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Genetic Variations in Human Diseases: 2nd Edition
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Genetic Variations in Human Diseases: 2nd Edition

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 31 October 2025 | Viewed by 2818

Special Issue Editor

Prof. Dr. Paweł Niemiec

E-Mail Website
Guest Editor
Department of Biochemistry and Medical Genetics, Faculty of Health Sciences in Katowice, Medical University of Silesia, Medykow Street 18, 40-752 Katowice, Poland
Interests: genetic determinants of the tendon healing process; coronary artery disease (CAD); autism spectrum disorder (ASD); osteoporosis;childhood ischemic stroke; inflammatory and free radical aspects of atherosclerosis; gene–gene and gene–environment interactions in individual susceptibility to multifactorial diseases

Special Issue Information

Dear Colleagues,

We are excited to invite you to submit articles for the upcoming Special Issue of the International Journal of Molecular Sciences, titled “Genetic Variations in Human Diseases: 2nd Edition”. Despite unprecedented progress in the identification of loci associated with human diseases, the completion of the Human Genome Project, and the development of genome-wide association studies (GWASs), many important aspects of the role of genetic variation in human physiology and pathology remain unexplored. Relatively little is known about the role of non-coding sequences and their potential impact on disease. Additionally, key gaps include the role of gene–gene and gene–environment interactions in understanding multifactorial diseases. Further investigation is needed into the effects of rare variants whose analysis poses methodological challenges, as well as epigenetic mechanisms, particularly their inheritance and their influence on disease susceptibility.

We invite contributions on both monogenic diseases with classic Mendelian inheritance and complex, multifactorial diseases with a genetic and environmental background. We especially welcome cohort and family-based studies focused on quantitative traits and specific patient phenotypes, along with well-designed association studies on the relationship between genetic variability and disease. We seek studies examining the role of protein-coding genes, various RNA types, and non-coding sequences that may be important in the pathogenesis of both rare and common human diseases. Additionally, studies analyzing gene–gene and gene–environment interactions using modern statistical algorithms and advanced bioinformatic tools, including in silico analyses, are highly encouraged. We look forward to your submissions of original research articles, high-quality meta-analyses, and critical reviews that will deepen our understanding of genetic variations in human diseases, from molecular background to clinical applications.

We look forward to receiving your contributions.

Prof. Dr. Paweł Niemiec
Guest Editor

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • genetic polymorphism
  • gene–gene interaction
  • gene–environment interaction
  • monogenic disorder
  • mutation
  • phenotype
  • quantitative trait locus
  • family-based study
  • cohort study
  • association study

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Published Papers (6 papers)

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Research

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25 pages, 5252 KiB  
Article
Predicting the Damaging Potential of Uncharacterized KCNQ1 and KCNE1 Variants
by Svetlana I. Tarnovskaya and Boris S. Zhorov
Int. J. Mol. Sci. 2025, 26(14), 6561; https://doi.org/10.3390/ijms26146561 - 8 Jul 2025
Viewed by 30
Abstract
Voltage-gated potassium channels Kv7.1, encoded by the gene KCNQ1, play critical roles in various physiological processes. In cardiomyocytes, the complex Kv7.1-KCNE1 mediates the slow component of the delayed rectifier potassium current that is essential for the action potential repolarization. Over 1000 [...] Read more.
Voltage-gated potassium channels Kv7.1, encoded by the gene KCNQ1, play critical roles in various physiological processes. In cardiomyocytes, the complex Kv7.1-KCNE1 mediates the slow component of the delayed rectifier potassium current that is essential for the action potential repolarization. Over 1000 KCNQ1 missense variants, many of which are associated with long QT syndrome, are reported in ClinVar and other databases. However, over 600 variants are of uncertain clinical significance (VUS), have conflicting interpretations of pathogenicity, or lack germline information. Computational prediction of the damaging potential of such variants is important for the diagnostics and treatment of cardiac disease. Here, we collected 1750 benign and pathogenic missense variants of Kv channels from databases ClinVar, Humsavar, and Ensembl Variation and tested 26 bioinformatics tools in their ability to identify known pathogenic or likely pathogenic (P/LP) variants. The best-performing tool, AlphaMissense, predicted the pathogenicity of 195 VUSs in Kv7.1. Among these, 79 variants of 66 wildtype residues (WTRs) are also reported as P/LP variants in sequentially matching positions of at least one hKv7.1 paralogue. In available cryoEM structures of Kv7.1 with activated and deactivated voltage-sensing domains, 52 WTRs form intersegmental contacts with WTRs of ClinVar-listed variants, including 21 WTRs with P/LP variants. ClinPred and paralogue annotation methods consistently predicted that 21 WTRs of KCNE1 have 34 VUSs with damaging potential. Among these, 8 WTRs are contacting 23 Kv7.1 WTRs with 13 ClinVar-listed variants in the AlphaFold3 model. Analysis of intersegmental contacts in CryoEM and AlphaFold3 structures suggests atomic mechanisms of dysfunction for some VUSs. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases: 2nd Edition)
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14 pages, 271 KiB  
Communication
Novel Genetic Variants Associated with Diabetic Neuropathy Risk in Type 2 Diabetes: A Whole-Exome Sequencing Approach
by Noémi Hajdú, Dóra Zsuzsanna Tordai, Ramóna Rácz, Zsófia Ludvig, Ildikó Istenes, Magdolna Békeffy, Orsolya Erzsébet Vági, Anna Erzsébet Körei, Bálint Tóbiás, Anett Illés, Henriett Pikó, János P. Kósa, Kristóf Árvai, Péter András Lakatos, Péter Kempler and Zsuzsanna Putz
Int. J. Mol. Sci. 2025, 26(13), 6239; https://doi.org/10.3390/ijms26136239 - 28 Jun 2025
Viewed by 137
Abstract
The pathogenesis of diabetic neuropathy involves complex interactions between metabolic and genetic factors. This study aimed to identify novel genetic variants associated with neuropathy risk in type 2 diabetes through reanalysis of whole-exome sequencing data. We identified seven new SNPs with significant associations, [...] Read more.
The pathogenesis of diabetic neuropathy involves complex interactions between metabolic and genetic factors. This study aimed to identify novel genetic variants associated with neuropathy risk in type 2 diabetes through reanalysis of whole-exome sequencing data. We identified seven new SNPs with significant associations, including intronic variants in TTN, PLCB1, CCNI, and CDC34 and a 5′-upstream variant in BTG2. These variants are implicated in muscle elasticity, neurotransmission, endothelial regeneration, and apoptosis resistance, suggesting multifaceted genetic contributions to neuropathy development. These findings enhance our understanding of diabetic neuropathy and may support future advances in risk stratification and therapy development. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases: 2nd Edition)
18 pages, 721 KiB  
Article
Identification of Monogenic Causes of Arterial Ischemic Stroke in Children with Arteriopathies by Next-Generation Sequencing
by Anna Balcerzyk-Matić, Ilona Kopyta, Celina Kruszniewska-Rajs, Paweł Niemiec and Joanna Gola
Int. J. Mol. Sci. 2025, 26(13), 6228; https://doi.org/10.3390/ijms26136228 - 27 Jun 2025
Viewed by 108
Abstract
The leading causes of pediatric arterial ischemic stroke (PAIS) are arteriopathies, which refer to pathologies of the arterial walls in the brain. Since traditional risk factors for cardiovascular diseases in children play a smaller role than in adults, it can be supposed that [...] Read more.
The leading causes of pediatric arterial ischemic stroke (PAIS) are arteriopathies, which refer to pathologies of the arterial walls in the brain. Since traditional risk factors for cardiovascular diseases in children play a smaller role than in adults, it can be supposed that genetic factors may be of particular importance in this age group. Therefore, this study aimed to identify mutations affecting the formation of vascular wall pathologies, which can subsequently lead to ischemic stroke. The study used a database of 92 Caucasian children diagnosed with ischemic stroke. From this group, 25 children with arteriopathies were selected. The study had an exploratory and descriptive design, with the aim of characterizing rare genetic variants in a selected cohort, without attempting formal statistical association testing. The sequencing was performed using the Illumina NextSeq 550 platform. A panel of 161 genes known to be associated with stroke or arteriopathies was selected for further analysis. We identified 10 pathogenic or likely pathogenic mutations in 15 patients. Among these, three are likely monogenic causes of stroke (ELN, SCN5A, and VHL genes), two are considered risk factors (FV and ADAMTS13), two have conflicting interpretations (ACAD9 and ENG), and three are most likely benign (CBS, PMM2, and PKD1). The frequency of genetic variants underlying ischemic stroke or acting as risk factors for the disease in the studied group is significantly higher than the estimated frequency of monogenic forms of stroke in young adults and higher than in the general population. NGS testing is worth considering, especially in patients who exhibit certain symptoms that may suggest the presence of mutations. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases: 2nd Edition)
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12 pages, 1717 KiB  
Article
Hemoglobin Disorders Associated with Neurological Impairment: First Report of ATR-X Syndrome and Recessive Congenital Methemoglobinemia Type II in Tunisia
by Houyem Ouragini, Emna Bouatrous, Manel Kasdallah, Sonia Nouira, Hamza Dallali, Samia Rekaya, Dorra Chaouachi, Monia Ouederni and Samia Menif
Int. J. Mol. Sci. 2025, 26(10), 4803; https://doi.org/10.3390/ijms26104803 - 16 May 2025
Viewed by 522
Abstract
Hemoglobin disorders are among the most common inherited diseases worldwide. Their clinical manifestations range from anemia to more severe forms associated with neurological impairments. These complications can result as secondary consequences of the disease’s clinical manifestations or be directly linked to genetic mutations. [...] Read more.
Hemoglobin disorders are among the most common inherited diseases worldwide. Their clinical manifestations range from anemia to more severe forms associated with neurological impairments. These complications can result as secondary consequences of the disease’s clinical manifestations or be directly linked to genetic mutations. In this study, we present two families with neurological impairments who were referred to us for complementary hematological and biochemical analyses. Complete blood count, methemoglobin level, and methemoglobin reductase activity were assessed. Molecular analyses were performed using whole-exome sequencing, and the segregation of the identified mutations was confirmed with direct sequencing. Their pathogenicity and conservation were evaluated using various bioinformatics tools. Clinical and hematological findings suggested X-linked alpha-thalassemia/impaired intellectual development syndrome in the first family and recessive congenital methemoglobinemia type II in the second. This was confirmed by the identification of pathogenic mutations ATRX: p.Arg2131Gln and CYB5R3: p.Ala179Thr, respectively. Although these variants have been previously reported worldwide, they were identified for the first time in our population. Our results contribute to the understanding of the pathogenesis of these rare disorders and provide a basis for diagnosis, treatment, and genetic counseling. The mechanisms by which these mutations contribute to neurological symptoms are discussed. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases: 2nd Edition)
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18 pages, 3085 KiB  
Article
Whole-Exome Sequencing Identifies Novel GATA5/6 Variants in Right-Sided Congenital Heart Defects
by Gloria K. E. Zodanu, John H. Hwang, Jordan Mudery, Carlos Sisniega, Xuedong Kang, Lee-Kai Wang, Alexander Barsegian, Reshma M. Biniwale, Ming-Sing Si, Nancy J. Halnon, UCLA Congenital Heart Defects-BioCore Faculty, Wayne W. Grody, Gary M. Satou, Glen S. Van Arsdell, Stanly F. Nelson and Marlin Touma
Int. J. Mol. Sci. 2025, 26(5), 2115; https://doi.org/10.3390/ijms26052115 - 27 Feb 2025
Viewed by 1017
Abstract
One out of every hundred live births present with congenital heart abnormalities caused by the aberrant development of the embryonic cardiovascular system. The conserved zinc finger transcription factor proteins, which include GATA binding protein 5 (GATA5) and GATA binding protein (GATA6) play important [...] Read more.
One out of every hundred live births present with congenital heart abnormalities caused by the aberrant development of the embryonic cardiovascular system. The conserved zinc finger transcription factor proteins, which include GATA binding protein 5 (GATA5) and GATA binding protein (GATA6) play important roles in embryonic development and their inactivation may result in congenital heart defects (CHDs). In this study, we performed genotypic–phenotypic analyses in two families affected by right-sided CHD diagnosed by echocardiography imaging. Proband A presented with pulmonary valve stenosis, and proband B presented with complex CHD involving the right heart structures. For variant detection, we employed whole-genome single-nucleotide polymorphism (SNP) microarray and family-based whole-exome sequencing (WES) studies. Proband A is a full-term infant who was admitted to the neonatal intensive care unit (NICU) at five days of life for pulmonary valve stenosis (PVS). Genomic studies revealed a normal SNP microarray; however, quad WES analysis identified a novel heterozygous [Chr20:g.61041597C>G (p.Arg237Pro)] variant in the GATA5 gene. Further analysis confirmed that the novel variant was inherited from the mother but was absent in the father and the maternal uncle with a history of heart murmur. Proband B was born prematurely at 35 weeks gestation with a prenatally diagnosed complex CHD. A postnatal evaluation revealed right-sided heart defects including pulmonary atresia with intact ventricular septum (PA/IVS), right ventricular hypoplasia, tricuspid valve hypoplasia, hypoplastic main and bilateral branch pulmonary arteries, and possible coronary sinusoids. Cardiac catheterization yielded anatomy and hemodynamics unfavorable to repair. Hence, heart transplantation was indicated. Upon genomic testing, a normal SNP microarray was observed, while trio WES analysis identified a novel heterozygous [Chr18:c.1757C>T (p.Pro586Leu)] variant in the GATA6 gene. This variant was inherited from the father, who carries a clinical diagnosis of tetralogy of Fallot. These findings provide new insights into novel GATA5/6 variants, elaborate on the genotypic and phenotypic association, and highlight the critical role of GATA5 and GATA6 transcription factors in a wide spectrum of right-sided CHDs. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases: 2nd Edition)
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Review

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15 pages, 800 KiB  
Review
Genetic Factors Related to the Development or Progression of Mesoamerican Endemic Nephropathy
by Alejandro Marín-Medina, Ingrid Patricia Dávalos-Rodríguez, Emiliano Peña-Durán, Luis Eduardo de la Torre-Castellanos, Luis Felipe González-Vargas and José Juan Gómez-Ramos
Int. J. Mol. Sci. 2025, 26(10), 4486; https://doi.org/10.3390/ijms26104486 - 8 May 2025
Viewed by 499
Abstract
Over the past two decades, Mesoamerican endemic nephropathy (MeN) has become a major public health problem in certain regions of Mexico and Central American countries. The etiology of this disease is multifactorial, and important environmental factors have been described, such as chronic heat [...] Read more.
Over the past two decades, Mesoamerican endemic nephropathy (MeN) has become a major public health problem in certain regions of Mexico and Central American countries. The etiology of this disease is multifactorial, and important environmental factors have been described, such as chronic heat stress, recurrent episodes of dehydration, infections, and exposure to toxins of chemical and biological origin. Genetic and epigenetic factors have been proposed to play significant roles in MeN. Recent studies have analyzed the role of these factors in MeN. In some cases, these factors appear to be associated with accelerated deterioration of established kidney disease due to preexisting endothelial dysfunction and tubulopathy. In other cases, they appear to be associated with early kidney damage, even before occupational exposure, suggesting that they may play a relevant role in the genesis of the disease. Other factors appear to act as risk reducers for developing MeN in areas with a high prevalence of the disease. Therefore, this disease has a rather complex multifactorial etiology, with possible polygenic contributions, possible epigenetic phenomena, and multiple environmental factors. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases: 2nd Edition)
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