Monogenic and oligogenic cardiovascular diseases: genetics of arrhythmias—Brugada syndrome

ESC CardioMed ◽  
2018 ◽  
pp. 679-682
Author(s):  
Sonia Van Dooren ◽  
Dorien Daneels ◽  
Gudrun Pappaert ◽  
Maryse Bonduelle ◽  
Pedro Brugada
Keyword(s):  
Sodium Channel ◽  
Brugada Syndrome ◽  
Rare Variants ◽  
Diagnostic Yield ◽  
Molecular Genetic ◽  
Susceptibility Gene ◽  
Incomplete Penetrance ◽  
Gene Encoding ◽  
Pathogenic Variants ◽  
Complex Inheritance

The heritable arrhythmogenic disorder Brugada syndrome (BrS), a cardiac ion channelopathy first described in 1992, is inherited as an autosomal dominant trait characterized by incomplete penetrance, variable expression, and phenotypic overlap. These characteristics all complicate the elucidation of the underlying molecular genetic pathway. Clearly, SCN5A, the gene encoding the pore-forming alpha subunit of the cardiac sodium channel, is the major susceptibility gene associated with BrS: 20–30% of BrS patients harbour pathogenic variants in this gene and BrS patients have a more than eight times higher burden of rare variants in this gene compared to controls. Rare pathogenic variants have also been reported in several sodium, potassium, and calcium channel genes, pacemaker genes, and sodium channel interacting genes. Given the minor collective contribution of these additional BrS-associated genes to the total genetic diagnostic yield, the hypothesis has been raised that other (genetic) determinants are involved. Indeed, the monogenic nature of BrS has been questioned and more support has recently been gained for the hypothesis of a complex inheritance based on genome-wide and gene panel studies. Probably, the BrS inheritance pattern is a continuum ranging from a monogenic, over an oligogenic towards even a polygenic spectrum. This, however, further impedes the interpretation of the contribution of (likely) pathogenic variants to the phenotype and urges for a cautious policy in a prenatal and preimplantation genetic diagnostic context: in many cases disease prevention will imply a risk reduction instead of an elimination of disease (development).

Abstract 5317: Identification and Characterization of a Novel Susceptibility Gene, SCN3B, for Idiopathic Ventricular Fibrillation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Carmen R Valdivia ◽  
Argelia Mereidos-Domingo ◽  
Thimothy J Algiers ◽  
Michael J Ackerman ◽  
Jonathan C Makielski
Keyword(s):  
Ventricular Fibrillation ◽  
Sodium Channel ◽  
Brugada Syndrome ◽  
Mutational Analysis ◽  
Sodium Current ◽  
Susceptibility Gene ◽  
Site Directed Mutagenesis ◽  
Macromolecular Complex ◽  
Patch Clamp Technique ◽  
Idiopathic Ventricular Fibrillation

Background: Mutations in the Na V 1.5 sodium channel macromolecular complex have been identified in some cases classified as idiopathic ventricular fibrillation (IVF). IVF and Brugada syndrome (BrS) are partially overlapping syndromes. Here, we report a mutation in SCN3B- encoded sodium channel β3 subunit as a novel pathogenic mechanism for IVF. Methods: Comprehensive open reading frame mutational analysis of SCN5A, GPD1L, and the beta subunit genes ( SCN1–4B ) was performed using PCR, DHPLC, and direct DNA sequencing of DNA extracted from a 20-year-old patient diagnosed with IVF. The SCN3B mutation was made by site directed mutagenesis and co-transfected with SCN5A into HEK-293 cells for functional chraracterization using the patch clamp technique. Results: A novel missense mutation, V54G-SCN3B, was identified in a 20-year-old male following collapse and external defibrillation from VF. After recovery, there was no detectable electrocardiographic abnormality. Imaging studies demonstrated a structurally normal heart, and the patient was diagnosed with IVF. The mutation was absent in 800 reference alleles and involved a highly conserved residue in the extracellular domain of the beta 3 subunit. No other mutations were identified in the 5 other genes. HEK cells expressing SCN5A and either WT-, or V54G-SCN3B were studied 24 hours after transfection. Cells expressing V54G-SCN3B showed significant decrease in sodium current density of 60±20 pA/pF compared to 203±35 pA/pF in WT-SCN3B (n=14–19). In addition V54G-SCN3B significantly shifted the activation curve +5 mV without affecting inactivation. Conclusions: This study provides the first molecular and cellular evidence implicating SCN3B in IVF. Given the marked loss-of-function to the sodium channel by V54G-SCN3B and the overlap between IVF and BrS, it will be interesting to determine whether mutations in SCN3B explain some cases of genotype negative Brugada syndrome.

scholarly journals Diagnostic exome sequencing in non-acquired focal epilepsies highlights a major role of GATOR1 complex genes

2020 ◽  
Vol 57 (9) ◽  
pp. 624-633 ◽  
Author(s):  
Martin Krenn ◽  
Matias Wagner ◽  
Christoph Hotzy ◽  
Elisabeth Graf ◽  
Sandrina Weber ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Rare Variants ◽  
Focal Epilepsy ◽  
Diagnostic Yield ◽  
Mammalian Target Of Rapamycin ◽  
High Rate ◽  
Molecular Heterogeneity ◽  
Pathogenic Variants ◽  
Uncertain Significance

BackgroundThe genetic architecture of non-acquired focal epilepsies (NAFEs) becomes increasingly unravelled using genome-wide sequencing datasets. However, it remains to be determined how this emerging knowledge can be translated into a diagnostic setting. To bridge this gap, we assessed the diagnostic outcomes of exome sequencing (ES) in NAFE.Methods112 deeply phenotyped patients with NAFE were included in the study. Diagnostic ES was performed, followed by a screen to detect variants of uncertain significance (VUSs) in 15 well-established focal epilepsy genes. Explorative gene prioritisation was used to identify possible novel candidate aetiologies with so far limited evidence for NAFE.ResultsES identified pathogenic or likely pathogenic (ie, diagnostic) variants in 13/112 patients (12%) in the genes DEPDC5, NPRL3, GABRG2, SCN1A, PCDH19 and STX1B. Two pathogenic variants were microdeletions involving NPRL3 and PCDH19. Nine of the 13 diagnostic variants (69%) were found in genes of the GATOR1 complex, a potentially druggable target involved in the mammalian target of rapamycin (mTOR) signalling pathway. In addition, 17 VUSs in focal epilepsy genes and 6 rare variants in candidate genes (MTOR, KCNA2, RBFOX1 and SCN3A) were detected. Five patients with reported variants had double hits in different genes, suggesting a possible (oligogenic) role of multiple rare variants.ConclusionThis study underscores the molecular heterogeneity of NAFE with GATOR1 complex genes representing the by far most relevant genetic aetiology known to date. Although the diagnostic yield is lower compared with severe early-onset epilepsies, the high rate of VUSs and candidate variants suggests a further increase in future years.

scholarly journals Two Novel Pathogenic Variants of TJP2 Gene and the Underlying Molecular Mechanisms in Progressive Familial Intrahepatic Cholestasis Type 4 Patients

2021 ◽  
Vol 9 ◽  
Author(s):  
Jia Tang ◽  
Meihua Tan ◽  
Yihui Deng ◽  
Hui Tang ◽  
Haihong Shi ◽  
...  
Keyword(s):  
Intrahepatic Cholestasis ◽  
Molecular Mechanisms ◽  
Rare Variants ◽  
Diagnostic Yield ◽  
Underlying Mechanism ◽  
Inherited Disease ◽  
Progressive Familial Intrahepatic Cholestasis ◽  
Pathogenic Variants ◽  
Number Of Patients ◽  
Junction Protein

Progressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease that accounts for 10%–15% childhood cholestasis and could lead to infant disability or death. There are three well-established types of PFIC (1–3), caused by mutations in the ATP8B1, ABCB11, and ABCB4 genes. Biallelic pathogenic variants in the tight junction protein 2 gene (TJP2) were newly reported as a cause for PFIC type 4; however, only a limited number of patients and undisputable variants have been reported for TJP2, and the underlying mechanism for PFIC 4 remains poorly understood. To explore the diagnostic yield of TJP2 analysis in suspected PFIC patients negative for the PFIC1–3 mutation, we designed a multiplex polymerase chain reaction-based next-generation sequencing method to analyze TJP2 gene variants in 267 PFIC patients and identified biallelic rare variants in three patients, including three known pathogenic variants and two novel variants in three patients. By using CRISPR-cas9 technology, we demonstrated that TJP2 c.1202A > G was pathogenic at least partially by increasing the expression and nuclear localization of TJP2 protein. With the minigene assay, we showed that TJP2 c.2668-11A > G was a new pathogenic variant by inducing abnormal splicing of TJP2 gene and translation of prematurely truncated TJP2 protein. Furthermore, knockdown of TJP2 protein by siRNA technology led to inhibition of cell proliferation, induction of apoptosis, dispersed F-actin, and disordered microfilaments in LO2 and HepG2celles. Global gene expression profiling of TJP2 knockdown LO2 cells and HepG2 cells identified the dysregulated genes involved in the regulation of actin cytoskeleton. Microtubule cytoskeleton genes were significantly downregulated in TJP2 knockdown cells. The results of this study demonstrate that TJP2 c.1202A > G and TJP2 c.2668-11A > G are two novel pathogenic variants and the cytoskeleton-related functions and pathways might be potential molecular pathogenesis for PFIC.

scholarly journals The Role of Seizure-RelatedSEZ6as a Susceptibility Gene in Febrile Seizures

2011 ◽  
Vol 2011 ◽  
pp. 1-4 ◽  
Author(s):  
John C. Mulley ◽  
Xenia Iona ◽  
Bree Hodgson ◽  
Sarah E. Heron ◽  
Samuel F. Berkovic ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Dna Sequence ◽  
Febrile Seizure ◽  
Rare Variants ◽  
Strong Association ◽  
Susceptibility Gene ◽  
Febrile Seizures ◽  
Chinese Cohort ◽  
Complex Inheritance

Sixty cases of febrile seizures from a Chinese cohort had previously been reported with a strong association between variants in the seizure-related (SEZ) 6 gene and febrile seizures. They found a striking lack of genetic variation in their controls. We found genetic variation inSEZ6at similar levels at the same DNA sequence positions in our 94 febrile seizure cases as in our 96 unaffected controls. Two of our febrile seizure cases carried rare variants predicted to have damaging consequences. Combined with some of the variants from the Chinese cohort, these data are compatible with a role forSEZ6as a susceptibility gene for febrile seizures. However, the polygenic determinants underlying most cases of febrile seizures with complex inheritance remain to be determined.

scholarly journals Insights into Genetic Susceptibility to Melanoma by Gene Panel Testing: Potential Pathogenic Variants in ACD, ATM, BAP1, and POT1

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1007 ◽  
Author(s):  
Lorenza Pastorino ◽  
Virginia Andreotti ◽  
Bruna Dalmasso ◽  
Irene Vanni ◽  
Giulia Ciccarese ◽  
...  
Keyword(s):  
Rare Variants ◽  
Diagnostic Yield ◽  
Susceptibility Genes ◽  
Gene Panel ◽  
Missing Heritability ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
Novel Variants ◽  
Uncertain Significance

The contribution of recently established or candidate susceptibility genes to melanoma missing heritability has yet to be determined. Multigene panel testing could increase diagnostic yield and better define the role of candidate genes. We characterized 273 CDKN2A/ARF and CDK4-negative probands through a custom-designed targeted gene panel that included CDKN2A/ARF, CDK4, ACD, BAP1, MITF, POT1, TERF2IP, ATM, and PALB2. Co-segregation, loss of heterozygosity (LOH)/protein expression analysis, and splicing characterization were performed to improve variant classification. We identified 16 (5.9%) pathogenic and likely pathogenic variants in established high/medium penetrance cutaneous melanoma susceptibility genes (BAP1, POT1, ACD, MITF, and TERF2IP), including two novel variants in BAP1 and 4 in POT1. We also found four deleterious and five likely deleterious variants in ATM (3.3%). Thus, including potentially deleterious variants in ATM increased the diagnostic yield to about 9%. Inclusion of rare variants of uncertain significance would increase the overall detection yield to 14%. At least 10% of melanoma missing heritability may be explained through panel testing in our population. To our knowledge, this is the highest frequency of putative ATM deleterious variants reported in melanoma families, suggesting a possible role in melanoma susceptibility, which needs further investigation.

scholarly journals Abnormal myocardial expression of SAP97 is associated with arrhythmogenic risk

2020 ◽  
Vol 318 (6) ◽  
pp. H1357-H1370
Author(s):  
Hassan Musa ◽  
Cherisse A. Marcou ◽  
Todd J. Herron ◽  
Michael A. Makara ◽  
David J. Tester ◽  
...  
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Brugada Syndrome ◽  
Susceptibility Gene ◽  
Susceptibility Genes ◽  
Interacting Proteins ◽  
Gene Encoding ◽  
Electrical Impulse ◽  
Genes Encoding ◽  
A Minor

The gene encoding SAP97 ( DLG1) joins a growing list of genes encoding ion channel interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. In this study we provide the first data supporting DLG1-encoded SAP97’s candidacy as a minor Brugada syndrome susceptibility gene.

scholarly journals Update on Genetic Basis of Brugada Syndrome: Monogenic, Polygenic or Oligogenic?

2020 ◽  
Vol 21 (19) ◽  
pp. 7155 ◽  
Author(s):  
Oscar Campuzano ◽  
Georgia Sarquella-Brugada ◽  
Sergi Cesar ◽  
Elena Arbelo ◽  
Josep Brugada ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Genetic Basis ◽  
Rare Variants ◽  
Genetic Diagnosis ◽  
Genetic Alterations ◽  
Pathogenic Variants ◽  
Oligogenic Inheritance ◽  
The Many ◽  
Scn5a Gene

Brugada syndrome is a rare inherited arrhythmogenic disease leading to ventricular fibrillation and high risk of sudden death. In 1998, this syndrome was linked with a genetic variant with an autosomal dominant pattern of inheritance. To date, rare variants identified in more than 40 genes have been potentially associated with this disease. Variants in regulatory regions, combinations of common variants and other genetic alterations are also proposed as potential origins of Brugada syndrome, suggesting a polygenic or oligogenic inheritance pattern. However, most of these genetic alterations remain of questionable causality; indeed, rare pathogenic variants in the SCN5A gene are the only established cause of Brugada syndrome. Comprehensive analysis of all reported genetic alterations identified the origin of disease in no more than 40% of diagnosed cases. Therefore, identifying the cause of this rare arrhythmogenic disease in the many families without a genetic diagnosis is a major current challenge in Brugada syndrome. Additional challenges are interpretation/classification of variants and translation of genetic data into clinical practice. Further studies focused on unraveling the pathophysiological mechanisms underlying the disease are needed. Here we provide an update on the genetic basis of Brugada syndrome.

scholarly journals The Mechanism of Ajmaline and Thus Brugada Syndrome: Not Only the Sodium Channel!

2021 ◽  
Vol 8 ◽  
Author(s):  
Michelle M. Monasky ◽  
Emanuele Micaglio ◽  
Sara D'Imperio ◽  
Carlo Pappone
Keyword(s):  
Sodium Channel ◽  
Brugada Syndrome ◽  
Rare Variants ◽  
Sodium Current ◽  
Gene Mutations ◽  
Calcium Currents ◽  
Sodium Channel Blocker ◽  
Sodium Potassium ◽  
Genetics Research

Ajmaline is an anti-arrhythmic drug that is used to unmask the type-1 Brugada syndrome (BrS) electrocardiogram pattern to diagnose the syndrome. Thus, the disease is defined at its core as a particular response to this or other drugs. Ajmaline is usually described as a sodium-channel blocker, and most research into the mechanism of BrS has centered around this idea that the sodium channel is somehow impaired in BrS, and thus the genetics research has placed much emphasis on sodium channel gene mutations, especially the gene SCN5A, to the point that it has even been suggested that only the SCN5A gene should be screened in BrS patients. However, pathogenic rare variants in SCN5A are identified in only 20–30% of cases, and recent data indicates that SCN5A variants are actually, in many cases, prognostic rather than diagnostic, resulting in a more severe phenotype. Furthermore, the misconception by some that ajmaline only influences the sodium current is flawed, in that ajmaline actually acts additionally on potassium and calcium currents, as well as mitochondria and metabolic pathways. Clinical studies have implicated several candidate genes in BrS, encoding not only for sodium, potassium, and calcium channel proteins, but also for signaling-related, scaffolding-related, sarcomeric, and mitochondrial proteins. Thus, these proteins, as well as any proteins that act upon them, could prove absolutely relevant in the mechanism of BrS.

Clinical characteristics and molecular genetic analysis of a cohort with idiopathic congenital hypogonadism

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Ayberk Turkyilmaz ◽  
Atilla Cayir ◽  
Oguzhan Yarali ◽  
Erdal Kurnaz ◽  
Emine Kartal Baykan ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Rare Variants ◽  
Single Gene ◽  
Hypogonadotropic Hypogonadism ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Chromosomal Anomalies ◽  
Incomplete Penetrance ◽  
Hormone Production ◽  
Variant Of Uncertain Significance

Abstract Objectives Hypogonadism is defined as inadequate sex hormone production due to defects in the hypothalamic-pituitary-gonadal axis. In recent years, rare single gene defects have been identified in both hypergonadotropic hypogonadism (Hh), and hypogonadotropic hypogonadism (HH) cases with no chromosomal anomalies. The aim of the present study is to investigate the underlying molecular genetic etiology and the genotype-phenotype relationship of a series of patients with Hh and HH. Methods In total, 27 HH and six Hh cases were evaluated. Clinical and laboratory features are extracted from patients’ hospital files. Whole exome sequencing (WES) analysis was performed. Results A total of 27 HH cases (15 female) (mean age: 15.8 ± 2.7 years) and six Hh patients (six females) (mean age: 14.9 ± 1.2 years) were included. In molecular genetic analysis, a pathogenic/likely pathogenic variant was identified in five (two patients from the same family) of 27 HH cases (two novel) and three of the six Hh. In HH group variants (pathogenic, likely pathogenic and variant of uncertain significance) were identified in KISS1R (n=2), PROK2 (n=1), FGFR1 (n=1), HS6ST1 (n=1), GNRH1 (n=1) genes. In the Hh group, splice-site mutations were detected in DCAF17 (n=1) and MCM9 (n=2) genes. Conclusions HH and Hh cases are genetically heterogeneous diseases due to oligogenic inheritance, incomplete penetrance, and variable expressivity. We found rare variants in CHH related genes in half of our HH cases, whereas they classified as pathogenic/likely pathogenic according to ACMG criteria in only about 15% of HH cases. Using advanced genetic analysis methods such as whole-genome sequencing and long-read sequencing may increase the mutation detection rate, which should always be associated with and expert genetic counseling to interpret the data.

Abstract 14629: Rare Variants for Electrocardiographic Traits Identify Arrhythmia Susceptibility Genes

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Sean J Jurgens ◽  
Seung Hoan Choi ◽  
Christopher M Haggerty ◽  
Amelia W Hall ◽  
Jennifer Halford ◽  
...  
Keyword(s):  
Rare Variants ◽  
Sequence Data ◽  
Low Frequency ◽  
Population Based ◽  
P Wave ◽  
Cardiac Conduction ◽  
Incomplete Penetrance ◽  
Loss Of Function ◽  
Discovery Sample ◽  
Pathogenic Variants

Introduction: Electrocardiogram (ECG) intervals are quantitative and heritable endophenotypes for arrhythmias and sudden cardiac death (SCD). Studying rare sequence variation related to ECG intervals may help identify the genetic underpinnings of cardiac conduction and SCD. Methods: Using a discovery sample of 29,000 individuals with whole-genome sequences from TOPMed and a replication sample of about 100,000 individuals with whole-exome sequence data from the UK Biobank and MyCode, we examined associations between low-frequency (MAF<1%) and rare (MAF<0.1%) coding variants with 5 routinely ascertained ECG intervals (RR, P-wave, PR, QRS, and QTc intervals). We further assessed pathogenic variants in identified genes using ClinVar. Results: In low-frequency single variant analysis, we observed associations for PR interval in PAM ( P =2x10 -7 ) and MFGE8 ( P =5x10 -8 ). In gene-based tests, we identified rare coding variation associated with marked effects in established SCD genes KCNQ1, KCNH2, SCN5A and KCNE1 . For example, loss-of-function or pathogenic variants in KCNQ1 and KCNH2 were carried in 0.2% of individuals, were associated with 29 ms longer QTc intervals ( P =2x10 -82 ) and conferred up to 23-fold increased odds of marked QTc prolongation ( P =4x10 -25 ). Nevertheless, over 75% of carriers had normal QTc intervals. Similarly, loss-of-function or pathogenic variants in SCN5A , carried by 0.1% of individuals, conferred marked PR prolongation (31 ms), yet less than 30% of carriers had first-degree atrioventricular block. Discussion: This study demonstrates the value of studying ECGs in large sequenced biobanks for identifying rare variants predisposing to cardiac arrhythmias. Results define the frequency of pathogenic variation in SCD genes in the population and document incomplete penetrance of such variation. Our findings may serve as a benchmark for future population-based analyses aimed at discovering clinically actionable variants and genes.

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