scholarly journals Two novel variants in the SLC4A3 gene in two families with Short QT Syndrome: the role of cascade screening

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
B Kovacs ◽  
U Graf ◽  
I Magyar ◽  
L Baehr ◽  
A Maspoli ◽  
...  
Keyword(s):  
Heart Disease ◽  
Genetic Testing ◽  
Structural Heart Disease ◽  
Missense Variant ◽  
Index Patient ◽  
Disease Association ◽  
Short Qt Syndrome ◽  
Cascade Screening ◽  
Novel Variants ◽  
Qt Syndrome

Abstract Background Short QT syndrome (SQTS) is a rare, autosomal dominant disease causing sudden cardiac death (SCD). Genetic testing is recommended according to current guidelines. Variants in KCNQ1, KCNH2, KCNJ2 and SLC4A3 genes have been reported in SQTS. Purpose We report implications of genetic testing and cascade screening (CS) in two families with phenotypical presentation of SQTS and novel genetic variants of unknown significance. Methods We performed a thorough clinical and electrophysiological work-up of the index patients of both families. In addition, genetic screening was conducted. Subsequently, segregation analysis of potentially pathogenic variants was carried out in available relatives. Results Index patient 1 presented with a history of recurrent syncope. His ECG showed a shortened QTc of 340ms. Family history was unremarkable. Structural heart disease was excluded by cardiac MRI and coronary angiography. Genetic testing detected a rare heterozygous missense variant in the KCNH2 gene (p.(Arg328Cys), frequency 0.053%), predicted to be pathogenic according to various prediction algorithms (Polyphen, SIFT, Align GVGD, mutation taster). CS of relatives did not confirm this variant as the causative mutation. Reanalysis of whole-exome sequencing data revealed a novel heterozygous missense variant, p.(Arg370Cys) in the recently identified SLC4A3 gene. A variant at the same position has previously been associated with SQTS. CS suggested disease association. The second index patient had a SCD at the age of 17. A previously registered ECG showed a shortened QTc of 340ms. Autopsy revealed no structural heart disease. Post-mortem genetic testing revealed variants in the LDB3, MYH7 and a novel heterozygous missense variant, p.(Ser1039Arg) also in the SLC4A3 gene. Family history was positive for SCD in three 2° relatives. The index patient's father had a positive phenotype with a QTc of 365ms. CS again suggested disease association of the variant in the SLC4A3 gene only. Conclusion Genetic testing revealed two novel variants in the SLC4A3 gene, which was recently implicated in the pathogenesis of the SQTS. Predictive bioinformatic algorithms to assess the pathogenicity of missense variants are of limited relevance, but genetic analysis of additional unaffected and affected family members may be instrumental to identify pathogenic DNA sequence variations. Family tree index patients 1 and 2 Funding Acknowledgement Type of funding source: None

A novel variant in the SLC4A3 gene with high penetrance in a family with short QT Syndrome

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
B Kovacs ◽  
U Graf ◽  
I Magyar ◽  
L Baehr ◽  
A Maspoli ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Family Members ◽  
Structural Heart Disease ◽  
Index Patient ◽  
Post Mortem ◽  
Short Qt Syndrome ◽  
Cascade Screening ◽  
Qt Syndrome ◽  
Work Up ◽  
Second Degree

Abstract Funding Acknowledgements Type of funding sources: None. Background Short QT syndrome (SQTS) is a rare, autosomal dominant disease causing sudden cardiac death (SCD). Current guidelines recommend genetic testing. Associated variants in KCNQ1, KCNH2, KCNJ2 and SLC4A3 genes have been reported. Purpose We report a family with a variant in the SLC4A3 gene with several presentations of SCD and high clinical penetrance of SQTS. Methods We performed a post-mortem genetic testing in the index patient in whom prior ECG was available. Subsequently, clinical and electrophysiological work-up and cascade screening (CS) of the detected suspected variant was carried out in available relatives. Results The index patient had suffered a SCD at the age of 17 (figure, upper panel, arrow). A previously registered ECG showed a shortened QTc of 340ms (figure, lower panel). Autopsy revealed no structural heart disease. Post-mortem genetic testing revealed variants in the LDB3, MYH7 and a novel heterozygous missense variant, p.(Ser1039Arg) also in the SLC4A3 gene. Although predictive bioinformatic algorithms (AlignGVGD, SIFT, MutationTaster, Polyphen2) showed conflicting classifications, family history was notable for SCD without post-mortem genetic work-up in three second degree relatives (figure, upper panel, patients 207, 208 and 305, age of death 33, 25 and 33 years respectively). CS was performed in first and second degree relatives of the index patient and was highly suggestive for disease association of the variant in the SLC4A3 gene with co-segregation in all clinically affected family members. Only one patient with the variant had a normal QTc (figure, upper panel, patient 202) of 407ms, however this patient was on regular QT-prolonging medication (risperidone and loperamide). Conclusion Genetic testing revealed a novel in the SLC4A3 gene, which was recently implicated in the pathogenesis of the SQTS. Although predictive bioinformatic algorithms yielded conflicting results, CS of family members suggests a likely pathogenicity (class IV) of the variant. Further CS or functional tests are necessary to establish causality. Abstract Figure. ECG of index patient and family tree

1268A family with a novel variant in the SLC4A3 gene leading to short QT phenotype - the importance of whole-exome-sequencing and cascade screening

EP Europace ◽  
2020 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
B Kovacs ◽  
U Graf ◽  
I Magyar ◽  
L Baehr ◽  
A Maspoli ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Variant ◽  
Missense Variant ◽  
Index Patient ◽  
Causative Mutation ◽  
Cascade Screening ◽  
Whole Exome ◽  
Work Up

Abstract Funding Acknowledgements none Introduction  Short QT syndrome (SQTS) is a rare, autosomal dominant disease causing ventricular fibrillation and sudden cardiac death. Genetic testing is recommended according to current guidelines. Mutations in KCNQ1, KCNH2, KCNJ2 and more recently SLC4A3 genes have been implicated in SQTS. These genes encode potassium channel subunits and a bicarbonate transporter regulating intracellular pH. A dominant mutation in this transporter can lead to increased intracellular pH and shortened action potential. Purpose  We present a family with a short QT phenotype and recurrent syncope in whom a novel genetic variant was detected by whole-exome sequencing (WES), confirmed by cascade screening. Methods  We performed a thorough work-up of the index patient including medical history, physical examination, 12-lead ECG, echocardiography, stress testing, coronary angiography, flecainide challenge, and genetic testing with NGS. QTc was determined using Bazett’s formula. CS of all 1° and two 2° relatives was performed. Results  The ECG of the index patient showed a QTc of 340ms and characteristics compatible with a SQTS (figure). Clinical work-up was unremarkable. A first genetic search with next generation sequencing focusing on genes that have been previously involved in the pathogenesis of channelopathies detected a rare known heterozygous missense variant in the KCNH2 gene (Arg328Cys, frequency 0.053%), which was predicted to be pathogenic according to various prediction algorithms (Polyphen, SIFT, Align GVGD, mutation taster). ECG screening of all asymptomatic first-degree family members identified a SQT phenotype in the mother (QTc 355ms), but not in the father (QTc 380ms) and sister (410ms). The KCNH2 variant was found in the father and sister but not the affected mother, which excludes this variant as the causative mutation in this family. Therefore, reanalysis of WES data was performed and revealed a novel heterozygous missense variant p.(Arg370Cys) in the SLC4A3 gene, recently associated with SQTS. A mutation in this gene at the same position has been previously reported in SQTS. The p.(Arg370Cys) mutation was found in the mother but not in the unaffected father or sister. Furthermore the mutation was present in two affected maternal uncles (QTc 319ms and 342ms) supporting the assumption that this was the causative mutation in this family. Conclusions  A novel genetic variant in the SLC4A3 gene leading to sQT phenotype could be detected using WES and cascade screening. Predictive bioinformatic algorithms to assess the pathogenicity of missense variants are of limited relevance, but genetic analysis of additional unaffected and affected family members may be instrumental to identify pathogenic DNA sequence variations. Abstract Figure. Pedigree and ECGs of the family

Abstract 2928: Sudden Arrhythmic Death Syndrome-Diagnostic Yield Of Combined Clinical & Genetic Screening In A British Specialist Clinic

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Pier D Lambiase ◽  
Juan C Kaski ◽  
Eileen Firman ◽  
Perry M Elliott ◽  
Akbar K Ahmed ◽  
...  
Keyword(s):  
Heart Disease ◽  
Genetic Testing ◽  
Screening Programme ◽  
Diagnostic Yield ◽  
Challenge Test ◽  
Structural Heart Disease ◽  
Clinical Screening ◽  
Arrhythmic Death ◽  
Sudden Arrhythmic Death Syndrome ◽  
Index Cases

Introduction: Sudden arrhythmic death syndrome (SADS) arises through disorders of ion channel function or structural heart disease. It accounts for over 400 deaths in the UK per annum. To date there has been no comprehensive analysis of the diagnostic yield and efficacy of a family screening approach in SADS index cases where the post mortem heart is structurally normal after expert pathological review. Methods: 118 SADS families where the SADS victim died between 1 and 35 years of age were evaluated in a systematic family screening programme between 2003–2006. All SADS index cases had a structurally normal heart after expert review of all available tissue. All studied relatives underwent resting, signal averaged ECG, 24h Holter, exercise ECG with V0 2 max, transthoracic echocardiography and an ajmaline challenge test after initial clinical screening. Systematic mutation analysis was performed on the known long QT (LQT)genes including SCN5A & ryanodine receptor/ARVC genes when clinically suspected. Results: The most common modes of death were rest in 28%, sleep in 25% and exercise in 18%. Clinical screening identified an inherited electrical cause of SADS in 41 of the 118 families (35%)-20 Brugada, 18 LQT Syndrome, 3 Catecholiminergic Polymorphic Ventricular Tachycardia (CPVT). Structural heart disease was identified in 5 ARVC & 2 DCM families. 26 ICDs have been implanted in affected family members-4 LQTS, 7 Brugada, 2 CPVT, 2 ARVC, 2 DCM and 9 on clinical grounds without a definitive diagnosis. The ECG (37%) and ajmaline challenge test (49%) had the highest diagnostic yield in families with a positive diagnosis. To date, genetic testing has increased the diagnostic yield by 5% (6/118 families-2 KCNQ1, 1 HERG, 2 SCN5A, 1 ARVC ), confirming a clinical diagnosis in 6.6%–3 KCNQ1, 3 SCN5A, 1 HERG, 1 KCNH2. Conclusions: Systematic clinical screening in relatives of SADS victims has a diagnostic yield of 35% increasing to 40% with genetic testing. Electrical causes of SADS predominate in these families. These findings demonstrate that a systematic clinical screening programme in SADS families is both achievable and effective. The full impact of gene testing (including RyR mutations) upon diagnostic yield is awaited.

scholarly journals Rapid genetic testing facilitating the diagnosis of short QT syndrome

2009 ◽  
Vol 25 (4) ◽  
pp. e133-e135 ◽  
Author(s):  
Calum J. Redpath ◽  
Martin S. Green ◽  
David H. Birnie ◽  
Michael H. Gollob
Keyword(s):  
Genetic Testing ◽  
Short Qt Syndrome ◽  
Qt Syndrome ◽  
Rapid Genetic Testing

scholarly journals Short QT syndrome in a boy diagnosed on screening for heart disease

2014 ◽  
Vol 56 (5) ◽  
pp. 774-776 ◽  
Author(s):  
Hiroshi Suzuki ◽  
Satoshi Hoshina ◽  
Junichi Ozawa ◽  
Akinori Sato ◽  
Tohru Minamino ◽  
...  
Keyword(s):  
Heart Disease ◽  
Short Qt Syndrome ◽  
Qt Syndrome

Genetic testing and cascade screening in pediatric long QT syndrome and hypertrophic cardiomyopathy

Heart Rhythm ◽  
2020 ◽  
Vol 17 (1) ◽  
pp. 106-112 ◽  
Author(s):  
Linda M. Knight ◽  
Erin Miller ◽  
Joshua Kovach ◽  
Patricia Arscott ◽  
Johannes C. von Alvensleben ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Hypertrophic Cardiomyopathy ◽  
Long Qt Syndrome ◽  
Cascade Screening ◽  
Long Qt ◽  
Qt Syndrome

Evaluation of Prolonged QT Interval: Structural Heart Disease Mimicking Long QT Syndrome

2017 ◽  
Vol 40 (4) ◽  
pp. 417-424 ◽  
Author(s):  
ADAYA WEISSLER-SNIR ◽  
MICHAEL H. GOLLOB ◽  
VIJAY CHAUHAN ◽  
MELANIE CARE ◽  
DANNA A. SPEARS
Keyword(s):  
Heart Disease ◽  
Long Qt Syndrome ◽  
Qt Interval ◽  
Structural Heart Disease ◽  
Long Qt ◽  
Prolonged Qt Interval ◽  
Prolonged Qt ◽  
Qt Syndrome

scholarly journals Clinical impact of low coverage in whole-exome genetic testing in the assessment of familial arrhythmogenic right ventricular cardiomyopathy: a case report

2021 ◽  
Vol 5 (6) ◽  
Author(s):  
Sarah Costa ◽  
Elisa Pons ◽  
Argelia Medeiros-Domingo ◽  
Ardan M Saguner
Keyword(s):  
Genetic Testing ◽  
Right Ventricular ◽  
Genetic Screening ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Screening Method ◽  
Missense Variant ◽  
Ventricular Cardiomyopathy ◽  
Cascade Screening ◽  
Good Tool ◽  
Whole Exome

Abstract Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited condition, with approximately 60% of patients carrying a possibly disease-causing genetic variant. Known desmosomal genes account for about 50% of those variants. We herein report a family with ARVC in which a pathogenic desmosomal variant was missed because of the initial genetic testing method. Case summary A 54-year-old man diagnosed with ARVC underwent genetic cascade screening for a heterozygous titin variant (TTN: c.26542C>T), detected in his phenotypically affected sister. He did not harbour this TTN variant. Moreover, reclassification of this variant based on the American College of Medical Genetics (ACMG) 2015 criteria showed it to be likely benign. Upon genetic re-screening with a dedicated cardiomyopathy panel a heterozygous missense variant in desmoglein-2 (DSG2: c.152G>C) was found. His sister’s DNA was re-analysed and the same DSG2 variant was detected, and classified as LP (likely pathogenic) by current literature. Discussion The initial genetic screening tool used in the patient’s sister (whole-exome sequencing, WES) failed to detect the likely causative desmosomal variant in our family. While WES represents a good tool in searching for novel genes in Trio Analysis, it has a low DNA coverage in important regions (mean 10×) of known ARVC-associated genes. We therefore propose using smaller panels with better coverage in the clinical setting, such as Trusight-cardio (mean DNA coverage 100–300×) as an initial genetic screening method.

scholarly journals Sudden death in a young patient with atrial fibrillation

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
María Tamargo ◽  
María Ángeles Espinosa ◽  
Víctor Gómez-Carrillo ◽  
Miriam Juárez ◽  
Francisco Fernández-Avilés ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Cardiac Arrest ◽  
Genetic Testing ◽  
Sudden Death ◽  
Clinical Data ◽  
Molecular Mechanisms ◽  
Young Patients ◽  
Structural Heart Disease ◽  
Polymorphic Ventricular Tachycardia ◽  
Qt Syndrome

Sudden cardiac death (SCD) in young patients without structural heart disease is frequently due to inherited channelopathies such as long QT syndrome (LQTS), Brugada syndrome or Catecholaminergic polymorphic ventricular tachycardia. Accordingly, the addition of genetic testing to clinical data may be useful to identify the cause of the sudden death in this population. Mutations in the KCNQ1 encoded Kv7.1 channel are related to type 1 LQTS, familial atrial fibrillation (AF), short QT syndrome, and SCD. We present a clinical case where the presence of AF after resuscitation in a young man with cardiac arrest was the key clinical data to suspect an inherited disorder and genetic testing was the main determinant for identifying the cause of the cardiac arrest. The KCNQ1 p.Arg231His mutation explained the combined phenotype of AF and susceptibility to ventricular arrhythmias. The case highlights the importance of continued research in genetics and molecular mechanisms of channelopathies.

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