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.

Genetic Spectrum of Left Ventricular Non-Compaction in Paediatric Patients

Cardiology ◽  
2020 ◽  
Vol 145 (11) ◽  
pp. 746-756
Author(s):  
Tatiana Vershinina ◽  
Yulia Fomicheva ◽  
Alexey Muravyev ◽  
John Jorholt ◽  
Alexandra Kozyreva ◽  
...  
Keyword(s):  
Ion Channel ◽  
Age Groups ◽  
Left Ventricular ◽  
Barth Syndrome ◽  
Reduced Ejection Fraction ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Paediatric Patients ◽  
Unknown Significance ◽  
Sarcomeric Genes

<b><i>Introduction:</i></b> Left ventricular non-compaction (LVNC) represents a genetically heterogeneous cardiomyopathy which occurs in both children and adults. Its genetic spectrum overlaps with other types of cardiomyopathy. However, LVNC phenotypes in different age groups can have distinct genetic aetiologies. The aim of the study was to decipher the genetic spectrum of LVNC presented in childhood. <b><i>Patient Group and Methods:</i></b> Twenty patients under the age of 18 years diagnosed with LVNC were enrolled in the study. Target sequencing and whole-exome sequencing were performed using a panel of 108 cardiomyopathy-associated genes. Pathogenic, likely pathogenic, and variants of unknown significance found in genes highly expressed in cardiomyocytes were considered as variants of interest for further analysis. <b><i>Results:</i></b> The median age at presentation was 8.0 (0.1–17) years, with 6 patients presenting before 1 year of age. Twelve (60%) patients demonstrated reduced ejection fraction. Right ventricular (RV) dilation was registered in 6 (30%), often in combination with reduced RV contractility (25%). Almost half (45%) of the patients demonstrated biventricular involvement already at disease presentation. For pathogenic and likely pathogenic variants, the positive genotyping rate was 45%, and these variants were found mainly in non-contractile structural sarcomeric genes (<i>ACTN2</i>, <i>MYPN</i>, and <i>TTN</i>) or in metabolic and signal transduction genes (<i>BRAF</i> and <i>TAZ</i>). Likely pathogenic <i>TAZ</i> variants were detected in all 5 patients suspected of having Barth syndrome. No pathogenic or likely pathogenic variants were found in genes encoding for sarcomeric contractile proteins, but variants of unknown significance were detected in 3 out of 20 patients (<i>MYH6</i>, <i>MYH7</i>, and <i>MYLK2</i>). In 4 patients, variants of unknown significance in ion-channel genes were detected. <b><i>Conclusion:</i></b> We detected a low burden of contractile sarcomeric variants in LVNC patients presenting below the age of 18 years, with the major number of variants residing in non-contractile structural sarcomeric genes. The identification of the variants in ion-channel and related genes not previously associated with LVNC in paediatric patients requires further examination of their functional role.

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 Molecular Autopsy of Sudden Cardiac Death in the Genomics Era

Diagnostics ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1378
Author(s):  
Vincenzo Castiglione ◽  
Martina Modena ◽  
Alberto Aimo ◽  
Enrica Chiti ◽  
Nicoletta Botto ◽  
...  
Keyword(s):  
Diagnostic Features ◽  
Molecular Autopsy ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Genome Wide ◽  
Unknown Significance ◽  
New Challenges ◽  
Next Generation Sequencing Ngs ◽  
Cascade Genetic Screening ◽  
Generation Sequencing

Molecular autopsy is the process of investigating sudden death through genetic analysis. It is particularly useful in cases where traditional autopsy is negative or only shows non-diagnostic features, i.e., in sudden unexplained deaths (SUDs), which are often due to an underlying inherited arrhythmogenic cardiac disease. The final goal of molecular autopsy in SUD cases is to aid medico-legal inquiries and to guide cascade genetic screening of the victim’s relatives. Early attempts of molecular autopsy relied on Sanger sequencing, which, despite being accurate and easy to use, has a low throughput and can only be employed to analyse a small panel of genes. Conversely, the recent adoption of next-generation sequencing (NGS) technologies has allowed exome/genome wide examination, providing an increase in detection of pathogenic variants and the discovery of newer genotype-phenotype associations. NGS has nonetheless brought new challenges to molecular autopsy, especially regarding the clinical interpretation of the large number of variants of unknown significance detected in each individual.

scholarly journals P.071 Novel mutations in SPG7 identified from patients with late-onset spasticity

2018 ◽  
Vol 45 (s2) ◽  
pp. S35-S35
Author(s):  
MM Almomen ◽  
KA Martens ◽  
A Hanson ◽  
L Korngut ◽  
G pfeffer
Keyword(s):  
Cerebellar Ataxia ◽  
Late Onset ◽  
Diagnostic Yield ◽  
Genetic Diseases ◽  
Transcript Level ◽  
Progressive External Ophthalmoplegia ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Unknown Significance ◽  
Leg Weakness

Background: Hereditary spastic paraplegia (HSP) is a group of genetic diseases that cause progressive degeneration of the corticospinal tract. Historically, this disease was divided into two types:the classic subtype, with leg weakness and hypertonic bladder, and the complicated subtype, with features such as cerebellar ataxia or optic atrophy.Mutations in SPG7 (encoding paraplegin) leads to complicated HSP causing cerebellar ataxia, progressive external ophthalmoplegia in addition to the classical symptoms. AFG3L2 is a binding partner of paraplegin and mutations in AFG3L2 cause a similar syndrome Methods: From a neurogenetic clinic , we identified 11 patients with late-onset HSP. Sequencing of SPG7 and AFG3L2 was performed using a customised assay, and/or clinical diagnostic sequencing panels.SPG7 transcript level quantification was performed from whole blood RNA on a digital droplet qPCR system. Results: We identified 4 patients with pathogenic variants or variants of unknown significance in SPG7. No AFG3L2 mutations were identified. We provide evidence for pathogenicity for three mutations that were not previously associated with SPG7-related disease, based on their occurrence in context of the correct phenotype, and the reduction of transcript levels measured with RT-qPCR.A curious association of the heterozygous p.Gly349Ser mutation in association with an ALS-like syndrome is reported. Conclusions:SPG7 mutations sequencing has high diagnostic yield in late onset paraparesis

P3567Genetic screening for monogenic hypertension in hypertensive individuals in a clinical setting

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Bao ◽  
J Zhong ◽  
J Cai ◽  
X Yang
Keyword(s):  
Functional Analysis ◽  
Diagnostic Yield ◽  
Basic Research ◽  
Functional Evaluation ◽  
Variants Of Unknown Significance ◽  
Treatment And Prevention ◽  
Pathogenic Variants ◽  
Unknown Significance ◽  
Monogenic Hypertension ◽  
Number Of Individuals

Abstract Objectives Monogenic hypertension describes a series of hypertension syndromes inherited by Mendelian law and present with complex phenotypes. Methods 1179 cases with monogenic hypertension potential were evaluated by sequencing 37 causative genes. Pathogenic variants were classified by using American College of Medical Genetics guidelines. Additionally, 49 variants of unknown significance were selected to receive functional analysis. The yield of combined genetic and functional analysis was evaluated. Results 21 deleterious variants were identified in 33 of 1179 (2.80%). Functional analysis for 49 unknown significant variants showed 32 variants harbored by 61 individuals led to abnormally expressed protein levels. Overall, combining genetic screening with functional analysis promoted diagnostic yield to 8.73%. The main etiology established was primary aldosteronism, with CACNA1H harboring the greatest mutation burden. Logistic regression analysis showed hypertension complicated with special manifestations had the strongest correlation with disease causing variants detection (p=0.03). Sequencing Results Summary Number of variants Number of individuals* Percentage† Individuals with no variant 0 524 44.44% Individuals with variants identified 592 655 55.56% Individuals with single contributing variant 297 480 40.71% Individuals with two or multiple contributing variants 295 175 14.84% Number of variants identified   Pathogenic and likely pathogenic variants 21 33 2.80%   Variants of unknown significance 570 634 53.77%   Benign or likely benign variants 1 1 0.08% Type of variant   Frameshift deletion 8 15 1.27%   Frameshift insertion 5 5 0.42%   Nonframeshift deletion 10 10 0.85%   Nonframeshift insertion 6 12 1.02%   Nonsynonymous SNV 546 607 51.48%   Stopgain SNV 18 30 2.54% WES, whole-exome sequencing. *The statistics in this table was based on 1179 individuals. †The percentage was calculated by the number of individuals in each category. A flow chart of this study. Conclusion Our findings demonstrate an enhanced diagnostic ability by combining genetic analysis with functional evaluation and enables targeted treatment and prevention of hypertension. Acknowledgement/Funding This work was supported by National Basic Research Program of China (973 Program, 2014CB542300, 2014CB542302).

scholarly journals Genetic architecture of left ventricular noncompaction in adults

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Samantha Barratt Ross ◽  
Emma S. Singer ◽  
Elizabeth Driscoll ◽  
Natalie Nowak ◽  
Laura Yeates ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Genetic Testing ◽  
Family History ◽  
Cardiac Dysfunction ◽  
Diagnostic Yield ◽  
Left Ventricular ◽  
Left Ventricular Noncompaction ◽  
Ventricular Noncompaction ◽  
Pathogenic Variants ◽  
Cardiac Transcription Factors

AbstractThe genetic etiology and heritability of left ventricular noncompaction (LVNC) in adults is unclear. This study sought to assess the value of genetic testing in adults with LVNC. Adults diagnosed with LVNC while undergoing screening in the context of a family history of cardiomyopathy were excluded. Clinical data for 35 unrelated patients diagnosed with LVNC at ≥18 years of age were retrospectively analyzed. Left ventricular (LV) dysfunction, electrocardiogram (ECG) abnormalities, cardiac malformations or syndromic features were identified in 25 patients; 10 patients had isolated LVNC in the absence of cardiac dysfunction or syndromic features. Exome sequencing was performed, and analysis using commercial panels targeted 193 nuclear and mitochondrial genes. Nucleotide variants in coding regions or in intron-exon boundaries with predicted impacts on splicing were assessed. Fifty-four rare variants were identified in 35 nuclear genes. Across all 35 LVNC patients, the clinically meaningful genetic diagnostic yield was 9% (3/35), with heterozygous likely pathogenic or pathogenic variants identified in the NKX2-5 and TBX5 genes encoding cardiac transcription factors. No pathogenic variants were identified in patients with isolated LVNC in the absence of cardiac dysfunction or syndromic features. In conclusion, the diagnostic yield of genetic testing in adult index patients with LVNC is low. Genetic testing is most beneficial in LVNC associated with other cardiac and syndromic features, in which it can facilitate correct diagnoses, and least useful in adults with only isolated LVNC without a family history. Cardiac transcription factors are important in the development of LVNC and should be included in genetic testing panels.

Whole‐Exome Sequencing of a Saudi Epilepsy Cohort Reveals Association Signals in Known and Potentially Novel Loci

2021 ◽  
Author(s):  
Amein Kadhem AlAli ◽  
Abdulrahman Al-Enazi ◽  
Ahmed Ammar ◽  
Mahmoud Hajj ◽  
Cyril Cyrus ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
High Rate ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variants ◽  
Unknown Significance ◽  
Rare Genetic Variants

Abstract Background Epilepsy, a serious chronic neurological condition effecting up to 100 million people globally, has clear genetic underpinnings including common and rare variants. In Saudi Arabia the prevalence of epilepsy is high and caused mainly by perinatal and genetic factors. No whole-exome sequencing (WES) studies have been performed to date in Saudi Arabian Epilepsy cohorts. This offers a unique opportunity for the discovery of rare genetic variants impacting this disease as there is a high rate of consanguinity amongst large tribal pedigrees. Results We performed WES on 144 individuals diagnosed with epilepsy, to interrogate known Epilepsy related genes for known and functional novel variants. We also used an American College of Medical Genetics (ACMG) guideline based variant prioritization approach in an attempt to discover putative causative variants. We identified a 32 potentially causative pathogenic variants across 30 different genes in 44/144 (30%) of these Saudi Epilepsy individuals. We also identified 232 variants of unknown significance (VUS) across 101 different genes in 133/144 (92%) subjects. Strong enrichment of variants of likely pathogenicity were observed in previously described epilepsy-associated loci, and a number of putative pathogenic variants in novel loci are also observed. Conclusion Several putative pathogenic variants known to be epilepsy-related loci were identified for the first time in our population, in addition to several potential new loci have been identified which may be prioritized for further investigation.

scholarly journals Targeted next generation sequencing identifies a genetic spectrum of DNA variants in patients with hemiplegic migraine

2019 ◽  
Vol 2 ◽  
pp. 251581631988163 ◽  
Author(s):  
Neven Maksemous ◽  
Robert A Smith ◽  
Heidi G Sutherland ◽  
Bridget H Maher ◽  
Omar Ibrahim ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Diagnostic Yield ◽  
Next Generation ◽  
Hemiplegic Migraine ◽  
Targeted Next Generation Sequencing ◽  
Variants Of Unknown Significance ◽  
High Mutation Frequency ◽  
Unknown Significance ◽  
Atp1a2 Gene ◽  
Generation Sequencing

Objective: Hemiplegic migraine in both familial (FHM) and sporadic (SHM) forms is a rare subtype of migraine with aura that can be traced to mutations in the CACNA1A, ATP1A2 and SCN1A genes. It is characterised by severe attacks of typical migraine accompanied by hemiparesis, as well as episodes of complex aura that vary significantly between individuals. Methods: Using a targeted next generation sequencing (NGS) multigene panel, we have sequenced the genomic DNA of 172 suspected hemiplegic migraine cases, in whom no mutation had previously been found by Sanger sequencing (SS) of a limited number of exons with high mutation frequency in FHM genes. Results: Genetic screening identified 29 variants, 10 of which were novel, in 35 cases in the three FHM genes ( CACNA1A, ATP1A2 and SCN1A). Interestingly, in this suspected HM cohort, the ATP1A2 gene harboured the highest number of variants with 24/35 cases (68.6%), while CACNA1A ranked the second gene, with 5 variants identified in 7/35 cases (20%). All detected variants were confirmed by SS and were absent in 100 non-migraine healthy control individuals. Assessment of variants with the American College of Medical Genetics and Genomics guidelines classified 8 variants as pathogenic, 3 as likely pathogenic and 18 as variants of unknown significance. Targeted NGS gene panel increased the diagnostic yield by fourfold over iterative SS in our diagnostics facility. Conclusion: We have identified 29 potentially causative variants in an Australian and New Zealand cohort of suspected HM cases and found that the ATP1A2 gene was the most commonly mutated gene. Our results suggest that screening using NGS multigene panels to investigate ATP1A2 alongside CACNA1A and SCN1A is a clinically useful and efficient method.

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