دورية أكاديمية
Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Desmosomal Variants Are Rarely De Novo.
| العنوان: | Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Desmosomal Variants Are Rarely De Novo. |
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| المؤلفون: | van Lint FHM; Department of Genetics, University Medical Center Utrecht, Utrecht University (F.H.M.v.L., J.J.v.d.S., D.D., J.P.v.T.).; Amsterdam UMC, University of Amsterdam, Department of Clinical Genetics, the Netherlands (F.H.M.v.L., R.Z., R.H.L.D., J.P.v.T., C.A.J.)., Murray B; Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD (B.M., C.T., N.A., H.C., D.P.J., C.A.J.)., Tichnell C; Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD (B.M., C.T., N.A., H.C., D.P.J., C.A.J.)., Zwart R; Amsterdam UMC, University of Amsterdam, Department of Clinical Genetics, the Netherlands (F.H.M.v.L., R.Z., R.H.L.D., J.P.v.T., C.A.J.)., Amat N; Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD (B.M., C.T., N.A., H.C., D.P.J., C.A.J.)., Lekanne Deprez RH; Amsterdam UMC, University of Amsterdam, Department of Clinical Genetics, the Netherlands (F.H.M.v.L., R.Z., R.H.L.D., J.P.v.T., C.A.J.)., Dittmann S; Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases, University Hospital Münster, Münster, Germany (S.D., B.S., E.S.-B.)., Stallmeyer B; Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases, University Hospital Münster, Münster, Germany (S.D., B.S., E.S.-B.)., Calkins H; Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD (B.M., C.T., N.A., H.C., D.P.J., C.A.J.)., van der Smagt JJ; Department of Genetics, University Medical Center Utrecht, Utrecht University (F.H.M.v.L., J.J.v.d.S., D.D., J.P.v.T.)., van den Wijngaard A; Department of Clinical Genetics, Maastricht University Medical Centre, the Netherlands (A.v.d.W.)., Dooijes D; Department of Genetics, University Medical Center Utrecht, Utrecht University (F.H.M.v.L., J.J.v.d.S., D.D., J.P.v.T.)., van der Zwaag PA; University of Groningen, Department of Genetics, University Medical Center Groningen (P.A.v.d.Z., J.D.H.J.)., Schulze-Bahr E; Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases, University Hospital Münster, Münster, Germany (S.D., B.S., E.S.-B.)., Judge DP; Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD (B.M., C.T., N.A., H.C., D.P.J., C.A.J.)., Jongbloed JDH; University of Groningen, Department of Genetics, University Medical Center Groningen (P.A.v.d.Z., J.D.H.J.)., van Tintelen JP; Department of Genetics, University Medical Center Utrecht, Utrecht University (F.H.M.v.L., J.J.v.d.S., D.D., J.P.v.T.).; Amsterdam UMC, University of Amsterdam, Department of Clinical Genetics, the Netherlands (F.H.M.v.L., R.Z., R.H.L.D., J.P.v.T., C.A.J.)., James CA; Amsterdam UMC, University of Amsterdam, Department of Clinical Genetics, the Netherlands (F.H.M.v.L., R.Z., R.H.L.D., J.P.v.T., C.A.J.).; Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD (B.M., C.T., N.A., H.C., D.P.J., C.A.J.). |
| المصدر: | Circulation. Genomic and precision medicine [Circ Genom Precis Med] 2019 Aug; Vol. 12 (8), pp. e002467. Date of Electronic Publication: 2019 Aug 06. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 101714113 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2574-8300 (Electronic) Linking ISSN: 25748300 NLM ISO Abbreviation: Circ Genom Precis Med Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [Baltimore, MD] : Lippincott Williams & Wilkins, [2018]- |
| مواضيع طبية MeSH: | Arrhythmogenic Right Ventricular Dysplasia/*genetics , Desmosomes/*genetics, Adult ; Female ; Genetic Variation ; Humans ; Male ; Middle Aged ; Mutation ; Pedigree ; Plakophilins/genetics ; Young Adult |
| مستخلص: | Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with pathogenic/likely pathogenic (P/LP) variants in genes encoding the cardiac desmosomal proteins. Origin of these variants, including de novo mutation rate and extent of founder versus recurrent variants has implications for variant adjudication and clinical care, yet this has never been systematically investigated. Methods: We identified arrhythmogenic right ventricular cardiomyopathy probands who met 2010 Task Force Criteria and had undergone genotyping that included sequencing of the desmosomal genes (PKP2, DSP, DSG2, DSC2, and JUP) from 3 arrhythmogenic right ventricular cardiomyopathy registries in America and Europe. We classified the desmosomal variants, defined the contribution of unique versus nonunique (ie, not family-specific) P/LP variants, and identified the frequency and characteristics of de novo variants. Next, we haplotyped nonunique variants to determine how often they likely represent a single mutation event in a common ancestor (implied by shared haplotypes) versus multiple mutation events at the same genetic location. Results: Of 501 arrhythmogenic right ventricular cardiomyopathy probands, 322 (64.3%) carried 327 desmosomal P/LP variants. Most variants (n=247, 75.6%, in 245 patients) were identified in more than one proband and, therefore, considered nonunique. For 212/327 variants (64.8%) genetic cascade screening was performed extensively enough to identify the parental origin of the P/LP variant. Only 3 variants were de novo, 2 of which were whole gene deletions. For 24 nonunique P/LP PKP2 variants, haplotyping was conducted in 183 available families. For all 24 variants, multiple seemingly unrelated families sharing identical haplotypes were identified, suggesting that these variants originate from common founders. Conclusions: Most desmosomal P/LP variants are inherited, nonunique, and originate from ancient founders. Two of 3 de novo variants were large deletions. These observations inform genetic testing, cascade screening, and variant adjudication. |
| فهرسة مساهمة: | Keywords: arrhythmogenic right ventricular cardiomyopathy; desmosome; genetics; genotype; haplotypes |
| المشرفين على المادة: | 0 (PKP2 protein, human) 0 (Plakophilins) |
| تواريخ الأحداث: | Date Created: 20190807 Date Completed: 20200723 Latest Revision: 20200723 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1161/CIRCGEN.119.002467 |
| PMID: | 31386562 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2574-8300 |
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| DOI: | 10.1161/CIRCGEN.119.002467 |