Clinical and genetic insights into non-compaction: a meta-analysis and systematic review on 7598 individuals

Kayvanpour, Elham; Sedaghat‐Hamedani, Farbod; Gi, Weng‐Tein; Tugrul, Oguz Firat; Amr, Ali; Haas, Jan; Zhu, Feng; Ehlermann, Philipp; Uhlmann, Lorenz; Katus, Hugo A.; Meder, Benjamin

doi:10.1007/s00392-019-01465-3

Cited by 67 publications

(57 citation statements)

References 78 publications

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“…Non-compaction cardiomyopathy can occur in isolation or in combination with various congenital heart diseases (e.g., ventricular septal defect, atrial septal defect, or pulmonary stenosis). Many gene loci have been identified that describe a combination of NCCM and other congenital heart diseases, such as hypoplastic left heart syndrome (Dystrobrevin alpha) or Ebstein anomaly (MYH7) [50]. Genetic variants that can be found code for sarcomeric proteins, nuclear envelope and Z-band components, as well as sarcolemma protein and ion channels [51].…”

Section: Left Ventricular Non-compaction Cardiomyopathymentioning

confidence: 99%

Dilated cardiomyopathies and non-compaction cardiomyopathy

Hänselmann

Veltmann

Bauersachs

et al. 2020

Herz

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Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy and one of the most common causes of heart failure. It is characterized by left or biventricular dilation and a reduced systolic function. The causes are manifold and range from myocarditis to alcohol and other toxins, to rheumatological, endocrinological, and metabolic diseases. Peripartum cardiomyopathy is a special form that occurs at the end of or shortly after pregnancy. Genetic mutations can be detected in approximately 30-50% of DCM patients. Owing to the growing possibilities of genetic diagnostics, increasingly more triggering variants and hereditary mechanisms emerge.

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Section: Left Ventricular Non-compaction Cardiomyopathymentioning

confidence: 99%

Dilated cardiomyopathies and non-compaction cardiomyopathy

Hänselmann

Veltmann

Bauersachs

et al. 2020

Herz

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“…The incidence of CHD in LVNC patients caused by NONO mutations seems to be significantly higher than its incidence in overall LVNC patients (Oechslin and Jenni, 2018;Richard et al, 2018;van Waning et al, 2018van Waning et al, , 2019aKayvanpour et al, 2019). In addition, LVNC is diagnosed early in all patients with NONO mutations: five in the prenatal period (Sun et al, 2020b), four in the neonatal period (Scott et al, 2016;Sewani et al, 2019), two in infancy (Reinstein et al, 2016;Carlston et al, 2019), and one at the age of 4 (Sewani et al, 2019), indicating that LVNC is an early diagnostic clue for MRXS34.…”

Section: Discussionmentioning

confidence: 92%

Case Report: Characterization of a Novel NONO Intronic Mutation in a Fetus With X-Linked Syndromic Mental Retardation-34

et al. 2020

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Background The NONO gene is located on chromosome Xq13.1 and encodes a nuclear protein involved in RNA synthesis, transcriptional regulation, and DNA repair. Hemizygous variants in NONO have been reported to cause mental retardation, X-linked, syndromic 34 (MRXS34) in males. Due to the scarcity of clinical reports, the clinical characteristics and mutation spectrum of NONO-related disorder have not been entirely determined. Methods We reported a fetus with hypoplastic left heart syndrome, performed a comprehensive genotyping examination, including copy-number variation sequencing and whole-exome sequencing, and screened for the genetic abnormality. We also conducted an in vitro mini-gene splicing assay to demonstrate the predicted deleterious effects of an intronic variant of NONO. Results Exome sequencing identified a novel intronic variant (c.154 + 9A > G) in intron 4 of the NONO gene (NM_001145408.1). It was predicted to insert 4 bp of intron 4 into the mature mRNA. Minigene assay revealed that the c.154 + 9A > G variant caused the activation of the intronic cryptic splice site and 4 bp insertion (c.154_155ins GTGT) in mature mRNA. Literature review shows that cardiac phenotype, including left ventricular non-compaction cardiomyopathy and congenital heart disease, are consistent features of MRXS34. Conclusion This study enlarges the mutation spectrum of NONO, further expands hypoplastic left heart syndrome to the phenotype of MRXS34 and points out the importance of intronic sequence analysis and the need for integrative functional studies in the interpretation of sequence variants.

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“…In adult cohorts, sarcomeric genes are the major disease genes for HCM (>70%), DCM (14%, 35%, or 37%), and LVNC (26% or 29%) . In all CMP subgroups, patients carried most frequently VOI in sarcomere genes suggesting them as major contributor in pediatric CMP as previously shown in meta‐analyses for adult‐onset CMP . A detailed genotype‐phenotype correlation was not intended in this study of index‐patients due to the composition and small size of the subgroups per CMP.…”

Section: Discussionmentioning

confidence: 95%

“…30,31 In all CMP subgroups, patients carried most frequently VOI in sarcomere genes suggesting them as major contributor in pediatric CMP as previously shown in meta-analyses for adult-onset CMP. 32,33 A detailed genotype-phenotype correlation was not intended in this study of index-patients due to the composition and small size of the This suggests a link of TTN truncation with pediatric RCM, potentially in combination with a more complex genetic alteration, and a critical importance of both TTN alleles for postnatal development. 24 In line with our observations, other studies showed that in children with DCM, the frequency of truncating TTN variants is much lower compared to adults.…”

Section: Left Ventricular Non-compactionmentioning

confidence: 99%

Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3

et al. 2019

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The underlying genetic mechanisms and early pathological events of children with primary cardiomyopathy (CMP) are insufficiently characterized. In this study, we aimed to characterize the mutational spectrum of primary CMP in a large cohort of patients ≤18 years referred to a tertiary center. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel‐based next‐generation sequencing approach of 89 genes. At least one pathogenic or probably pathogenic variant was identified in 30/80 (38%) index patients. In all CMP subgroups, patients carried most frequently variants of interest in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. In MYH7, MYBPC3, and TNNI3, we identified 18 pathogenic/probably pathogenic variants (MYH7 n = 7, MYBPC3 n = 6, TNNI3 n = 5, including one homozygous (TNNI3 c.24+2T>A) truncating variant. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of TNNI3 revealed that the TNNI3 protein is absent and associated with upregulation of the fetal isoform TNNI1. The present study further supports the clinical importance of sarcomeric mutation—not only in adult—but also in pediatric primary CMP. TNNI3 is the third most important disease gene in this cohort and complete loss of TNNI3 leads to severe pediatric CMP.

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Clinical and genetic insights into non-compaction: a meta-analysis and systematic review on 7598 individuals

Cited by 67 publications

References 78 publications

Dilated cardiomyopathies and non-compaction cardiomyopathy

Dilated cardiomyopathies and non-compaction cardiomyopathy

Case Report: Characterization of a Novel NONO Intronic Mutation in a Fetus With X-Linked Syndromic Mental Retardation-34

Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3

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