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Recent Advance in Cardiovascular Genetics
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Recent Advance in Cardiovascular Genetics

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (15 October 2022) | Viewed by 15459

Special Issue Editors

Dr. Andreas Brodehl

E-Mail Website
Guest Editor
Heart and Diabetes Centre NRW, University Hospital Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany
Interests: genetic cardiomyopathies; ARVC; DCM; RCM; cardiovascular biochemistry
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Hendrik Milting

E-Mail Website
Guest Editor
Heart and Diabetes Centre NRW, University Hospital Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany
Interests: molecular and cellular pathomechanism of cardiomyopathies
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Brenda Gerull

E-Mail Website
Guest Editor
Comprehensive Heart Failure Center and Department of Internal Medicine I, University Hospital Würzburg, D-97080 Würzburg, Germany
Interests: clinical and molecular genetics of cardiomyopathies; genetic diagnostics; molecular and cellular mechanisms; therapy in pre-clinical model systems
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Over thirty years ago, the first pathogenic mutation in MYH7, encoding the myosin heavy chain associated with hypertrophic cardiomyopathy was described. Since the beginnings of cardiovascular genetics, it became evident in thousands of clinical cases that many cardiomyopathies—channelopathies as well as complex multi-genetic diseases like coronary artery disease—have a genetic etiology. The development of next-generation sequencing techniques led to an impressive gain of genetic insights into cardiovascular diseases during the last several decades. However, the increasing number of different genes and mutations involved in cardiomyopathies and channelopathies as well as the complexity of polygenic cardiovascular diseases cause novel challenges in research and in clinical practice. Technical progress in genomics, bioinformatics, as well as genome editing lead to remarkable molecular insights and translational aspects in the context of personalized medicine. Novel animal and cell culture models like cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) contribute to important discoveries in cardiovascular genetics.

In summary, the aim of this Special Issue entitled “Cardiovascular Genetics 2.0 Edition” is to present state-of-the art review articles summarizing trends within the scientific community as well as to publish original articles providing novel molecular insights into genetic or genomic aspects of cardiovascular diseases. Especially, studies with a focus on translational research or the development of suitable gene-specific therapies for cardiovascular diseases are highly welcome.

Dr. Andreas Brodehl
Prof. Dr. Hendrik Milting
Prof. Dr. Brenda Gerull
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Cardiovascular genetics
  • Cardiomyopathies
  • Channelopathies
  • Heart failure
  • Coronary artery disease
  • Gene therapy

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Published Papers (4 papers)

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Research

12 pages, 522 KiB  
Article
Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA
by Ilse Meerschaut, Wouter Steyaert, Thierry Bové, Katrien François, Thomas Martens, Katya De Groote, Hans De Wilde, Laura Muiño Mosquera, Joseph Panzer, Kristof Vandekerckhove, Lara Moons, Petra Vermassen, Sofie Symoens, Paul J. Coucke, Daniël De Wolf and Bert Callewaert
Genes 2022, 13(7), 1214; https://doi.org/10.3390/genes13071214 - 7 Jul 2022
Cited by 7 | Viewed by 2650
Abstract
Congenital heart defects (CHD) are the most common congenital anomalies in liveborn children. In contrast to syndromic CHD (SCHD), the genetic basis of isolated CHD (ICHD) is complex, and the underlying pathogenic mechanisms appear intricate and are incompletely understood. Next to rare Mendelian [...] Read more.
Congenital heart defects (CHD) are the most common congenital anomalies in liveborn children. In contrast to syndromic CHD (SCHD), the genetic basis of isolated CHD (ICHD) is complex, and the underlying pathogenic mechanisms appear intricate and are incompletely understood. Next to rare Mendelian conditions, somatic mosaicism or a complex multifactorial genetic architecture are assumed for most ICHD. We performed exome sequencing (ES) in 73 parent–offspring ICHD trios using proband DNA extracted from cardiac tissue. We identified six germline de novo variants and 625 germline rare inherited variants with ‘damaging’ in silico predictions in cardiac-relevant genes expressed in the developing human heart. There were no CHD-relevant somatic variants. Transmission disequilibrium testing (TDT) and association testing (AT) yielded no statistically significant results, except for the AT of missense variants in cilia genes. Somatic mutations are not a common cause of ICHD. Rare de novo and inherited protein-damaging variants may contribute to ICHD, possibly as part of an oligogenic or polygenic disease model. TDT and AT failed to provide informative results, likely due to the lack of power, but provided a framework for future studies in larger cohorts. Overall, the diagnostic value of ES on cardiac tissue is limited in individual ICHD cases. Full article
(This article belongs to the Special Issue Recent Advance in Cardiovascular Genetics)
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18 pages, 2431 KiB  
Article
Examining the Association between Mitochondrial Genome Variation and Coronary Artery Disease
by Baiba Vilne, Aniket Sawant and Irina Rudaka
Genes 2022, 13(3), 516; https://doi.org/10.3390/genes13030516 - 15 Mar 2022
Cited by 3 | Viewed by 3399
Abstract
Large-scale genome-wide association studies have identified hundreds of single-nucleotide variants (SNVs) significantly associated with coronary artery disease (CAD). However, collectively, these explain <20% of the heritability. Hypothesis: Here, we hypothesize that mitochondrial (MT)-SNVs might present one potential source of this “missing heritability”. Methods: [...] Read more.
Large-scale genome-wide association studies have identified hundreds of single-nucleotide variants (SNVs) significantly associated with coronary artery disease (CAD). However, collectively, these explain <20% of the heritability. Hypothesis: Here, we hypothesize that mitochondrial (MT)-SNVs might present one potential source of this “missing heritability”. Methods: We analyzed 265 MT-SNVs in ~500,000 UK Biobank individuals, exploring two different CAD definitions: a more stringent (myocardial infarction and/or revascularization; HARD = 20,405), and a more inclusive (angina and chronic ischemic heart disease; SOFT = 34,782). Results: In HARD cases, the most significant (p < 0.05) associations were for m.295C>T (control region) and m.12612A>G (ND5), found more frequently in cases (OR = 1.05), potentially related to reduced cardiorespiratory fitness in response to exercise, as well as for m.12372G>A (ND5) and m.11467A>G (ND4), present more frequently in controls (OR = 0.97), previously associated with lower ROS production rate. In SOFT cases, four MT-SNVs survived multiple testing corrections (at FDR < 5%), all potentially conferring increased CAD risk. Of those, m.11251A>G (ND4) and m.15452C>A (CYB) have previously shown significant associations with body height. In line with this, we observed that CAD cases were slightly less physically active, and their average body height was ~2.00 cm lower compared to controls; both traits are known to be related to increased CAD risk. Gene-based tests identified CO2 associated with HARD/SOFT CAD, whereas ND3 and CYB associated with SOFT cases (p < 0.05), dysfunction of which has been related to MT oxidative stress, obesity/T2D (CO2), BMI (ND3), and angina/exercise intolerance (CYB). Finally, we observed that macro-haplogroup I was significantly (p < 0.05) more frequent in HARD cases vs. controls (3.35% vs. 3.08%), potentially associated with response to exercise. Conclusions: We found only spurious associations between MT genome variation and HARD/SOFT CAD and conclude that more MT-SNV data in even larger study cohorts may be needed to conclusively determine the role of MT DNA in CAD. Full article
(This article belongs to the Special Issue Recent Advance in Cardiovascular Genetics)
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15 pages, 1725 KiB  
Article
A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family
by Shafaq Ramzan, Stephanie Tennstedt, Muhammad Tariq, Sheraz Khan, Hafiza Noor Ul Ayan, Aamir Ali, Matthias Munz, Holger Thiele, Asad Aslam Korejo, Abdul Razzaq Mughal, Syed Zahid Jamal, Peter Nürnberg, Shahid Mahmood Baig, Jeanette Erdmann and Ilyas Ahmad
Genes 2021, 12(8), 1282; https://doi.org/10.3390/genes12081282 - 21 Aug 2021
Cited by 9 | Viewed by 4498
Abstract
Cardiac conduction disease (CCD), which causes altered electrical impulse propagation in the heart, is a life-threatening condition with high morbidity and mortality. It exhibits genetic and clinical heterogeneity with diverse pathomechanisms, but in most cases, it disrupts the synchronous activity of impulse-generating nodes [...] Read more.
Cardiac conduction disease (CCD), which causes altered electrical impulse propagation in the heart, is a life-threatening condition with high morbidity and mortality. It exhibits genetic and clinical heterogeneity with diverse pathomechanisms, but in most cases, it disrupts the synchronous activity of impulse-generating nodes and impulse-conduction underlying the normal heartbeat. In this study, we investigated a consanguineous Pakistani family comprised of four patients with CCD. We applied whole exome sequencing (WES) and co-segregation analysis, which identified a novel homozygous missense mutation (c.1531T>C;(p.Ser511Pro)) in the highly conserved kinase domain of the cardiac troponin I-interacting kinase (TNNI3K) encoding gene. The behaviors of mutant and native TNNI3K were compared by performing all-atom long-term molecular dynamics simulations, which revealed changes at the protein surface and in the hydrogen bond network. Furthermore, intra and intermolecular interaction analyses revealed that p.Ser511Pro causes structural variation in the ATP-binding pocket and the homodimer interface. These findings suggest p.Ser511Pro to be a pathogenic variant. Our study provides insights into how the variant perturbs the TNNI3K structure-function relationship, leading to a disease state. This is the first report of a recessive mutation in TNNI3K and the first mutation in this gene identified in the Pakistani population. Full article
(This article belongs to the Special Issue Recent Advance in Cardiovascular Genetics)
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13 pages, 2213 KiB  
Article
The Combined Human Genotype of Truncating TTN and RBM20 Mutations Is Associated with Severe and Early Onset of Dilated Cardiomyopathy
by Anna Gaertner, Julia Bloebaum, Andreas Brodehl, Baerbel Klauke, Katharina Sielemann, Astrid Kassner, Henrik Fox, Michiel Morshuis, Jens Tiesmeier, Uwe Schulz, Ralph Knoell, Jan Gummert and Hendrik Milting
Genes 2021, 12(6), 883; https://doi.org/10.3390/genes12060883 - 8 Jun 2021
Cited by 15 | Viewed by 3786
Abstract
A major cause of heart failure is cardiomyopathies, with dilated cardiomyopathy (DCM) as the most common form. Over 40 genes are linked to DCM, among them TTN and RBM20. Next Generation Sequencing in clinical DCM cohorts revealed truncating variants in TTN ( [...] Read more.
A major cause of heart failure is cardiomyopathies, with dilated cardiomyopathy (DCM) as the most common form. Over 40 genes are linked to DCM, among them TTN and RBM20. Next Generation Sequencing in clinical DCM cohorts revealed truncating variants in TTN (TTNtv), accounting for up to 25% of familial DCM cases. Mutations in the cardiac splicing factor RNA binding motif protein 20 (RBM20) are also known to be associated with severe cardiomyopathies. TTN is one of the major RBM20 splicing targets. Most of the pathogenic RBM20 mutations are localized in the highly conserved arginine serine rich domain (RS), leading to a cytoplasmic mislocalization of mutant RBM20. Here, we present a patient with an early onset DCM carrying a combination of (likely) pathogenic TTN and RBM20 mutations. We show that the splicing of RBM20 target genes is affected in the mutation carrier. Furthermore, we reveal RBM20 haploinsufficiency presumably caused by the frameshift mutation in RBM20. Full article
(This article belongs to the Special Issue Recent Advance in Cardiovascular Genetics)
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