scholarly journals Identification of a nonsense mutation in TNNI3K associated with cardiac conduction disease and dilated cardiomyopathy

2019 ◽  
Author(s):  
Jiang Liu ◽  
Da Liu ◽  
Muzheng Li ◽  
Keke Wu ◽  
Na Liu ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Dilated Cardiomyopathy ◽  
Nonsense Mutation ◽  
Underlying Disease ◽  
Cardiac Conduction ◽  
Chinese Family ◽  
Loss Of Function ◽  
Life Threatening ◽  
Next Generation Sequencing Ngs ◽  
Autosomal Dominant Inheritance Pattern

Abstract Background Cardiac conduction disease(CCD) and dilated cardiomyopathy(DCM) are two common cardiovascular diseases which can lead to life-threatening conditions. The importance of heredity in these two diseases has been realized in recent years. Several casual genes have been found to be implicated in CCD and DCM such as LMNA,SCN5A,TTN,TNNI3K and so on. Rare genetic mutations in TNNI3K have been identified to be in connection with CCD and DCM.Methods Next generation sequencing(NGS) was carried out in order to identify the underlying disease-causing mutation in a Chinese family with CCD and DCM. The mutations were validated by Sanger sequencing.Results A nonsense mutation in TNNI3K(NM_015978.2: g.170891C>T,c.1441C>T) was identified in this family and validated by Sanger sequencing.Conclusions This study described a Chinese family with CCD and DCM caused by a nonsense TNNI3K mutation.TNNI3K harboring the mutation(c.1441C>T) possibly implicated a loss-of-function pathogenic mechanism with an autosomal dominant inheritance pattern. This research enriches the phenotypic spectrum of TNNI3K mutations, casting a new light upon the genotype-phenotype correlations between TNNI3K mutations and cardiovascular diseases.

scholarly journals Clinical Implications of the Genetic Architecture of Dilated Cardiomyopathy

2020 ◽  
Vol 22 (12) ◽  
Author(s):  
Lisa D. Wilsbacher
Keyword(s):  
Genetic Testing ◽  
Dilated Cardiomyopathy ◽  
Ventricular Arrhythmias ◽  
Genetic Architecture ◽  
Genetic Diagnosis ◽  
Clinical Approach ◽  
Loss Of Function ◽  
Increase Risk ◽  
Life Threatening ◽  
New Evidence

Abstract Purpose of Review Dilated cardiomyopathy (DCM) frequently involves an underlying genetic etiology, but the clinical approach for genetic diagnosis and application of results in clinical practice can be complex. Recent Findings International sequence databases described the landscape of genetic variability across populations, which informed guidelines for the interpretation of DCM gene variants. New evidence indicates that loss-of-function mutations in filamin C (FLNC) contribute to DCM and portend high risk of ventricular arrhythmia. Summary A clinical framework aids in referring patients for DCM genetic testing and applying results to patient care. Results of genetic testing can change medical management, particularly in a subset of genes that increase risk for life-threatening ventricular arrhythmias, and can influence decisions for defibrillator therapy. Clinical screening and cascade genetic testing of family members should be diligently pursued to identify those at risk of developing DCM.

scholarly journals Jervell and Lange-Nielsen Syndrome due to a Novel Compound Heterozygous KCNQ1 Mutation in a Chinese Family

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Yue Qiu ◽  
Sen Chen ◽  
Xia Wu ◽  
Wen-Juan Zhang ◽  
Wen Xie ◽  
...  
Keyword(s):  
Deaf Child ◽  
Gene Mutations ◽  
Deaf Children ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Qtc Interval ◽  
Cardiac Events ◽  
Life Threatening ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Jervell and Lange-Nielsen syndrome (JLNS) is a rare but severe autosomal recessive disease characterized by profound congenital deafness and a prolonged QTc interval (greater than 500 milliseconds) in the ECG waveforms. The prevalence of JLNS is about 1/1000000 to 1/200000 around the world. However, exceed 25% of JLNS patients suffered sudden cardiac death with kinds of triggers containing anesthesia. Approximately 90% of JLNS cases are caused by KCNQ1 gene mutations. Here, using next-generation sequencing (NGS), we identified a compound heterozygosity for two mutations c.1741A>T (novel) and c.477+5G>A (known) in KCNQ1 gene as the possible pathogenic cause of JLNS, which suggested a high risk of cardiac events in a deaf child. The hearing of this patient improved significantly with the help of cochlear implantation (CI). But life-threatening arrhythmias occurred with a trigger of anesthesia after the end of the CI surgery. Our findings extend the KCNQ1 gene mutation spectrum and contribute to the management of deaf children diagnosed with JLNS for otolaryngologists (especially cochlear implant teams).

scholarly journals A NOTCH3 homozygous nonsense mutation in familial Sneddon syndrome with pediatric stroke

2020 ◽  
Author(s):  
Elli Katharine Greisenegger ◽  
Sara Llufriu ◽  
Angel Chamorro ◽  
Alvaro Cervera ◽  
Adriano Jimenez-Escrig ◽  
...  
Keyword(s):  
Nonsense Mutation ◽  
Underlying Disease ◽  
Allelic Loss ◽  
Pediatric Stroke ◽  
Loss Of Function ◽  
Whole Exome ◽  
Epidermal Growth ◽  
Epidermal Growth Factor Repeat ◽  
Homozygous Nonsense Mutation ◽  
Sneddon Syndrome

Abstract Sneddon syndrome is a rare disorder affecting small and medium-sized blood vessels that is characterized by the association of livedo reticularis and stroke. We performed whole-exome sequencing (WES) in 2 affected siblings of a consanguineous family with childhood-onset stroke and identified a homozygous nonsense mutation within the epidermal growth factor repeat (EGFr) 19 of NOTCH3, p.(Arg735Ter). WES of 6 additional cases with adult-onset stroke revealed 2 patients carrying heterozygous loss-of-function variants in putative NOTCH3 downstream genes, ANGPTL4, and PALLD. Our findings suggest that impaired NOTCH3 signaling is one underlying disease mechanism and that bi-allelic loss-of-function mutation in NOTCH3 is a cause of familial Sneddon syndrome with pediatric stroke.

Detection and functional characterization of a novel MEF2A variation responsible for familial dilated cardiomyopathy

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Qi Qiao ◽  
Cui-Mei Zhao ◽  
Chen-Xi Yang ◽  
Jia-Ning Gu ◽  
Yu-Han Guo ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Dilated Cardiomyopathy ◽  
Sanger Sequencing ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Functional Characterization ◽  
Luciferase Assay ◽  
Chinese Family ◽  
Sequencing Analysis ◽  
Loss Of Function

AbstractObjectivesDilated cardiomyopathy (DCM) represents the most frequent form of cardiomyopathy, leading to heart failure, cardiac arrhythmias and death. Accumulating evidence convincingly demonstrates the crucial role of genetic defects in the pathogenesis of DCM, and over 100 culprit genes have been implicated with DCM. However, DCM is of substantial genetic heterogeneity, and the genetic determinants underpinning DCM remain largely elusive.MethodsWhole-exome sequencing and bioinformatical analyses were implemented in a consanguineous Chinese family with DCM. A total of 380 clinically annotated control individuals and 166 more DCM index cases then underwent Sanger sequencing analysis for the identified genetic variation. The functional characteristics of the variant were delineated by utilizing a dual-luciferase assay system.ResultsA heterozygous variation in the MEF2A gene (encoding myocyte enhancer factor 2A, a transcription factor pivotal for embryonic cardiogenesis and postnatal cardiac adaptation), NM_001365204.1: c.718G>T; p. (Gly240*), was identified, and verified by Sanger sequencing to segregate with autosome-dominant DCM in the family with complete penetrance. The nonsense variation was neither detected in 760 control chromosomes nor found in 166 more DCM probands. Functional analyses revealed that the variant lost transactivation on the validated target genes MYH6 and FHL2, both causally linked to DCM. Furthermore, the variation nullified the synergistic activation between MEF2A and GATA4, another key transcription factor involved in DCM.ConclusionsThe findings firstly indicate that MEF2A loss-of-function variation predisposes to DCM in humans, providing novel insight into the molecular mechanisms of DCM and suggesting potential implications for genetic testing and prognostic evaluation of DCM patients.

scholarly journals Identification of SCN5a p.C335R Variant in a Large Family with Dilated Cardiomyopathy and Conduction Disease

2021 ◽  
Vol 22 (23) ◽  
pp. 12990
Author(s):  
Farbod Sedaghat-Hamedani ◽  
Sabine Rebs ◽  
Ibrahim El-Battrawy ◽  
Safak Chasan ◽  
Tobias Krause ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Xenopus Oocytes ◽  
Family Members ◽  
Large Family ◽  
Left Ventricular ◽  
Cardiac Conduction ◽  
Left Ventricular Ejection ◽  
Na Channel ◽  
Loss Of Function ◽  
Induced Pluripotent

Familial dilated cardiomyopathy (DCM) is clinically variable and has been associated with mutations in more than 50 genes. Rapid improvements in DNA sequencing have led to the identification of diverse rare variants with unknown significance (VUS), which underlines the importance of functional analyses. In this study, by investigating human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we evaluated the pathogenicity of the p.C335R sodium voltage-gated channel alpha subunit 5 (SCN5a) variant in a large family with familial DCM and conduction disease. Methods: A four-generation family with autosomal dominant familial DCM was investigated. Next-generation sequencing (NGS) was performed in all 16 family members. Clinical deep phenotyping, including endomyocardial biopsy, was performed. Skin biopsies from two patients and one healthy family member were used to generate human-induced pluripotent stem cells (iPSCs), which were then differentiated into cardiomyocytes. Patch-clamp analysis with Xenopus oocytes and iPSC-CMs were performed. Results: A SCN5a variant (c.1003T>C; p.C335R) could be detected in all family members with DCM or conduction disease. A novel truncating TTN variant (p.Ser24998LysfsTer28) could also be identified in two family members with DCM. Family members with the SCN5a variant (p.C335R) showed significantly longer PQ and QRS intervals and lower left ventricular ejection fractions (LV-EF). All four patients who received CRT-D were non-responders. Electrophysiological analysis with Xenopus oocytes showed a loss of function in SCN5a p.C335R. Na+ channel currents were also reduced in iPSC-CMs from DCM patients. Furthermore, iPSC-CM with compound heterozygosity (SCN5a p.C335R and TTNtv) showed significant dysregulation of sarcomere structures, which may be contributed to the severity of the disease and earlier onset of DCM. Conclusion: The SCN5a p.C335R variant is causing a loss of function of peak INa in patients with DCM and cardiac conduction disease. The co-existence of genetic variants in channels and structural genes (e.g., SCN5a p.C335R and TTNtv) increases the severity of the DCM phenotype.

scholarly journals Early-Onset Osteoporosis

2021 ◽  
Author(s):  
Outi Mäkitie ◽  
M. Carola Zillikens
Keyword(s):  
Young Adults ◽  
Early Onset ◽  
Type I Collagen ◽  
Young Patients ◽  
Fragility Fractures ◽  
Underlying Disease ◽  
Bone Fragility ◽  
Sphingolipid Metabolism ◽  
Type I ◽  
Loss Of Function

AbstractOsteoporosis is a skeletal disorder with enhanced bone fragility, usually affecting the elderly. It is very rare in children and young adults and the definition is not only based on a low BMD (a Z-score < − 2.0 in growing children and a Z-score ≤ − 2.0 or a T-score ≤ − 2.5 in young adults) but also on the occurrence of fragility fractures and/or the existence of underlying chronic diseases or secondary factors such as use of glucocorticoids. In the absence of a known chronic disease, fragility fractures and low BMD should prompt extensive screening for secondary causes, which can be found in up to 90% of cases. When fragility fractures occur in childhood or young adulthood without an evident secondary cause, investigations should explore the possibility of an underlying monogenetic bone disease, where bone fragility is caused by a single variant in a gene that has a major role in the skeleton. Several monogenic forms relate to type I collagen, but other forms also exist. Loss-of-function variants in LRP5 and WNT1 may lead to early-onset osteoporosis. The X-chromosomal osteoporosis caused by PLS3 gene mutations affects especially males. Another recently discovered form relates to disturbed sphingolipid metabolism due to SGMS2 mutations, underscoring the complexity of molecular pathology in monogenic early-onset osteoporosis. Management of young patients consists of treatment of secondary factors, optimizing lifestyle factors including calcium and vitamin D and physical exercise. Treatment with bone-active medication should be discussed on a personalized basis, considering the severity of osteoporosis and underlying disease versus the absence of evidence on anti-fracture efficacy and potential harmful effects in pregnancy.

Severe pulmonary complications in Japanese patients after bortezomib treatment for refractory multiple myeloma

Blood ◽  
2006 ◽  
Vol 107 (9) ◽  
pp. 3492-3494 ◽  
Author(s):  
Shigesaburo Miyakoshi ◽  
Masahiro Kami ◽  
Koichiro Yuji ◽  
Tomoko Matsumura ◽  
Masaaki Takatoku ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Effects ◽  
Gastrointestinal Symptoms ◽  
Japanese Patients ◽  
The United States ◽  
Underlying Disease ◽  
Pulmonary Complications ◽  
Bortezomib Treatment ◽  
Toranomon Hospital ◽  
Life Threatening

Bortezomib is a novel proteasome inhibitor with significant antimyeloma activity. Its frequent adverse effects are manageable, including gastrointestinal symptoms, peripheral neuropathy, and thrombocytopenia. Severe lung toxicity has not previously been reported. Between June 2004 and September 2005, 13 Japanese patients with multiple myeloma were treated with bortezomib in Toranomon Hospital, Juntendo University School of Medicine, and Jichi Medical School. Four of them developed severe pulmonary complications, and 2 died of respiratory failure without progression of underlying disease. To our knowledge, this is the first report on life-threatening pulmonary adverse effects after bortezomib therapy. Previous clinical studies on bortezomib, mostly in the United States and Europe, have shown low incidences of pulmonary adverse effects. Our study suggests that bortezomib can cause serious lung injury, and that its incidence might vary among different ethnicities. Clinicians need to be alert to the possibility.

scholarly journals Regulation of Cardiac Conduction and Arrhythmias by Ankyrin/Spectrin-Based Macromolecular Complexes

2021 ◽  
Vol 8 (5) ◽  
pp. 48
Author(s):  
Drew Nassal ◽  
Jane Yu ◽  
Dennison Min ◽  
Cemantha Lane ◽  
Rebecca Shaheen ◽  
...  
Keyword(s):  
Ion Channels ◽  
Cardiac Disease ◽  
Conduction System ◽  
Cytoskeletal Proteins ◽  
Cardiac Conduction ◽  
Proper Function ◽  
Cardiac Conduction System ◽  
Loss Of Function ◽  
Macromolecular Complexes ◽  
Conduction Disturbances

The cardiac conduction system is an extended network of excitable tissue tasked with generation and propagation of electrical impulses to signal coordinated contraction of the heart. The fidelity of this system depends on the proper spatio-temporal regulation of ion channels in myocytes throughout the conduction system. Importantly, inherited or acquired defects in a wide class of ion channels has been linked to dysfunction at various stages of the conduction system resulting in life-threatening cardiac arrhythmia. There is growing appreciation of the role that adapter and cytoskeletal proteins play in organizing ion channel macromolecular complexes critical for proper function of the cardiac conduction system. In particular, members of the ankyrin and spectrin families have emerged as important nodes for normal expression and regulation of ion channels in myocytes throughout the conduction system. Human variants impacting ankyrin/spectrin function give rise to a broad constellation of cardiac arrhythmias. Furthermore, chronic neurohumoral and biomechanical stress promotes ankyrin/spectrin loss of function that likely contributes to conduction disturbances in the setting of acquired cardiac disease. Collectively, this review seeks to bring attention to the significance of these cytoskeletal players and emphasize the potential therapeutic role they represent in a myriad of cardiac disease states.

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