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

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

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

scholarly journals Cost-Effectiveness of Genetic Testing in Family Members of Patients With Long-QT Syndrome

2011 ◽  
Vol 4 (1) ◽  
pp. 76-84 ◽  
Author(s):  
Marco V. Perez ◽  
Narmadan A. Kumarasamy ◽  
Douglas K. Owens ◽  
Paul J. Wang ◽  
Mark A. Hlatky
Keyword(s):  
Genetic Testing ◽  
Cost Effectiveness ◽  
Long Qt Syndrome ◽  
Family Members ◽  
Long Qt ◽  
Qt Syndrome

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

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

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.

Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Emily Breidbart ◽  
Liyong Deng ◽  
Patricia Lanzano ◽  
Xiao Fan ◽  
Jiancheng Guo ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Exome Sequencing ◽  
Large Scale ◽  
Age Of Onset ◽  
Family Members ◽  
Ethnically Diverse ◽  
Monogenic Diabetes ◽  
Diabetes Diagnosis ◽  
Pathogenic Variants ◽  
Atypical Diabetes

Abstract Objectives There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY. Methods We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A. The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%. Results Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A. Less frequently, mutations were identified in PDX1, HNF4A, HNF1B, and KCNJ11. For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation. Conclusions Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.

scholarly journals Clinical impact of post-mortem genetic testing in cardiac death and cardiomyopathy

Open Medicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 435-446
Author(s):  
Isabelle Marey ◽  
Véronique Fressart ◽  
Caroline Rambaud ◽  
Paul Fornes ◽  
Laurent Martin ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Cardiac Death ◽  
De Novo ◽  
Family Care ◽  
Prenatal Testing ◽  
Added Value ◽  
Molecular Testing ◽  
Post Mortem ◽  
Genetic Analyses ◽  
Conventional Autopsy

AbstractPost-mortem genetic analyses may help to elucidate the cause of cardiac death. The added value is however unclear when a cardiac disease is already suspected or affirmed. Our aim was to study the feasibility and medical impact of post-mortem genetic analyses in suspected cardiomyopathy. We studied 35 patients with cardiac death and suspected cardiomyopathy based on autopsy or clinical data. After targeted sequencing, we identified 15 causal variants in 15 patients (yield 43%) in sarcomeric (n = 8), desmosomal (n = 3), lamin A/C (n = 3) and transthyretin (n = 1) genes. The results had various impacts on families, i.e. allowed predictive genetic testing in relatives (15 families), planned early therapeutics based on the specific underlying gene (5 families), rectified the suspected cardiomyopathy subtype (2 families), assessed the genetic origin of cardiomyopathy that usually has an acquired cause (1 family), assessed the diagnosis in a patient with uncertain borderline cardiomyopathy (1 family), reassured the siblings because of a de novo mutation (2 families) and allowed prenatal testing (1 family). Our findings suggest that post-mortem molecular testing should be included in the strategy of family care after cardiac death and suspected cardiomyopathy, since genetic findings provide additional information useful for relatives, which are beyond conventional autopsy.

scholarly journals Cascade screening for glaucoma in high-risk family members of African-Caribbean glaucoma patients in an urban population in London

2020 ◽  
pp. bjophthalmol-2020-317373
Author(s):  
Anindyt Nagar ◽  
Sam Myers ◽  
Diana Kozareva ◽  
Mark Simcoe ◽  
Christopher Hammond
Keyword(s):  
High Risk ◽  
Genetic Diseases ◽  
Family Doctor ◽  
Family Members ◽  
Hospital Setting ◽  
High Risk Group ◽  
Cascade Screening ◽  
Specialist Referral ◽  
High Risk Family ◽  
African Caribbean

Background/aimsCascade screening has been used successfully in relatives of patients with inherited cancers and other genetic diseases to identify presymptomatic disease. This study was designed to examine if this approach would be successful in a high-risk group: first-degree relatives (FDR) of African-Caribbean glaucoma patients resident in London.MethodsAfrican-Caribbean patients (probands) with glaucoma from an inner London hospital setting in a deprived area were asked to disseminate personalised information to their FDR over the age of 30 and to arrange a free hospital-based screening. Data collected, including optical coherence tomography imaging, were reviewed by a glaucoma specialist and if glaucoma was diagnosed or suspected, local specialist referral via family doctor was made.Results203 probands were recruited from glaucoma clinics. 248 suitable FDR were identified as potentially eligible to attend screening. 57 (23%) FDR made contact with the research team of whom 18 (7%) attended a subsequent screening visit. No patients were diagnosed with glaucoma; one participant was diagnosed as glaucoma suspect. Reasons for poor uptake included reluctance by probands to involve their family members, and retirees spending significant time abroad.ConclusionCascade screening of FDR of African-Caribbean glaucoma patients in inner city London was unsuccessful. Research confidentiality guidance prohibiting research teams directly contacting family members was a barrier. Greater community engagement, community-based screening and permission to contact FDR directly might have improved uptake.

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