients with DCM- or HCM-causing variants. In contrast, five variant classes were uniquely enriched in LVNC cases, of which truncating variants in MYH7, ACTN2 and PRDM16 may represent a distinct LVNC aetiology. MYH7 truncating variants are generally considered as non-pathogenic but were detected in 2% of LVNC cases compared to 0.1% of controls, including a cluster of variants around a single splice region. Individuals with MYH7 truncating variants identified in the UK Biobank and cohorts of healthy volunteers also displayed significantly greater non-compaction compared to matched controls, with 50% meeting the diagnostic criteria for LVNC. Additionally, structural variants (exon deletions) in RYR2 and missense variants in the transmembrane region of HCN4 were enriched in LVNC cases, confirming prior reports regarding the association of these variant classes with combined LVNC and arrhythmia phenotypes. Conclusions: We demonstrated that genetic association analysis can clarify the relationship between LVNC and established cardiomyopathies, highlighted substantial overlap with DCM/HCM but also identified variant classes associated with distinct LVNC and with joint LVNC/arrhythmia phenotypes. These results underline the complex genetic landscape of LVNC and inform how genetic testing in LVNC cases should be pursued and interpreted.

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Targeted panel sequencing in adult patients with left ventricular non-compaction reveals a large genetic heterogeneity

Cited by 17 publications

References 13 publications

Genetic Spectrum of Left Ventricular Non-Compaction in Paediatric Patients

Genetic Spectrum of Left Ventricular Non-Compaction in Paediatric Patients

A new congenital multicore titinopathy associated with fast myosin heavy chain deficiency

The genetic architecture of left ventricular non-compaction reveals both substantial overlap with other cardiomyopathies and a distinct aetiology in a subset of cases

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