scholarly journals Diagnostic yield of hypertrophic cardiomyopathy in first-degree relatives of decedents with idiopathic left ventricular hypertrophy

EP Europace ◽  
2020 ◽  
Vol 22 (4) ◽  
pp. 632-642 ◽  
Author(s):  
Gherardo Finocchiaro ◽  
Harshil Dhutia ◽  
Belinda Gray ◽  
Bode Ensam ◽  
Stathis Papatheodorou ◽  
...  
Keyword(s):  
Ventricular Hypertrophy ◽  
Clinical Phenotype ◽  
Left Ventricular ◽  
Disease Entity ◽  
Long Qt ◽  
Molecular Autopsy ◽  
First Degree Relatives ◽  
Pathogenic Variants ◽  
The Family ◽  
Qt Syndrome

Abstract Aims Idiopathic left ventricular hypertrophy (LVH) is defined as LVH in the absence of myocyte disarray or secondary causes. It is unclear whether idiopathic LVH represents the phenotypic spectrum of hypertrophic cardiomyopathy (HCM) or whether it is a unique disease entity. We aimed to ascertain the prevalence of HCM in first-degree relatives of decedents from sudden death with idiopathic LVH at autopsy. Decedents also underwent molecular autopsy to identify the presence of pathogenic variants in genes implicated in HCM. Methods and results  Families of 46 decedents with idiopathic LVH (125 first-degree relatives) were investigated with electrocardiogram, echocardiogram exercise tolerance test, cardiovascular magnetic resonance imaging, 24-h Holter, and ajmaline provocation test. Next-generation sequencing molecular autopsy was performed in 14 (30%) cases. Decedents with idiopathic LVH were aged 33 ± 14 years and 40 (87%) were male. Fourteen families (30%) comprising 16 individuals were diagnosed with cardiac disease, including Brugada syndrome (n = 8), long QT syndrome (n = 3), cardiomyopathy (n = 2), and Wolff–Parkinson–White syndrome (n = 1). None of the family members were diagnosed with HCM. Molecular autopsy did not identify any pathogenic or likely pathogenic variants in genes encoding sarcomeric proteins. Two decedents had pathogenic variants associated with long QT syndrome, which were confirmed in relatives with the clinical phenotype. One decedent had a pathogenic variant associated with Danon disease in the absence of any histopathological findings of the condition or clinical phenotype in the family. Conclusion  Idiopathic LVH appears to be a distinct disease entity from HCM and is associated with fatal arrhythmias in individuals with primary arrhythmia syndromes. Family screening in relatives of decedents with idiopathic LVH should be comprehensive and encompass the broader spectrum of inherited cardiac conditions, including channelopathies.

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

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.

Learning from tragedy–The Jessica Barnett story: challenges in the diagnosis of long QT syndrome

Diagnosis ◽  
2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Mark L. Graber ◽  
Andrew P. J. Olson ◽  
Tanya Barnett
Keyword(s):  
Anxiety Disorder ◽  
Long Qt Syndrome ◽  
Adolescent Girl ◽  
Ventricular Cardiomyopathy ◽  
Long Qt ◽  
Genetic Studies ◽  
The Family ◽  
Qt Syndrome ◽  
Hyperventilation Test ◽  
Congenital Long Qt Syndrome

Abstract We describe the case of Jessica Barnett, an adolescent girl whose repeated episodes of syncope and near-syncope were ascribed to a seizure or anxiety disorder. The correct diagnoses (congenital long QT syndrome; arrythmogenic right ventricular cardiomyopathy) were established by autopsy and genetic studies only after her death at age 17. The perspective of the family is presented, along with an analysis of what went right and what went wrong in Jessica’s diagnostic journey. Key lessons in this case include the value of family as engaged members of the diagnostic team, that a ‘hyperventilation test’ should not be used to exclude cardiac origins of syncope or pre-syncope, and the inherent challenges in the diagnosis of the long QT syndrome.

Effect of clinical phenotype on yield of long QT syndrome genetic testing

Heart Rhythm ◽  
2005 ◽  
Vol 2 (5) ◽  
pp. S46 ◽  
Author(s):  
David J. Tester ◽  
Melissa L. Will ◽  
Carla M. Haglund ◽  
Michael J. Ackerman
Keyword(s):  
Genetic Testing ◽  
Long Qt Syndrome ◽  
Clinical Phenotype ◽  
Long Qt ◽  
Qt Syndrome

scholarly journals Abnormal left ventricular relaxation in patients with long QT syndrome: reply

2009 ◽  
Vol 30 (22) ◽  
pp. 2814-2815
Author(s):  
K. H. Haugaa ◽  
T. Edvardsen ◽  
T. P. Leren ◽  
O. A. Smiseth ◽  
J. P. Amlie
Keyword(s):  
Long Qt Syndrome ◽  
Left Ventricular ◽  
Long Qt ◽  
Left Ventricular Relaxation ◽  
Ventricular Relaxation ◽  
Qt Syndrome

scholarly journals Type 8 long QT syndrome: pathogenic variants in CACNA1C-encoded Cav1.2 cluster in STAC protein binding site

EP Europace ◽  
2019 ◽  
Vol 21 (11) ◽  
pp. 1725-1732 ◽  
Author(s):  
Greg J Mellor ◽  
Pankaj Panwar ◽  
Andrea K Lee ◽  
Christian Steinberg ◽  
Julie A Hathaway ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Rare Variants ◽  
Clinical Information ◽  
Long Qt ◽  
T Wave ◽  
Pathogenic Variants ◽  
Loop Region ◽  
Wave Morphology ◽  
History Of ◽  
Qt Syndrome

Abstract Aims Pathogenic gain-of-function variants in CACAN1C cause type-8 long QT syndrome (LQT8). We sought to describe the electrocardiographic features in LQT8 and utilize molecular modelling to gain mechanistic insights into its genetic culprits. Methods and results Rare variants in CACNA1C were identified from genetic testing laboratories. Treating physicians provided clinical information. Variant pathogenicity was independently assessed according to recent guidelines. Pathogenic (P) and likely pathogenic (LP) variants were mapped onto a 3D modelled structure of the Cav1.2 protein. Nine P/LP variants, identified in 23 patients from 19 families with non-syndromic LQTS were identified. Six variants, found in 79% of families, clustered to a 4-residue section in the cytosolic II–III loop region which forms a region capable of binding STAC SH3 domains. Therefore, variants may affect binding of SH3-domain containing proteins. Arrhythmic events occurred in similar proportions of patients with II–III loop variants and with other P/LP variants (53% vs. 48%, P = 0.41) despite shorter QTc intervals (477 ± 31 ms vs. 515 ± 37 ms, P = 0.03). A history of sudden death was reported only in families with II–III loop variants (60% vs. 0%, P = 0.03). The predominant T-wave morphology was a late peaking T wave with a steep descending limb. Exercise testing demonstrated QTc prolongation on standing and at 4 min recovery after exercise. Conclusion The majority of P/LP variants in patients with CACNA1C-mediated LQT8 cluster in an SH3-binding domain of the cytosolic II–III loop. This represents a ‘mutation hotspot’ in LQT8. A late-peaking T wave with a steep descending limb and QT prolongation on exercise are commonly seen.

Sign in / Sign up

Export Citation Format

Share Document