A novel de novo <i>CASZ1</i> heterozygous frameshift variant causes dilated cardiomyopathy and left ventricular noncompaction cardiomyopathy

Guo, Jun; Li, Zheng; Hao, Chanjuan; Guo, Ruolan; Hu, Xuyun; Qian, Suyun; Jing, Zeng; Gao, Hengmiao; Li, Wei

doi:10.1002/mgg3.828

Cited by 19 publications

(18 citation statements)

References 22 publications

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“…Trio WES of the two probands and their parents was performed as previously described 10 . In brief, DNA was isolated from 200 μL blood samples from the two probands and their family members, using a QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…Trio WES of the two probands and their parents was performed as previously described. 10 In brief, DNA was isolated from 200 μL blood samples from the two probands and their family members, using a QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany). Exon capture was performed using the Agilent SureSelect Human All Exome V6 kit (Agilent Technologies Inc., Santa Clara, CA, USA).…”

Section: Sequencingmentioning

confidence: 99%

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Whole‐exome sequencing reveals two de novo variants in the RBM20 gene in two Chinese patients with left ventricular non‐compaction cardiomyopathy

Sun

Guo

Hao

et al. 2020

Pediatric Investigation

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Importance Pathogenic variants in the RBM20 gene are associated with aggressive dilated cardiomyopathy (DCM). Recently, RBM20 was found to be associated with left ventricular non‐compaction cardiomyopathy (LVNC). Thus far, only five families with LVNC have been reported to carry variants in RBM20. It remains unknown whether the variants in RBM20 associated with DCM can also cause LVNC. Objective To elucidate the causative RBM20 variant in two unrelated patients with both LVNC and DCM, and to identify the clinical characteristics associated with variants in RBM20. Methods Trio whole‐exome sequencing (WES) was performed. Variants were filtered and classified in accordance with the guidelines of the American College of Medical Genetics and Genomics (ACMG). Results We identified two distinct de novo variants in RBM20 (one per patient) in these two patients with LVNC. Both variants have been reported in patients with DCM, without the LVNC phenotype. Patient 1 was an 11‐year‐old girl who had DCM, LVNC, and heart failure; the ratio of noncompacted‐to‐compacted myocardium was 2.7:1. A de novo heterozygous variant c.1907G>A (p.Arg636His) in exon 9 was identified in this patient. Patient 2 was a 13‐year‐old boy who had clinical phenotypes identical to those of Patient 1; the ratio of noncompacted‐to‐compacted myocardium was 3.2:1 in this patient. WES revealed a de novo heterozygous variant c.1909A>G (p.Ser637Gly) in exon 9. Both variants were previously characterized as pathogenic, and our study classified them as pathogenic variants based on the ACMG guidelines. Interpretation We found that two patients with LVNC had variants in RBM20. Our results extended the clinical spectrum of the two RBM20 variants and illustrated that the same variant in RBM20 can cause DCM, with or without the LVNC phenotype.

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Section: Methodsmentioning

confidence: 99%

Section: Sequencingmentioning

confidence: 99%

Whole‐exome sequencing reveals two de novo variants in the RBM20 gene in two Chinese patients with left ventricular non‐compaction cardiomyopathy

Sun

Guo

Hao

et al. 2020

Pediatric Investigation

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“…Perhaps the most intriguing feature is that the prevalence of the CHDs remains the same notwithstanding the decrease in reproductive potential of the patients with CHDs [52,53], suggesting that the mutations might not be inherited but rather de novo [54,55]. Evolutionarily, we would expect the prevalence of CHDs to be decreasing as the negative selection could have removed the inherited mutation.…”

Section: Introductionmentioning

confidence: 99%

Congenital heart diseases: genetics, non-inherited risk factors, and signaling pathways

Suluba

Liu

Xia

et al. 2020

Egypt J Med Hum Genet

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Background: Congenital heart diseases (CHDs) are the most common congenital anomalies with an estimated prevalence of 8 in 1000 live births. CHDs occur as a result of abnormal embryogenesis of the heart. Congenital heart diseases are associated with significant mortality and morbidity. The damage of the heart is irreversible due to a lack of regeneration potential, and usually, the patients may require surgical intervention. Studying the developmental biology of the heart is essential not only in understanding the mechanisms and pathogenesis of congenital heart diseases but also in providing us with insight towards developing new preventive and treatment methods. Main body: The etiology of congenital heart diseases is still elusive. Both genetic and environmental factors have been implicated to play a role in the pathogenesis of the diseases. Recently, cardiac transcription factors, cardiacspecific genes, and signaling pathways, which are responsible for early cardiac morphogenesis have been extensively studied in both human and animal experiments but leave much to be desired. The discovery of novel genetic methods such as next generation sequencing and chromosomal microarrays have led to further study the genes, non-coding RNAs and subtle chromosomal changes, elucidating their implications to the etiology of congenital heart diseases. Studies have also implicated non-hereditary risk factors such as rubella infection, teratogens, maternal age, diabetes mellitus, and abnormal hemodynamics in causing CHDs. These etiological factors raise questions on multifactorial etiology of CHDs. It is therefore important to endeavor in research based on finding the causes of CHDs. Finding causative factors will enable us to plan intervention strategies and mitigate the consequences associated with CHDs. This review, therefore, puts forward the genetic and non-genetic causes of congenital heart diseases. Besides, it discusses crucial signaling pathways which are involved in early cardiac morphogenesis. Consequently, we aim to consolidate our knowledge on multifactorial causes of CHDs so as to pave a way for further research regarding CHDs. Conclusion: The multifactorial etiology of congenital heart diseases gives us a challenge to explicitly establishing specific causative factors and therefore plan intervention strategies. More well-designed studies and the use of novel genetic technologies could be the way through the discovery of etiological factors implicated in the pathogenesis of congenital heart diseases.

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“…Other common mutations of genes encoding cytoskeletal, Z-line, and mitochondrial proteins include myosin heavy chain ( MYH7 ), protein-binding protein C myosin ( MYBPC3 ), tropomyosin alfa ( TPM1 ), myocardial actin ( ACTC1 ), troponin T ( TNNT2 ), and cardiac troponin I. The less common mutations of genes inducing LVNC include Z-band protein mutations, such as Cypher/ZASP cytoskeleton protein, alpha-distrobrevin ( DTNA ), calcium transport proteins, calsequestrin, phospholamban, membrane proteins (A/C lamina), para-zinc-finger transcription factor [ 8 ], and mitochondrial enzymes. Our study identifies a proband with rare overlap phenotypes of LVNC and HCM from a Chinese Han family and explores the potential pathogenesis via genetic screening and molecular experiments.…”

Section: Introductionmentioning

confidence: 99%

Overlap phenotypes of the left ventricular noncompaction and hypertrophic cardiomyopathy with complex arrhythmias and heart failure induced by the novel truncated DSC2 mutation

Lin

Huang

Zhu

et al. 2021

Orphanet J Rare Dis

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Background The left ventricular noncompaction cardiomyopathy (LVNC) is a rare subtype of cardiomyopathy associated with a high risk of heart failure (HF), thromboembolism, arrhythmia, and sudden cardiac death. Methods The proband with overlap phenotypes of LVNC and hypertrophic cardiomyopathy (HCM) complicates atrial fibrillation (AF), ventricular tachycardia (VT), and HF due to the diffuse myocardial lesion, which were diagnosed by electrocardiogram, echocardiogram and cardiac magnetic resonance imaging. Peripheral blood was collected from the proband and his relatives. DNA was extracted from the peripheral blood of proband for high-throughput target capture sequencing. The Sanger sequence verified the variants. The protein was extracted from the skin of the proband and healthy volunteer. The expression difference of desmocollin2 was detected by Western blot. Results The novel heterozygous truncated mutation (p.K47Rfs*2) of the DSC2 gene encoding an important component of desmosomes was detected by targeted capture sequencing. The western blots showed that the expressing level of functional desmocollin2 protein (~ 94kd) was lower in the proband than that in the healthy volunteer, indicating that DSC2 p.K47Rfs*2 obviously reduced the functional desmocollin2 protein expression in the proband. Conclusion The heterozygous DSC2 p.K47Rfs*2 remarkably and abnormally reduced the functional desmocollin2 expression, which may potentially induce the overlap phenotypes of LVNC and HCM, complicating AF, VT, and HF.

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A novel de novo CASZ1 heterozygous frameshift variant causes dilated cardiomyopathy and left ventricular noncompaction cardiomyopathy

Cited by 19 publications

References 22 publications

Whole‐exome sequencing reveals two de novo variants in the RBM20 gene in two Chinese patients with left ventricular non‐compaction cardiomyopathy

Whole‐exome sequencing reveals two de novo variants in the RBM20 gene in two Chinese patients with left ventricular non‐compaction cardiomyopathy

Congenital heart diseases: genetics, non-inherited risk factors, and signaling pathways

Overlap phenotypes of the left ventricular noncompaction and hypertrophic cardiomyopathy with complex arrhythmias and heart failure induced by the novel truncated DSC2 mutation

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