Genetic architecture of left ventricular noncompaction in adults

AbstractThe genetic etiology and heritability of left ventricular noncompaction (LVNC) in adults is unclear. This study sought to assess the value of genetic testing in adults with LVNC. Adults diagnosed with LVNC while undergoing screening in the context of a family history of cardiomyopathy were excluded. Clinical data for 35 unrelated patients diagnosed with LVNC at ≥18 years of age were retrospectively analyzed. Left ventricular (LV) dysfunction, electrocardiogram (ECG) abnormalities, cardiac malformations or syndromic features were identified in 25 patients; 10 patients had isolated LVNC in the absence of cardiac dysfunction or syndromic features. Exome sequencing was performed, and analysis using commercial panels targeted 193 nuclear and mitochondrial genes. Nucleotide variants in coding regions or in intron-exon boundaries with predicted impacts on splicing were assessed. Fifty-four rare variants were identified in 35 nuclear genes. Across all 35 LVNC patients, the clinically meaningful genetic diagnostic yield was 9% (3/35), with heterozygous likely pathogenic or pathogenic variants identified in the NKX2-5 and TBX5 genes encoding cardiac transcription factors. No pathogenic variants were identified in patients with isolated LVNC in the absence of cardiac dysfunction or syndromic features. In conclusion, the diagnostic yield of genetic testing in adult index patients with LVNC is low. Genetic testing is most beneficial in LVNC associated with other cardiac and syndromic features, in which it can facilitate correct diagnoses, and least useful in adults with only isolated LVNC without a family history. Cardiac transcription factors are important in the development of LVNC and should be included in genetic testing panels.

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Spectrum of Clinical Features and Genetic Profile of Left Ventricular Noncompaction Cardiomyopathy in Children

Cardiogenetics ◽

10.3390/cardiogenetics11040020 ◽

2021 ◽

Vol 11 (4) ◽

pp. 191-203

Author(s):

Agata Paszkowska ◽

Alicja Mirecka-Rola ◽

Dorota Piekutowska-Abramczuk ◽

Elżbieta Ciara ◽

Łukasz Mazurkiewicz ◽

...

Keyword(s):

Heart Failure ◽

Family History ◽

Clinical Symptoms ◽

Sinus Bradycardia ◽

Left Ventricular ◽

Genetic Profile ◽

Left Ventricular Noncompaction ◽

Genetic Syndromes ◽

Ventricular Noncompaction ◽

Characteristic Features

Background: Left ventricular noncompaction (LVNC) is a genetically determined cardiomyopathy that occurs following a disruption of endomyocardial morphogenesis. The purpose of this study was to identify the clinical characteristics and genetic profile of children with LVNC. Methods: From February 2008 to July 2020, a total of 32 children (median 11.5 years) with LVNC were prospectively enrolled and followed up for a median of 4.02 years. Diagnosis was made based on characteristic features of LVNC in echocardiography and cardiovascular magnetic resonance (CMR). Patients’ clinical symptoms, family history, ECG, Holter ECG, and genetic tests were also evaluated. Results: The most common presenting symptom was heart failure (31% of children). ECG abnormalities were noted in 56% of patients. The most prominent features were ventricular arrhythmias, sinus bradycardia, and paroxysmal third-degree atrioventricular block. Most of the patients (94%) met the criteria for LVNC and CMR confirmed this diagnosis in 82% of cases. The molecular etiology was found in 53% of children. Conclusion: Although heart failure and arrhythmias were very frequent in our study group, thromboembolic events and genetic syndromes were rare. For the accurate and reliable assessment of children with LVNC, it is necessary to get to know their family history and detailed clinical profile.

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P2250Role of family screening and genetic testing in left ventricular noncompaction

European Heart Journal ◽

10.1093/eurheartj/ehy565.p2250 ◽

2018 ◽

Vol 39 (suppl_1) ◽

Author(s):

G Casas ◽

G Oristrell ◽

J Rodriguez-Palomares ◽

M Borregan ◽

J Limeres ◽

...

Keyword(s):

Genetic Testing ◽

Left Ventricular ◽

Left Ventricular Noncompaction ◽

Ventricular Noncompaction ◽

Family Screening

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Increased Burden of Ion Channel Gene Variants Is Related to Distinct Phenotypes in Pediatric Patients With Left Ventricular Noncompaction

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.119.002940 ◽

2020 ◽

Vol 13 (4) ◽

Author(s):

Keiichi Hirono ◽

Yukiko Hata ◽

Nariaki Miyao ◽

Mako Okabe ◽

Shinya Takarada ◽

...

Keyword(s):

Ventricular Tachycardia ◽

Ion Channel ◽

Left Ventricular ◽

Gene Variants ◽

Left Ventricular Noncompaction ◽

Ventricular Noncompaction ◽

Channel Gene ◽

Pathogenic Variants ◽

Generation Sequencing ◽

Ion Channel Gene

Background: Left ventricular noncompaction (LVNC) is a hereditary type of cardiomyopathy. Although it is associated with high morbidity and mortality, the related ion channel gene variants in children have not been fully investigated. This study aimed to elucidate the ion channel genetic landscape of LVNC and identify genotype-phenotype correlations in a large Japanese cohort. Methods: We enrolled 206 children with LVNC from 2002 to 2017 in Japan. LVNC was classified as follows: LVNC with congenital heart defects, arrhythmia, dilated phenotype, or normal function. In the enrolled patients, 182 genes associated with cardiomyopathy were screened using next-generation sequencing. Results: We identified 99 pathogenic variants in 40 genes in 87 patients. Of the pathogenic variants, 8.8% were in genes associated with channelopathies, 27% were in sarcomere genes, and 11.5% were in mitochondrial genes. Ion channel gene variants were mostly associated with the arrhythmia classification, whereas sarcomere and mitochondrial gene variants were associated with the dilated phenotype. Echocardiography revealed that the group with ion channel gene variants had almost normal LV ejection fraction and LV diastolic diameter Z scores. Fragmented QRS, old age, and an arrhythmia phenotype were the most significant risk factors for ventricular tachycardia ( P =0.165, 0.0428, and 0.0074, respectively). Moreover, the group with ion channel variants exhibited a greater risk of a higher prevalence of arrhythmias such as ventricular tachycardia, rather than congestive heart failure. Conclusions: This is the first study that focused on genotype-phenotype correlations in a large pediatric LVNC patient cohort with ion channel gene variants that were determined using next-generation sequencing. Ion channel gene variants were strongly correlated with arrhythmia phenotypes. Genetic testing and phenotype specification allow for appropriate medical management of specific LVNC targets.

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Genetic Testing in Pediatric Left Ventricular Noncompaction

Circulation Cardiovascular Genetics ◽

10.1161/circgenetics.117.001735 ◽

2017 ◽

Vol 10 (6) ◽

Cited By ~ 25

Author(s):

Erin M. Miller ◽

Robert B. Hinton ◽

Richard Czosek ◽

Angela Lorts ◽

Ashley Parrott ◽

...

Keyword(s):

Genetic Testing ◽

Left Ventricular ◽

Left Ventricular Noncompaction ◽

Ventricular Noncompaction

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Diagnostic Yield of Genetic Testing in Sudden Cardiac Death with Autopsy Findings of Uncertain Significance

Journal of Clinical Medicine ◽

10.3390/jcm10091806 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1806

Author(s):

Mercedes Iglesias ◽

Tomas Ripoll-Vera ◽

Consuelo Perez-Luengo ◽

Ana Belen García ◽

Susana Moyano ◽

...

Keyword(s):

Genetic Testing ◽

Ventricular Hypertrophy ◽

Diagnostic Yield ◽

Left Ventricular ◽

Molecular Autopsy ◽

Variants Of Unknown Significance ◽

Pathogenic Variants ◽

Unknown Significance ◽

Uncertain Significance ◽

Frequent Variant

Background: Sudden death (SD) in the young usually has an underlying genetic cause. In many cases, autopsy reveals unspecific and inconclusive results, like idiopathic left ventricular hypertrophy (LVH), nonsignificant coronary atherosclerosis (CA), and primary myocardial fibrosis (PMF). Their pathogenicity and their relation to SD cause is unknown. This study aims to evaluate the diagnostic yield of genetic testing in these cases. Methods: SD cases, between 1 and 50 years old, with findings of uncertain significance (idiopathic LVH, nonsignificant CA and PMF) on autopsy were evaluated prospectively, including information about medical and family history and circumstances of death. Genetic testing was performed. Results: In a series of 195 SD cases, we selected 31 cases presenting idiopathic LVH (n = 16, 51.61%), nonsignificant CA (n = 17, 54.84%), and/or PMF (n = 24, 77.42%) in the autopsy. Mean age was 41 ± 7.2 years. Diagnostic yield of genetic test was 67.74%, considering variants of unknown significance (VUS), pathogenic variants (PV) and likely pathogenic variants (LPV); 6.45% including only PV and LPV. Structural genes represented 41,93% (n = 13) of cases, while 38,7% (n = 12) were related to channelopathies. Conclusion: Molecular autopsy in SD cases between 1 and 50 years old, with findings of uncertain significance, has a low diagnostic yield, being VUS the most frequent variant observed.

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Spectrum of Clinical Features and Genetic Profile of Left Ventricular Noncompaction Cardiomyopathy in Children

10.20944/preprints202106.0276.v1 ◽

2021 ◽

Author(s):

Agata Paszkowska ◽

Alicja Mirecka-Rola ◽

Dorota Piekutowska-Abramczuk ◽

Elżbieta Ciara ◽

Łukasz Mazurkiewicz ◽

...

Keyword(s):

Heart Failure ◽

Family History ◽

Clinical Symptoms ◽

Sinus Bradycardia ◽

Left Ventricular ◽

Genetic Profile ◽

Left Ventricular Noncompaction ◽

Genetic Syndromes ◽

Ventricular Noncompaction ◽

Characteristic Features

Background: Left ventricular noncompaction (LVNC) is a genetically determined cardiomyopathy, that occurs following a disruption of endomyocardial morphogenesis. The purpose of this study was to identify the clinical characteristics and genetic profile of children with LVNC. Methods: From February 2008 to July 2020, a total of 32 children (median 11.5 years) with LVNC were prospectively enrolled and followed up for the median of 4.02 years. Diagnosis was made based on characteristic features of LVNC in echocardiography and cardiovascular magnetic resonance (CMR). Patients’ clinical symptoms, family history, ECG, Holter ECG and genetic tests were also evaluated. Results: The most common presenting symptom was heart failure (31% of children). ECG abnormalities were noted in 56% of patients. The most prominent features were ventricular arrhythmias, sinus bradycardia and paroxysmal third-degree atrioventricular block. Most of the patients (94%) met the criteria for LVNC and CMR confirmed this diagnosis in 82% of cases. The molecular etiology was found in 53% of children. Conclusion: Although heart failure and arrhythmias were very frequent in our study group, thromboembolic events and genetic syndromes were rare. For accurate and reliable assessment of children with LVNC, it is necessary to get to know their family history and detailed clinical profile.

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Abstract 17212: Whole Exome Sequencing Identifies Novel Genetic Variants in Left Ventricular Noncompaction Cardiomyopathy

Circulation ◽

10.1161/circ.138.suppl_1.17212 ◽

2018 ◽

Vol 138 (Suppl_1) ◽

Author(s):

John Collyer ◽

Fuyi Xu ◽

Undral Munkhsaikhan ◽

Wenying Zhang ◽

Lu Lu ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Left Ventricular ◽

Left Ventricular Noncompaction ◽

Ventricular Noncompaction ◽

Pathogenic Variants ◽

Whole Exome ◽

History Of ◽

Left Ventricular Noncompaction Cardiomyopathy ◽

Genotype Correlation

Introduction: Causal and modifier genes associated with left ventricular noncompaction (LVNC) often occurring in conjunction with other familial cardiomyopathies remain elusive. Hypothesis: The LVNC-associated di- and multigenic abnormalities can be identified by whole exome sequencing (WES). Methods: Five families with a history of LVNC, including five affected probands, three affected family members, and twelve unaffected relatives, were studied. Genomic DNA was extracted from whole blood samples followed by WES and Sanger sequencing to confirm possibly pathogenic variants predicted by in-silico analysis. Phenotype-genotype correlation and quantitative co-segregation studies are performed. Results: We identified nine missense possibly pathogenic variants, a 2-bp frameshift insertion, and a 9-bp in-frame insertion in the five families. Two affected siblings in Family 1 were found carrying digenic heterozygous variants: c.4048G>A (p.E1350K) in MYH7 and c.827C>T (p.A276V) in ANKRD1. Unaffected parents were carriers for each of the two variants. Three affected members, father and two daughters, of Family 2 carried c.550A>C (p.K184Q) variant in MYH7 in contrast to two unaffected members, mother and another daughter. In Family 3, multigenic heterozygosity (c.673G>T (p.D225Y) in CACNA2D1 ; c.440T>A (p.V147E) in COQ4 and c.3700C>A (p.H1234N) in MYH7) was identified in the proband. These variants were found in none of three unaffected relatives. The proband of Family 4 was positive for heterozygous variants: c.2684_2685insAG (p.A897Kfs*3) in DSC2 , c.8633T>C (p.V2878A) in OBSCN , and c.11717C >T (p.T3906I) in PLEC. The T3906I PLEC variant was identified in his unaffected half-sibling and his father, but not in his mother. In Family 5, c. 2591A>T (p.D864V) in HDAC9 , c.9616C>T (p.R3206W) in PLEC and c.954_955insT (p.L319Sfs*74) in MYH14 were identified in the proband. None of those variants were identified in his unaffected sibling. Conclusions: We report several potential pathogenic LVNC-associated variants in novel genes (ANKRD1, DSC2, OBSCN , PLEC, HDAC9, MYH14, COQ4, CACNA2D1) and known genes ( MYH7 and MYH7B). The diverse profile of inheritance (digenic and multigenic heterogeneity) that may cause and modify the heterogeneous LVNC phenotypes.

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Reduced Systolic Function and Not Genetic Variants Determine Outcome in Pediatric and Adult Left Ventricular Noncompaction Cardiomyopathy

Frontiers in Pediatrics ◽

10.3389/fped.2021.722926 ◽

2021 ◽

Vol 9 ◽

Author(s):

Alina Schultze-Berndt ◽

Jirko Kühnisch ◽

Christopher Herbst ◽

Franziska Seidel ◽

Nadya Al-Wakeel-Marquard ◽

...

Keyword(s):

Multivariate Analysis ◽

Genetic Variants ◽

Systolic Function ◽

Left Ventricular ◽

Left Ventricular Noncompaction ◽

Ventricular Noncompaction ◽

Noncompaction Cardiomyopathy ◽

Pathogenic Variants ◽

Lv Systolic Function ◽

Left Ventricular Noncompaction Cardiomyopathy

Background: Left ventricular noncompaction cardiomyopathy (LVNC CMP) is a genetic cardiomyopathy. Genotype-phenotype correlation and clinical outcome of genetic variants in pediatric and adult LVNC CMP patients are still unclear.Methods: The retrospective multicenter study was conducted in unrelated index patients with LVNC CMP, diagnosed between the years 1987 and 2017, and all available family members. All index patients underwent next-generation sequencing for genetic variants in 174 target genes using the Illumina TruSight Cardio Sequencing Panel. Major adverse cardiac events (MACE) included mechanical circulatory support, heart transplantation, survivor of cardiac death, and/or all-cause death as combined endpoint.Results: Study population included 149 LVNC CMP patients with a median age of 27.8 (9.2–44.8) years at diagnosis; 58% of them were symptomatic, 18% suffered from non-sustained and sustained arrhythmias, and 17% had an implantable cardioverter defibrillator (ICD) implanted. 55/137 patients (40%) were ≤ 18 years at diagnosis.A total of 134 variants were identified in 87/113 (77%) index patients. 93 variants were classified as variant of unknown significance (VUS), 24 as likely pathogenic and 15 as pathogenic. The genetic yield of (likely) pathogenic variants was 35/113 (31%) index patients. Variants occurred most frequently in MYH7 (n=19), TTN (n = 10) and MYBPC3 (n = 8). Altogether, sarcomere gene variants constituted 42.5% (n = 57) of all variants. The presence or absence of (likely) pathogenic variants or variants in specific genes did not allow risk stratification for MACE.Reduced left ventricular (LV) systolic function and increased left ventricular end-diastolic diameter (LVEDD) were risk factors for event-free survival in the Kaplan-Meier analysis. Through multivariate analysis we identified reduced LV systolic function as the main risk factor for MACE. Patients with reduced LV systolic function were at a 4.6-fold higher risk for MACE.Conclusions: Genetic variants did not predict the risk of developing a MACE, neither in the pediatric nor in the adult cohort. Multivariate analysis emphasized reduced LV systolic function as the main independent factor that is elevating the risk for MACE. Genetic screening is useful for cascade screening to identify family members at risk for developing LVNC CMP.

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