scholarly journals Biallelic loss-of-function in NRAP is a cause of recessive dilated cardiomyopathy

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0245681
Author(s):  
Juha W. Koskenvuo ◽  
Inka Saarinen ◽  
Saija Ahonen ◽  
Johanna Tommiska ◽  
Sini Weckström ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Dilated Cardiomyopathy ◽  
Molecular Diagnosis ◽  
Reference Population ◽  
Control Group ◽  
Loss Of Function ◽  
Familial Dilated Cardiomyopathy ◽  
Anchoring Protein ◽  
And Control ◽  
Cardiac Group

Background Familial dilated cardiomyopathy (DCM) is typically a monogenic disorder with dominant inheritance. Although over 40 genes have been linked to DCM, more than half of the patients undergoing comprehensive genetic testing are left without molecular diagnosis. Recently, biallelic protein-truncating variants (PTVs) in the nebulin-related anchoring protein gene (NRAP) were identified in a few patients with sporadic DCM. Methods and results We determined the frequency of rare NRAP variants in a cohort of DCM patients and control patients to further evaluate role of this gene in cardiomyopathies. A retrospective analysis of our internal variant database consisting of 31,639 individuals who underwent genetic testing (either panel or direct exome sequencing) was performed. The DCM group included 577 patients with either a confirmed or suspected DCM diagnosis. A control cohort of 31,062 individuals, including 25,912 individuals with non-cardiac (control group) and 5,150 with non-DCM cardiac indications (Non-DCM cardiac group). Biallelic (n = 6) or two (n = 5) NRAP variants (two PTVs or PTV+missense) were identified in 11 unrelated probands with DCM (1.9%) but none of the controls. None of the 11 probands had an alternative molecular diagnosis. Family member testing supports co-segregation. Biallelic or potentially biallelic NRAP variants were enriched in DCM vs. controls (OR 1052, p<0.0001). Based on the frequency of NRAP PTVs in the gnomAD reference population, and predicting full penetrance, biallelic NRAP variants could explain 0.25%-2.46% of all DCM cases. Conclusion Loss-of-function in NRAP is a cause for autosomal recessive dilated cardiomyopathy, supporting its inclusion in comprehensive genetic testing.

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.

ZBTB17 loss-of-function mutation contributes to familial dilated cardiomyopathy

2018 ◽  
Vol 33 (7) ◽  
pp. 722-732 ◽  
Author(s):  
Yu-Min Sun ◽  
Jun Wang ◽  
Ying-Jia Xu ◽  
Xin-Hua Wang ◽  
Fang Yuan ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Loss Of Function ◽  
Familial Dilated Cardiomyopathy

MEF2C loss-of-function mutation associated with familial dilated cardiomyopathy

2018 ◽  
Vol 56 (3) ◽  
pp. 502-511 ◽  
Author(s):  
Fang Yuan ◽  
Zhao-Hui Qiu ◽  
Xing-Hua Wang ◽  
Yu-Min Sun ◽  
Jun Wang ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Cardiac Development ◽  
Index Patient ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
Complete Penetrance ◽  
Familial Dilated Cardiomyopathy ◽  
Wild Type Counterpart ◽  
New Gene ◽  
Close Relatives

AbstractBackground:The MADS-box transcription factor myocyte enhancer factor 2C (MEF2C) is required for the cardiac development and postnatal adaptation and in mice-targeted disruption of theMEF2Cgene results in dilated cardiomyopathy (DCM). However, in humans, the association ofMEF2Cvariation with DCM remains to be investigated.Methods:The coding regions and splicing boundaries of theMEF2Cgene were sequenced in 172 unrelated patients with idiopathic DCM. The available close relatives of the index patient harboring an identifiedMEF2Cmutation and 300 unrelated, ethnically matched healthy individuals used as controls were genotyped forMEF2C. The functional effect of the mutant MEF2C protein was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system.Results:A novel heterozygous MEF2C mutation, p.Y157X, was detected in an index patient with adult-onset DCM. Genetic screen of the mutation carrier’s family members revealed that the mutation co-segregated with DCM, which was transmitted as an autosomal dominant trait with complete penetrance. The non-sense mutation was absent in 300 control individuals. Functional analyses unveiled that the mutant MEF2C protein had no transcriptional activity. Furthermore, the mutation abolished the synergistic transactivation between MEF2C and GATA4 as well as HAND1, two other transcription factors that have been associated with DCM.Conclusions:This study indicatesMEF2Cas a new gene responsible for human DCM, which provides novel insight into the mechanism underpinning DCM, suggesting potential implications for development of innovative prophylactic and therapeutic strategies for DCM, the most prevalent form of primary myocardial disease.

scholarly journals A novel NKX2-5 loss-of-function mutation predisposes to familial dilated cardiomyopathy and arrhythmias

2014 ◽  
Vol 35 (2) ◽  
pp. 478-486 ◽  
Author(s):  
FANG YUAN ◽  
XING-BIAO QIU ◽  
RUO-GU LI ◽  
XIN-KAI QU ◽  
JUAN WANG ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Loss Of Function ◽  
Familial Dilated Cardiomyopathy

scholarly journals Arrhythmic Genotypes in Familial Dilated Cardiomyopathy: Implications for Genetic Testing and Clinical Management

2019 ◽  
Vol 28 (1) ◽  
pp. 31-38 ◽  
Author(s):  
Stacey Peters ◽  
Saurabh Kumar ◽  
Perry Elliott ◽  
Jonathan M. Kalman ◽  
Diane Fatkin
Keyword(s):  
Genetic Testing ◽  
Dilated Cardiomyopathy ◽  
Clinical Management ◽  
Familial Dilated Cardiomyopathy

scholarly journals P1439 Familial dilated cardiomyopathy: assessment of left ventricular systolic and diastolic function by echocardiogram in asymptomatic patients

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
M Quezada ◽  
M Ramos ◽  
R Ayala ◽  
M Calderon- Dominguez ◽  
P Guerrero De La Riva ◽  
...  
Keyword(s):  
Ejection Fraction ◽  
Dilated Cardiomyopathy ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Control Group ◽  
Healthy Controls ◽  
Ventricular Ejection Fraction ◽  
Familial Dilated Cardiomyopathy ◽  
Diastolic Velocity ◽  
Sphericity Index

Abstract Funding Acknowledgements Alfonso X El Sabio University Introduction Familial dilated cardiomyopathy (fDCM) represents 20% to 30% of idiopathic DCM (iDCM) ethiology. The assessment of cardiac function of these patients is awfully complex. Usually, myocardial fiber damages can not be detected in the early DCM stages. In this sense echocardiogram could be useful to detect incipient changes. Purpose The aim of this study was to characterize the systolic function of asymptomatic fDCM, compared within iDCM and control patients. Material and methods This study was carried out in 33 fDCM patients. A total of 4 fDCM families with LMNA gene mutation and 3 fDCM families with BLC2-associated athanogene 3 (BAG3) mutation were recruited. Moreover, a total of 30 iDCM and 66 healthy matched controls were enrolled in the study. Results 58.14% were male. The average age was 45.3 ± 17 years. 72% showed sinus rhythm. Left bundle branch block (LBBB) was observed in 7.8% of patients. The LV ejection fraction (LVEF), sphericity index and mitral annular plane systolic excursion (MAPSE), were significantly improved in the fDCM patients compared to iDCM subjects. However, these parameters were aggravated compared with healthy controls. LVEF was enhanced in fDCM in contrast to iDCM (56% versus 35%; P &lt; 0.001). Nevertheless, LVEF value was deteriorated in fDCM compared to healthy controls (56% versus 65%; P &lt; 0.001). The values of septal and lateral annulus early diastolic velocity measured by DTI, were also diminished. All results are presented in Table 1. Conclusions Asymptomatic fDCM shown an intermediate value of LVEF between the iDCM and the control group. This ventricular remodeling process could be the consequence of a slight increase in the end-systolic diameter. Patients Characteristics Patients Characteristics iDCM 30 patients fDCM 33 patients Control Group 66 Healthy P LVEF 32 (29.78-40) 56.0 (39.7-64.2) 65 (62-69.5) 0.001 EDD 62.5 (59.2-65.7) 53.7 (45.7-57.6) 45.50 (43-48.8) 0.001 ESD 53 (47-58.75) 36 (30.9-54.2) 27.9 (24-31) 0.001 MAPSE 11 (10-12.50) 14 (14-18) 19 (17-20) 0.001 Sphericity index 0.70 (0.66–0.79) 0.69 (0.66-0.79) 0.53 (0.48-58) 0.001 LA volume 61.5 (57-75.1) 32 (23-46.5) 17 (14.2-20) NS Septal annulus Early diastolic Velocity (cm/s) DTI 3.5 (3-4.2) 7.5 (1.6-8.8) 9 (7.9-11) 0.001 Lateral annulus Early diastolic Velocity (cm/s) DT 7.2 (5-8.9) 9.5 (1.8-11.8) 13 (10.37-15) 0.001 Table1. Echocardiografic findings in patients. LVEF: left ventricular ejection fraction; EDD: end-diastolic diameter; ESD: end systolic diameter; MAPSE:mitral annular plane systoluc excursion; LA: left atrium; TDI: Tissue Doppler imagin. Abstract P1439 Figure. Familial dilated cardiomyopathy

scholarly journals Complexities of Genetic Testing in Familial Dilated Cardiomyopathy

2016 ◽  
Vol 9 (1) ◽  
pp. 95-99 ◽  
Author(s):  
Matthew J. Wolf ◽  
Dagny Noeth ◽  
Chidambaram Rammohan ◽  
Svati H. Shah
Keyword(s):  
Genetic Testing ◽  
Dilated Cardiomyopathy ◽  
Familial Dilated Cardiomyopathy

scholarly journals GATA5 loss-of-function mutation in familial dilated cardiomyopathy

2014 ◽  
Vol 35 (3) ◽  
pp. 763-770 ◽  
Author(s):  
XIAN-LING ZHANG ◽  
NENG DAI ◽  
KAI TANG ◽  
YAN-QING CHEN ◽  
WEI CHEN ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Loss Of Function ◽  
Familial Dilated Cardiomyopathy

HAND1 loss-of-function mutation associated with familial dilated cardiomyopathy

2016 ◽  
Vol 54 (7) ◽  
Author(s):  
Yi-Meng Zhou ◽  
Xiao-Yong Dai ◽  
Xing-Biao Qiu ◽  
Fang Yuan ◽  
Ruo-Gu Li ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Molecular Mechanisms ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Loss Of Function ◽  
Coding Region ◽  
Helix Loop Helix ◽  
Complete Penetrance ◽  
Familial Dilated Cardiomyopathy ◽  
Synergistic Activation

AbstractThe basic helix-loop-helix transcription factor HAND1 is essential for cardiac development and structural remodeling, and mutations in HAND1 have been causally linked to various congenital heart diseases. However, whether genetically compromised HAND1 predisposes to dilated cardiomyopathy (DCM) in humans remains unknown.The whole coding region and splicing junctions of theA novel heterozygous HAND1 mutation, p.R105X, was identified in a family with DCM transmitted as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. The nonsense mutation was absent in 520 control chromosomes. Functional analyses unveiled that the mutant HAND1 had no transcriptional activity. Furthermore, the mutation abolished the synergistic activation between HAND1 and GATA4, another crucial cardiac transcription factors that has been associated with various congenital cardiovascular malformations and DCM.This study firstly reports the association of HAND1 loss-of-function mutation with increased susceptibility to DCM in humans, which provides novel insight into the molecular mechanisms underpinning DCM.

X-linked dilated cardiomyopathy: the important role of genetic tests and imaging in the early diagnosis and treatment

2020 ◽  
Author(s):  
Sotirios Tsalamandris ◽  
Evangelos Oikonomou ◽  
Georgia Vogiatzi ◽  
Antigoni Miliou ◽  
George Lazaros ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Early Diagnosis ◽  
Dilated Cardiomyopathy ◽  
Positive Family History ◽  
Correct Identification ◽  
Early Management ◽  
Familial Dilated Cardiomyopathy ◽  
Crete Island ◽  
History Of

Familial dilated cardiomyopathy predominantly affects younger adults and may cause advanced heart failure and sudden cardiac death. Therefore, detailed family history, family members screening, appropriate genetic testing and counselling may allow correct identification of cardiac remodeling etiology, as well as earlier disease detection. Accordingly, we present a case with an early diagnosis of an X-linked dilated cardiomyopathy guided by clinical features, cardiac MRI and genetic testing. The diagnostic workup was guided by the positive family history of cardiomyopathy and sudden cardiac deaths. Clinical implications including early management, better arrythmia risk stratification and the revealing of a potential endemic entity clustering in several male subjects of a community on Crete island are further discussed.

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