Identification of <i>SCN5a</i> p.C335R Variant in a Large Family with Dilated Cardiomyopathy and Conduction Disease
Introduction: Familial dilated cardiomyopathy (DCM) is clinically variable and has been associated with mutations in more than 50 genes. Rapid improvements in DNA sequencing have led to the identification of diverse rare variants with unknown significance (VUS), which underlines the importance of fu...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-11-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/23/12990 |
| _version_ | 1797507694731460608 |
|---|---|
| author | Farbod Sedaghat-Hamedani Sabine Rebs Ibrahim El-Battrawy Safak Chasan Tobias Krause Jan Haas Rujia Zhong Zhenxing Liao Qiang Xu Xiaobo Zhou Ibrahim Akin Edgar Zitron Norbert Frey Katrin Streckfuss-Bömeke Elham Kayvanpour |
| author_facet | Farbod Sedaghat-Hamedani Sabine Rebs Ibrahim El-Battrawy Safak Chasan Tobias Krause Jan Haas Rujia Zhong Zhenxing Liao Qiang Xu Xiaobo Zhou Ibrahim Akin Edgar Zitron Norbert Frey Katrin Streckfuss-Bömeke Elham Kayvanpour |
| author_sort | Farbod Sedaghat-Hamedani |
| collection | DOAJ |
| description | Introduction: Familial dilated cardiomyopathy (DCM) is clinically variable and has been associated with mutations in more than 50 genes. Rapid improvements in DNA sequencing have led to the identification of diverse rare variants with unknown significance (VUS), which underlines the importance of functional analyses. In this study, by investigating human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we evaluated the pathogenicity of the p.C335R sodium voltage-gated channel alpha subunit 5 (<i>SCN5a</i>) variant in a large family with familial DCM and conduction disease. Methods: A four-generation family with autosomal dominant familial DCM was investigated. Next-generation sequencing (NGS) was performed in all 16 family members. Clinical deep phenotyping, including endomyocardial biopsy, was performed. Skin biopsies from two patients and one healthy family member were used to generate human-induced pluripotent stem cells (iPSCs), which were then differentiated into cardiomyocytes. Patch-clamp analysis with <i>Xenopus</i> oocytes and iPSC-CMs were performed. Results: A <i>SCN5a</i> variant (c.1003T>C; p.C335R) could be detected in all family members with DCM or conduction disease. A novel truncating <i>TTN</i> variant (p.Ser24998LysfsTer28) could also be identified in two family members with DCM. Family members with the <i>SCN5a</i> variant (p.C335R) showed significantly longer PQ and QRS intervals and lower left ventricular ejection fractions (LV-EF). All four patients who received CRT-D were non-responders. Electrophysiological analysis with <i>Xenopus</i> oocytes showed a loss of function in <i>SCN5a</i> p.C335R. Na<sup>+</sup> channel currents were also reduced in iPSC-CMs from DCM patients. Furthermore, iPSC-CM with compound heterozygosity (<i>SCN5a</i> p.C335R and <i>TTNtv</i>) showed significant dysregulation of sarcomere structures, which may be contributed to the severity of the disease and earlier onset of DCM. Conclusion: The <i>SCN5a</i> p.C335R variant is causing a loss of function of peak INa in patients with DCM and cardiac conduction disease. The co-existence of genetic variants in channels and structural genes (e.g., <i>SCN5a</i> p.C335R and <i>TTNtv</i>) increases the severity of the DCM phenotype. |
| first_indexed | 2024-03-10T04:52:05Z |
| format | Article |
| id | doaj.art-378146170755471f826219b3da298792 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:52:05Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-378146170755471f826219b3da2987922023-11-23T02:31:22ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122231299010.3390/ijms222312990Identification of <i>SCN5a</i> p.C335R Variant in a Large Family with Dilated Cardiomyopathy and Conduction DiseaseFarbod Sedaghat-Hamedani0Sabine Rebs1Ibrahim El-Battrawy2Safak Chasan3Tobias Krause4Jan Haas5Rujia Zhong6Zhenxing Liao7Qiang Xu8Xiaobo Zhou9Ibrahim Akin10Edgar Zitron11Norbert Frey12Katrin Streckfuss-Bömeke13Elham Kayvanpour14Department of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University of Heidelberg, 69120 Heidelberg, GermanyClinic for Cardiology and Pneumology, Georg-August-University Göttingen, 37073 Göttingen, GermanyDZHK (German Centre for Cardiovascular Research), Heidelberg-Mannheim, 17475 Greifswald, GermanyDepartment of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University of Heidelberg, 69120 Heidelberg, GermanyDepartment of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University of Heidelberg, 69120 Heidelberg, GermanyDepartment of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University of Heidelberg, 69120 Heidelberg, GermanyDepartment of Medicine, University Medical Centre Mannheim (UMM), 68159 Mannheim, GermanyDepartment of Medicine, University Medical Centre Mannheim (UMM), 68159 Mannheim, GermanyDepartment of Medicine, University Medical Centre Mannheim (UMM), 68159 Mannheim, GermanyDZHK (German Centre for Cardiovascular Research), Heidelberg-Mannheim, 17475 Greifswald, GermanyDZHK (German Centre for Cardiovascular Research), Heidelberg-Mannheim, 17475 Greifswald, GermanyDepartment of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University of Heidelberg, 69120 Heidelberg, GermanyDepartment of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University of Heidelberg, 69120 Heidelberg, GermanyClinic for Cardiology and Pneumology, Georg-August-University Göttingen, 37073 Göttingen, GermanyDepartment of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University of Heidelberg, 69120 Heidelberg, GermanyIntroduction: Familial dilated cardiomyopathy (DCM) is clinically variable and has been associated with mutations in more than 50 genes. Rapid improvements in DNA sequencing have led to the identification of diverse rare variants with unknown significance (VUS), which underlines the importance of functional analyses. In this study, by investigating human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we evaluated the pathogenicity of the p.C335R sodium voltage-gated channel alpha subunit 5 (<i>SCN5a</i>) variant in a large family with familial DCM and conduction disease. Methods: A four-generation family with autosomal dominant familial DCM was investigated. Next-generation sequencing (NGS) was performed in all 16 family members. Clinical deep phenotyping, including endomyocardial biopsy, was performed. Skin biopsies from two patients and one healthy family member were used to generate human-induced pluripotent stem cells (iPSCs), which were then differentiated into cardiomyocytes. Patch-clamp analysis with <i>Xenopus</i> oocytes and iPSC-CMs were performed. Results: A <i>SCN5a</i> variant (c.1003T>C; p.C335R) could be detected in all family members with DCM or conduction disease. A novel truncating <i>TTN</i> variant (p.Ser24998LysfsTer28) could also be identified in two family members with DCM. Family members with the <i>SCN5a</i> variant (p.C335R) showed significantly longer PQ and QRS intervals and lower left ventricular ejection fractions (LV-EF). All four patients who received CRT-D were non-responders. Electrophysiological analysis with <i>Xenopus</i> oocytes showed a loss of function in <i>SCN5a</i> p.C335R. Na<sup>+</sup> channel currents were also reduced in iPSC-CMs from DCM patients. Furthermore, iPSC-CM with compound heterozygosity (<i>SCN5a</i> p.C335R and <i>TTNtv</i>) showed significant dysregulation of sarcomere structures, which may be contributed to the severity of the disease and earlier onset of DCM. Conclusion: The <i>SCN5a</i> p.C335R variant is causing a loss of function of peak INa in patients with DCM and cardiac conduction disease. The co-existence of genetic variants in channels and structural genes (e.g., <i>SCN5a</i> p.C335R and <i>TTNtv</i>) increases the severity of the DCM phenotype.https://www.mdpi.com/1422-0067/22/23/12990familial DCM<i>SCN5a</i>conduction disease |
| spellingShingle | Farbod Sedaghat-Hamedani Sabine Rebs Ibrahim El-Battrawy Safak Chasan Tobias Krause Jan Haas Rujia Zhong Zhenxing Liao Qiang Xu Xiaobo Zhou Ibrahim Akin Edgar Zitron Norbert Frey Katrin Streckfuss-Bömeke Elham Kayvanpour Identification of <i>SCN5a</i> p.C335R Variant in a Large Family with Dilated Cardiomyopathy and Conduction Disease International Journal of Molecular Sciences familial DCM <i>SCN5a</i> conduction disease |
| title | Identification of <i>SCN5a</i> p.C335R Variant in a Large Family with Dilated Cardiomyopathy and Conduction Disease |
| title_full | Identification of <i>SCN5a</i> p.C335R Variant in a Large Family with Dilated Cardiomyopathy and Conduction Disease |
| title_fullStr | Identification of <i>SCN5a</i> p.C335R Variant in a Large Family with Dilated Cardiomyopathy and Conduction Disease |
| title_full_unstemmed | Identification of <i>SCN5a</i> p.C335R Variant in a Large Family with Dilated Cardiomyopathy and Conduction Disease |
| title_short | Identification of <i>SCN5a</i> p.C335R Variant in a Large Family with Dilated Cardiomyopathy and Conduction Disease |
| title_sort | identification of i scn5a i p c335r variant in a large family with dilated cardiomyopathy and conduction disease |
| topic | familial DCM <i>SCN5a</i> conduction disease |
| url | https://www.mdpi.com/1422-0067/22/23/12990 |
| work_keys_str_mv | AT farbodsedaghathamedani identificationofiscn5aipc335rvariantinalargefamilywithdilatedcardiomyopathyandconductiondisease AT sabinerebs identificationofiscn5aipc335rvariantinalargefamilywithdilatedcardiomyopathyandconductiondisease AT ibrahimelbattrawy identificationofiscn5aipc335rvariantinalargefamilywithdilatedcardiomyopathyandconductiondisease AT safakchasan identificationofiscn5aipc335rvariantinalargefamilywithdilatedcardiomyopathyandconductiondisease AT tobiaskrause identificationofiscn5aipc335rvariantinalargefamilywithdilatedcardiomyopathyandconductiondisease AT janhaas identificationofiscn5aipc335rvariantinalargefamilywithdilatedcardiomyopathyandconductiondisease AT rujiazhong identificationofiscn5aipc335rvariantinalargefamilywithdilatedcardiomyopathyandconductiondisease AT zhenxingliao identificationofiscn5aipc335rvariantinalargefamilywithdilatedcardiomyopathyandconductiondisease AT qiangxu identificationofiscn5aipc335rvariantinalargefamilywithdilatedcardiomyopathyandconductiondisease AT xiaobozhou identificationofiscn5aipc335rvariantinalargefamilywithdilatedcardiomyopathyandconductiondisease AT ibrahimakin identificationofiscn5aipc335rvariantinalargefamilywithdilatedcardiomyopathyandconductiondisease AT edgarzitron identificationofiscn5aipc335rvariantinalargefamilywithdilatedcardiomyopathyandconductiondisease AT norbertfrey identificationofiscn5aipc335rvariantinalargefamilywithdilatedcardiomyopathyandconductiondisease AT katrinstreckfussbomeke identificationofiscn5aipc335rvariantinalargefamilywithdilatedcardiomyopathyandconductiondisease AT elhamkayvanpour identificationofiscn5aipc335rvariantinalargefamilywithdilatedcardiomyopathyandconductiondisease |