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Genetics, Genomics and Precision Medicine in Heart Diseases
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Genetics, Genomics and Precision Medicine in Heart Diseases

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

Deadline for manuscript submissions: 20 September 2024 | Viewed by 6776

Special Issue Editors

Dr. Enkhsaikhan Purevjav

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Guest Editor
Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA
Interests: pediatric cardiology; genetics of cardiovascular diseases; animal and cellular modeling; editing; reviewing; reading
Dr. Jeanne M. James

E-Mail Website
Guest Editor
School of Medicine, University of Kansas, Kansas City, KS, USA
Interests: pediatric cardiology; congenital heart diseases; arrhythmias in children; genetics; genetic syndromes; cardiomyopathy
Dr. Hugo R. Martinez

E-Mail Website
Guest Editor
Health Science Center, University of Tennessee, Memphis, TN, USA
Interests: advanced cardiac therapies; heart transplant; cardiovascular genetics; cardiomyopathy; cardio-oncology

Special Issue Information

Dear Colleagues,

Numerous pathogenic and modifier gene variants predispose to heritable cardiovascular morbidity and mortality. In addition, some of these disorders can be syndromic, affecting other organs and systems. These diseases encompass a wide range of conditions, including congenital malformations, cardiomyopathies, arrhythmogenic disorders, dyslipidemias, and vasculopathy. Furthermore, it has been shown that environmental and non-genetic factors play important roles in the phenotype expression of cardiovascular diseases.

In the current precision medicine era, discoveries in genetics, genomics, and genotype–phenotype association investigations have started to emerge toward precision therapies. We believe that proactive precision medicine represents the future of preventive and predictive individualized healthcare. This Special Issue is dedicated to the discoveries and emerging concepts of genetics, genomics, and precision medicine of inherited cardiovascular diseases, particularly in pediatric patients. We welcome reviews and original articles uncovering the clues of genetic and genomic bases, finding the mechanisms and pathogenesis, and employing novel genetics-oriented diagnosis and treatments of heritable cardiovascular diseases.

Dr. Enkhsaikhan Purevjav
Dr. Jeanne M. James
Dr. Hugo R. Martinez
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

  • congenital heart diseases
  • cardiomyopathy
  • arrhythmias in pediatric patients
  • sudden cardiac death syndrome
  • genetic syndromes
  • inherited mitochondrial disorder
  • inherited metabolic syndrome
  • mutation

Published Papers (7 papers)

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Research

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24 pages, 1974 KiB  
Article
Clinical Decision Analysis of Genetic Evaluation and Testing in 1013 Intensive Care Unit Infants with Congenital Heart Defects Supports Universal Genetic Testing
by Benjamin M. Helm and Stephanie M. Ware
Genes 2024, 15(4), 505; https://doi.org/10.3390/genes15040505 - 18 Apr 2024
Viewed by 357
Abstract
Extracardiac anomalies (ECAs) are strong predictors of genetic disorders in infants with congenital heart disease (CHD), but there are no prior studies assessing performance of ECA status as a screen for genetic diagnoses in CHD patients. This retrospective cohort study assessed this in [...] Read more.
Extracardiac anomalies (ECAs) are strong predictors of genetic disorders in infants with congenital heart disease (CHD), but there are no prior studies assessing performance of ECA status as a screen for genetic diagnoses in CHD patients. This retrospective cohort study assessed this in our comprehensive inpatient CHD genetics service focusing on neonates and infants admitted to the intensive care unit (ICU). The performance and diagnostic utility of using ECA status to screen for genetic disorders was assessed using decision curve analysis, a statistical tool to assess clinical utility, determining the threshold of phenotypic screening by ECA versus a Test-All approach. Over 24% of infants had genetic diagnoses identified (n = 244/1013), and ECA-positive status indicated a 4-fold increased risk of having a genetic disorder. However, ECA status had low–moderate screening performance based on predictive summary index, a compositive measure of positive and negative predictive values. For those with genetic diagnoses, nearly one-third (32%, 78/244) were ECA-negative but had cytogenetic and/or monogenic disorders identified by genetic testing. Thus, if the presence of multiple congenital anomalies is the phenotypic driver to initiate genetic testing, 13.4% (78/580) of infants with isolated CHD with identifiable genetic causes will be missed. Given the prevalence of genetic disorders and limited screening performance of ECA status, this analysis supports genetic testing in all CHD infants in intensive care settings rather than screening based on ECA. Full article
(This article belongs to the Special Issue Genetics, Genomics and Precision Medicine in Heart Diseases)
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10 pages, 537 KiB  
Article
SNARE-ing the Reason for Post-Cardiac Surgery Critical Illness-Related Corticosteroid Insufficiency
by Nicholas Diehl, Natalia Kibiryeva, Jennifer Marshall, Sarah L. Tsai, Juan S. Farias, Jaime Silva-Gburek and Lori A. Erickson
Genes 2024, 15(1), 128; https://doi.org/10.3390/genes15010128 - 20 Jan 2024
Viewed by 857
Abstract
Critical illness-related corticosteroid insufficiency (CIRCI) can cause hemodynamic instability in neonates after congenital heart surgery with manifestations that increase morbidity and potential mortality. We retrospectively reviewed neonates who underwent cardiac surgery between August 2018 and July 2020 at a freestanding children’s hospital, had [...] Read more.
Critical illness-related corticosteroid insufficiency (CIRCI) can cause hemodynamic instability in neonates after congenital heart surgery with manifestations that increase morbidity and potential mortality. We retrospectively reviewed neonates who underwent cardiac surgery between August 2018 and July 2020 at a freestanding children’s hospital, had next-generation sequencing performed, and had their cortisol levels drawn as standard clinical care after cardiac surgery. The groups were defined as CIRCI (with a cortisol level ≤ 4.5 mcg/dL) and non-CIRCI (level > 4.5 mcg/dL). The CIRCI group (n = 8) had a 100% incidence of heterozygous gene mutation on STX1A with splicing or loss of function, and this mutation was not found in the non-CIRCI group (n = 8). Additional gene mutations were found in the CIRCI group on RAB6A, ABCA3, SIDT2, and LILRB3, with no incidence in the non-CIRCI group. Three additional mutations were found across the CIRCI group in INPPL1 and FAM189A2 (both splicing and missense), with 12–25% of patients in the non-CIRCI group also displaying these mutations. Novel genetic abnormalities were seen in neonates with symptoms of CIRCI with potential cardiac implications from a gene mutation for STX1A. Compounding effects of additional gene mutations need to be confirmed and explored for potential predisposition to hemodynamic instability during times of stress. Full article
(This article belongs to the Special Issue Genetics, Genomics and Precision Medicine in Heart Diseases)
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17 pages, 1241 KiB  
Article
SLCO1B1 Genetic Variation Influence on Atorvastatin Systemic Exposure in Pediatric Hypercholesterolemia
by Jonathan B. Wagner, Susan Abdel-Rahman, Geetha Raghuveer, Andrea Gaedigk, Erin C. Boone, Roger Gaedigk, Vincent S. Staggs, Gregory A. Reed, Na Zhang and J. Steven Leeder
Genes 2024, 15(1), 99; https://doi.org/10.3390/genes15010099 - 15 Jan 2024
Viewed by 1130
Abstract
This clinical study examined the influence of SLCO1B1 c.521T>C (rs4149056) on plasma atorvastatin concentrations in pediatric hypercholesterolemia. The participants (8–21 years), including heterozygous (c.521T/C, n = 13), homozygous (c.521C/C, n = 2) and controls (c.521T/T, n = 13), completed a single-oral-dose pharmacokinetic study. [...] Read more.
This clinical study examined the influence of SLCO1B1 c.521T>C (rs4149056) on plasma atorvastatin concentrations in pediatric hypercholesterolemia. The participants (8–21 years), including heterozygous (c.521T/C, n = 13), homozygous (c.521C/C, n = 2) and controls (c.521T/T, n = 13), completed a single-oral-dose pharmacokinetic study. Similar to in adults, the atorvastatin (AVA) area-under-concentration-time curve from 0 to 24 h (AUC0–24) was 1.7-fold and 2.8-fold higher in participants with c.521T/C and c.521C/C compared to the c.521T/T participants, respectively. The inter-individual variability in AVA exposure within these genotype groups ranged from 2.3 to 4.8-fold, indicating that additional factors contribute to the inter-individual variability in the AVA dose–exposure relationship. A multivariate model reinforced the SLCO1B1 c.521T>C variant as the central factor contributing to AVA systemic exposure in this pediatric cohort, accounting for ~65% of the variability in AVA AUC0–24. Furthermore, lower AVA lactone concentrations in participants with increased body mass index contributed to higher exposure within the c.521T/T and c.521T/C genotype groups. Collectively, these factors contributing to higher systemic exposure could increase the risk of toxicity and should be accounted for when individualizing the dosing of atorvastatin in eligible pediatric patients. Full article
(This article belongs to the Special Issue Genetics, Genomics and Precision Medicine in Heart Diseases)
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19 pages, 18120 KiB  
Article
Exploring the Regulation and Function of Rpl3l in the Development of Early-Onset Dilated Cardiomyopathy and Congestive Heart Failure Using Systems Genetics Approach
by Akhilesh K. Bajpai, Qingqing Gu, Buyan-Ochir Orgil, Neely R. Alberson, Jeffrey A. Towbin, Hugo R. Martinez, Lu Lu and Enkhsaikhan Purevjav
Genes 2024, 15(1), 53; https://doi.org/10.3390/genes15010053 - 29 Dec 2023
Viewed by 1122
Abstract
Background: Cardiomyopathies, diseases affecting the myocardium, are common causes of congestive heart failure (CHF) and sudden cardiac death. Recently, biallelic variants in ribosomal protein L3-like (RPL3L) have been reported to be associated with severe neonatal dilated cardiomyopathy (DCM) and CHF. This study employs [...] Read more.
Background: Cardiomyopathies, diseases affecting the myocardium, are common causes of congestive heart failure (CHF) and sudden cardiac death. Recently, biallelic variants in ribosomal protein L3-like (RPL3L) have been reported to be associated with severe neonatal dilated cardiomyopathy (DCM) and CHF. This study employs a systems genetics approach to gain understanding of the regulatory mechanisms underlying the role of RPL3L in DCM. Methods: Genetic correlation, expression quantitative trait loci (eQTL) mapping, differential expression analysis and comparative functional analysis were performed using cardiac gene expression data from the patients and murine genetic reference populations (GRPs) of BXD mice (recombinant inbred strains from a cross of C57BL/6J and DBA/2J mice). Additionally, immune infiltration analysis was performed to understand the relationship between DCM, immune cells and RPL3L expression. Results: Systems genetics analysis identified high expression of Rpl3l mRNA, which ranged from 11.31 to 12.16 across murine GRPs of BXD mice, with an ~1.8-fold difference. Pathways such as “diabetic cardiomyopathy”, “focal adhesion”, “oxidative phosphorylation” and “DCM” were significantly associated with Rpl3l. eQTL mapping suggested Myl4 (Chr 11) and Sdha (Chr 13) as the upstream regulators of Rpl3l. The mRNA expression of Rpl3l, Myl4 and Sdha was significantly correlated with multiple echocardiography traits in BXD mice. Immune infiltration analysis revealed a significant association of RPL3L and SDHA with seven immune cells (CD4, CD8-naive T cell, CD8 T cell, macrophages, cytotoxic T cell, gamma delta T cell and exhausted T cell) that were also differentially infiltrated between heart samples obtained from DCM patients and normal individuals. Conclusions: RPL3L is highly expressed in the heart tissue of humans and mice. Expression of Rpl3l and its upstream regulators, Myl4 and Sdha, correlate with multiple cardiac function traits in murine GRPs of BXD mice, while RPL3L and SDHA correlate with immune cell infiltration in DCM patient hearts, suggesting important roles for RPL3L in DCM and CHF pathogenesis via immune inflammation, necessitating experimental validations of Myl4 and Sdha in Rpl3l regulation. Full article
(This article belongs to the Special Issue Genetics, Genomics and Precision Medicine in Heart Diseases)
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Review

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22 pages, 1580 KiB  
Review
Pediatric Beta Blocker Therapy: A Comprehensive Review of Development and Genetic Variation to Guide Precision-Based Therapy in Children, Adolescents, and Young Adults
by Mollie Walton and Jonathan B. Wagner
Genes 2024, 15(3), 379; https://doi.org/10.3390/genes15030379 - 20 Mar 2024
Viewed by 789
Abstract
Beta adrenergic receptor antagonists, known as beta blockers, are one of the most prescribed medications in both pediatric and adult cardiology. Unfortunately, most of these agents utilized in the pediatric clinical setting are prescribed off-label. Despite regulatory efforts aimed at increasing pediatric drug [...] Read more.
Beta adrenergic receptor antagonists, known as beta blockers, are one of the most prescribed medications in both pediatric and adult cardiology. Unfortunately, most of these agents utilized in the pediatric clinical setting are prescribed off-label. Despite regulatory efforts aimed at increasing pediatric drug labeling, a majority of pediatric cardiovascular drug agents continue to lack pediatric-specific data to inform precision dosing for children, adolescents, and young adults. Adding to this complexity is the contribution of development (ontogeny) and genetic variation towards the variability in drug disposition and response. In the absence of current prospective trials, the purpose of this comprehensive review is to illustrate the current knowledge gaps regarding the key drivers of variability in beta blocker drug disposition and response and the opportunities for investigations that will lead to changes in pediatric drug labeling. Full article
(This article belongs to the Special Issue Genetics, Genomics and Precision Medicine in Heart Diseases)
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Other

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9 pages, 1232 KiB  
Case Report
Novel MYH7 Variant in the Neonate of a Mother with Gestational Diabetes Mellitus Showing Left Ventricular Hypertrophy and Noncompaction
by Sayaka W Ozawa, Satomi Inomata, Yukiko Hata, Shinya Takarada, Mako Okabe, Hideyuki Nakaoka, Keijiro Ibuki, Naoki Nishida, Fukiko Ichida and Keiichi Hirono
Genes 2024, 15(3), 381; https://doi.org/10.3390/genes15030381 - 20 Mar 2024
Viewed by 638
Abstract
Background: Left ventricular hypertrophy (LVH) is a well-recognized cardiac dysfunction in infants of mothers with gestational diabetes mellitus (GDM). Left ventricular noncompaction (LVNC) is a cardiomyopathy that is morphologically characterized by numerous prominent trabeculations and deep intertrabecular recesses on cardiovascular imaging. However, there [...] Read more.
Background: Left ventricular hypertrophy (LVH) is a well-recognized cardiac dysfunction in infants of mothers with gestational diabetes mellitus (GDM). Left ventricular noncompaction (LVNC) is a cardiomyopathy that is morphologically characterized by numerous prominent trabeculations and deep intertrabecular recesses on cardiovascular imaging. However, there have been no case reports on neonates of mothers with GDM showing LVH and LVNC. Case presentation: A patient, with LVH of a mother with GDM, was delivered at 36 weeks of gestation. Prominent trabeculations in the LV, suggesting LVNC, instead of LVH, were apparent 1 week after birth. A heterozygous deletion variant in the MYH7 gene (NM_000257.4: c.1090T>C, p.Phe364Leu) was discovered through genetic testing using a cardiomyopathy-associated gene panel in the patient and his father and the older brother who had LVNC. The patient is now 5 years old and does not have major cardiac events, although LVNC persisted. This is the first case of LVH secondary to a mother with GDM and LVNC with a novel variant in the MYH7 gene. Conclusion: Genetic testing should be conducted to obtain an accurate outcome and medical care in a patient with LVH and subsequently prominent hypertrabeculation in the LV. Full article
(This article belongs to the Special Issue Genetics, Genomics and Precision Medicine in Heart Diseases)
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11 pages, 1619 KiB  
Case Report
A Novel Homozygous Loss-of-Function Variant in SPRED2 Causes Autosomal Recessive Noonan-like Syndrome
by Maria Elena Onore, Martina Caiazza, Antonella Farina, Gioacchino Scarano, Alberto Budillon, Rossella Nicoletta Borrelli, Giuseppe Limongelli, Vincenzo Nigro and Giulio Piluso
Genes 2024, 15(1), 32; https://doi.org/10.3390/genes15010032 - 25 Dec 2023
Viewed by 1403
Abstract
Noonan syndrome is an autosomal dominant developmental disorder characterized by peculiar facial dysmorphisms, short stature, congenital heart defects, and hypertrophic cardiomyopathy. In 2001, PTPN11 was identified as the first Noonan syndrome gene and is responsible for the majority of Noonan syndrome cases. Over [...] Read more.
Noonan syndrome is an autosomal dominant developmental disorder characterized by peculiar facial dysmorphisms, short stature, congenital heart defects, and hypertrophic cardiomyopathy. In 2001, PTPN11 was identified as the first Noonan syndrome gene and is responsible for the majority of Noonan syndrome cases. Over the years, several other genes involved in Noonan syndrome (KRAS, SOS1, RAF1, MAP2K1, BRAF, NRAS, RIT1, and LZTR1) have been identified, acting at different levels of the RAS-mitogen-activated protein kinase pathway. Recently, SPRED2 was recognized as a novel Noonan syndrome gene with autosomal recessive inheritance, and only four families have been described to date. Here, we report the first Italian case, a one-year-old child with left ventricular hypertrophy, moderate pulmonary valve stenosis, and atrial septal defect, with a clinical suspicion of RASopathy supported by the presence of typical Noonan-like facial features and short stature. Exome sequencing identified a novel homozygous loss-of-function variant in the exon 3 of SPRED2 (NM_181784.3:c.325del; p.Arg109Glufs*7), likely causing nonsense-mediated decay. Our results and the presented clinical data may help us to further understand and dissect the genetic heterogeneity of Noonan syndrome. Full article
(This article belongs to the Special Issue Genetics, Genomics and Precision Medicine in Heart Diseases)
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