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Molecular Progression of Genome-Related Diseases: 2nd Edition
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Molecular Progression of Genome-Related 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: 25 June 2027 | Viewed by 20993

Editor

Prof. Dr. Salvatore Saccone

E-Mail Website
Guest Editor
Department of Biological, Geological and Environmental Sciences, University of Catania, 95124 Catania, Italy
Interests: genetics; genomics; molecular cytogenetics; chromosomes; nuclear chromatin organization; evolutionary genetics; developmental genetics; forensic genetics; environmental mutagenesis; epigenetics; neurodevelopmental diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous successful Special Issue “Molecular Progression of Genome-Related Diseases” (www.mdpi.com/journal/ijms/special_issues/O5FBS1057F).

Advancements in genomic technologies, such as next-generation sequencing, have revolutionized our ability to unravel the molecular basis of genome-related diseases. By analyzing genetic variations and mutations, the key genes and pathways involved in the development of several diseases have been identified. This knowledge has not only facilitated accurate diagnosis and personalized medicine but has also opened avenues for innovative therapies targeting specific genetic aberrations. Our current capacity to rapidly analyze entire exome and genome sequences at an affordable cost has the potential to yield greater benefits, supporting the genetic investigation of complex diseases and generating opportunities which may arise from examining specific and distinct phenotypes.

Despite these significant strides, challenges remain, including the complexity of some genetic diseases and the need for more comprehensive databases to catalog genetic variants and their clinical implications. The definition of gene panels to analyze with NGS for diagnostic purposes is certainly a relevant subject in human health, considering the various diseases with a genetic basis of increasing interest such as, but not limited to, neurological or neuromuscular disorders, cardiomyopathies, and hereditary cancer syndromes and hematological disorders.

For this Special Issue, we invite researchers in the field to publish reviews or original research papers covering recent advances in the use of gene panels to detect mutations/variants related to the diagnosis of complex genetic diseases and improvements related to new tools for genomic analysis. Our aim is to have a Special Issue that presents up-to-date information on genomic analysis systems for complex genetic diseases and serves as a reference to researchers in the field and users of these technologies for diagnostic purposes.

Prof. Dr. Salvatore Saccone
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 250 words) can be sent to the Editorial Office for assessment.

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-anonymized 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

  • next-generation sequencing
  • genetic diseases
  • multifactorial diseases
  • diagnostic tolls
  • human health

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Related Special Issue

Published Papers (5 papers)

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Research

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18 pages, 5987 KB  
Article
Potential Link Between a Disruptive CAPN6 Variant and Neurodevelopmental Disorders
by Francesco Calì, Simone Treccarichi, Mirella Vinci, Emanuela Avola, Antonino Musumeci, Alda Ragalmuto, Carola Costanza, Donatella Greco, Desiree Brancato, Concetta Federico, Santina Città, Francesco Domenico Di Blasi, Salvatore Saccone, Paolo Scudieri, Federico Zara and Maurizio Elia
Int. J. Mol. Sci. 2026, 27(3), 1140; https://doi.org/10.3390/ijms27031140 - 23 Jan 2026
Cited by 2 | Viewed by 839
Abstract
The placenta is often described as the “window to the brain” due to its crucial role in fetal neurological development. In this study, we investigated a family where the older male offspring exhibited severe neurodevelopmental and mild motor coordination disorders. His brother displayed [...] Read more.
The placenta is often described as the “window to the brain” due to its crucial role in fetal neurological development. In this study, we investigated a family where the older male offspring exhibited severe neurodevelopmental and mild motor coordination disorders. His brother displayed emotional and behavioral dysregulation along with mild motor coordination disorders. The father was asymptomatic, while the mother and daughter showed mild learning disabilities. Whole exome sequencing (WES) identified a disruptive X-linked pathogenic variant, c.1088_1089del p.Asp363GlyfsTer2, within the calpain-6 (CAPN6) gene. We have submitted this variant to the ClinVar database (RCV005234146.2). The variant was found in hemizygous condition in the affected male offspring and in heterozygous condition in both the mother and daughter. As predicted, the variant undergoes nonsense-mediated mRNA decay (NMD), preventing the translation of the CAPN6 gene into a functional protein. CAPN6 is a critical gene predominantly expressed in placental and trophoblast tissues. Although its function is not well characterized, CAPN6 is also expressed in several regions of the developing brain. Recent studies have shown that genetic variants in CAPN6 significantly influence vascular endothelial growth factor (VEGF) activity, thereby affecting angiogenesis and the blood supply essential for fetal growth and development. Although CAPN6 lacks an MIM phenotype code, we hypothesize that it might be enumerated as a novel candidate gene contributing to neurodevelopmental disorders. Functional studies are imperative to elucidate the role of CAPN6 in placental function and its potential implications for neurodevelopmental processes. This work aims to inspire further research into the role of CAPN6 in placental biology and its relevance to neurodevelopmental disorders. Full article
(This article belongs to the Special Issue Molecular Progression of Genome-Related Diseases: 2nd Edition)
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18 pages, 2296 KB  
Article
Rescue of Iqsec2 Knockout Mice with Human IQSEC2 Adeno-Associated Virus Mediated Gene Therapy
by Divyalakshmi Soundararajan, Emi Kouyama-Suzuki, Yoshinori Shirai, Shaun Orth, Veronika Borisov, Yonat Israel, Yisrael Weiss, Leah Avi-Isaac, Niguse H. Garoma, Orit Lache, Nina S. Levy, Suyao Li, Weichen Zang, Shai Netser, Shlomo Wagner, Gabriel Jimenez, Wayne N. Frankel, Katsuhiko Tabuchi, Tristan T. Sands and Andrew P. Levy
Int. J. Mol. Sci. 2025, 26(17), 8311; https://doi.org/10.3390/ijms26178311 - 27 Aug 2025
Cited by 1 | Viewed by 5370
Abstract
The IQSEC2 protein is a guanine nucleotide exchange factor for Arf6. Pathogenic variants in the X-linked IQSEC2 gene are associated with drug-resistant epilepsy, severe intellectual disability, and autism. The vast majority of disease-causing variants introduce premature termination codons into the IQSEC2 gene, resulting [...] Read more.
The IQSEC2 protein is a guanine nucleotide exchange factor for Arf6. Pathogenic variants in the X-linked IQSEC2 gene are associated with drug-resistant epilepsy, severe intellectual disability, and autism. The vast majority of disease-causing variants introduce premature termination codons into the IQSEC2 gene, resulting in little or no IQSEC2 protein being produced. Approximately 20% of cases are missense variants in the seven functional domains of the IQSEC2 protein. We sought to determine whether an adeno-associated virus (AAV) containing the IQSEC2 gene could rescue abnormal phenotypes in mice in two different Iqsec2 mouse models with premature Iqsec2 termination codons resulting in a knockout of the Iqsec2 gene expression and in mice with an A350V Iqsec2 missense mutation. In the Iqsec2 knockout mice, the AAV significantly improved growth, corrected behavioral abnormalities, and normalized the seizure threshold. Behavioral abnormalities were partially rescued in A350V mice, which expression studies suggest may have been due to the feedback inhibition of the endogenous Iqsec2 allele by viral IQSEC2. We propose that the success in the Iqsec2 knockout mice warrants a proof-of-concept study for gene replacement therapy in boys with IQSEC2 premature termination variants. Full article
(This article belongs to the Special Issue Molecular Progression of Genome-Related Diseases: 2nd Edition)
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15 pages, 2389 KB  
Article
A Machine Learning Approach to Understanding the Genetic Role in COVID-19 Prognosis: The Influence of Gene Polymorphisms Related to Inflammation, Vitamin D, and ACE2
by Sofía Jaurrieta-Largo, José Pablo Miramontes-González, Luis Corral-Gudino, Miriam Gabella-Martín, Sofía Pérez-Arroyo, Ana M. Torres, Jorge Mateo, José Luis Pérez-Castrillón and Ricardo Usategui-Martín
Int. J. Mol. Sci. 2025, 26(16), 7975; https://doi.org/10.3390/ijms26167975 - 18 Aug 2025
Viewed by 1376
Abstract
The genetic background influences the outcomes of COVID-19. This study aimed to evaluate the incidence of polymorphisms in genes linked to the RAAS system, cytokine production, and vitamin D on COVID-19 severity, with the goal of gaining a deeper understanding of the genetic [...] Read more.
The genetic background influences the outcomes of COVID-19. This study aimed to evaluate the incidence of polymorphisms in genes linked to the RAAS system, cytokine production, and vitamin D on COVID-19 severity, with the goal of gaining a deeper understanding of the genetic etiology related to COVID-19. This study involved 338 COVID-19 patients and employed machine learning methods to identify the genetic variants that most significantly affect COVID-19 severity. The results revealed that polymorphisms in the IL6, IL6R, IL1α, IL1R, IFNγ, TNFα, CRP, VDR, VDBP, and ACE2 genes are the most significant genetic factors influencing COVID-19 prognosis, particularly in terms of the risks of COVID-19 pneumonia, mortality, rehospitalization, and associated mortality. The machine learning methods achieved an AUC of 0.86 for predicting COVID-19 pneumonia, mortality, and mortality related to rehospitalization, as well as an AUC of 0.85 for rehospitalization within the first year. These results confirm the crucial role of genetic background in COVID-19 prognosis, facilitating the identification of patients at increased risk. In summary, this research demonstrates that genetics-driven machine learning models can pinpoint patients at heightened risk by primarily focusing on genetic variants associated with ACE2, inflammation, and vitamin D. Full article
(This article belongs to the Special Issue Molecular Progression of Genome-Related Diseases: 2nd Edition)
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Review

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41 pages, 4458 KB  
Review
Impaired Myogenic Differentiation Is a Shared Feature Across Genetic Myopathies
by Tyler G. B. Soule, Mikhaela B. Slavin, Carly S. Pontifex, Mohamed Z. Dabaja, Arthur Melnyk, Antoine Dufour, Nicolas A. Dumont, Timothy E. Shutt and Gerald Pfeffer
Int. J. Mol. Sci. 2026, 27(14), 6338; https://doi.org/10.3390/ijms27146338 - 16 Jul 2026
Viewed by 548
Abstract
There is a shared hallmark of defective differentiation across genetic myopathies, a process that has been extensively described in Duchenne muscular dystrophy and also observed in Emery–Dreifuss muscular dystrophy. In this article, we broaden the discussion on myopathies associated with differentiation defects, examining [...] Read more.
There is a shared hallmark of defective differentiation across genetic myopathies, a process that has been extensively described in Duchenne muscular dystrophy and also observed in Emery–Dreifuss muscular dystrophy. In this article, we broaden the discussion on myopathies associated with differentiation defects, examining their implications in less characterized muscle conditions that can have onset in adulthood, including facioscapulohumeral muscular dystrophy (FSHD), oculopharyngeal muscular dystrophy (OPMD), and myotonic dystrophies (DM), as well as myopathies caused by genetic variants in FHL1, GNE, DES, CAPN3, and members of the HNRNP family. Muscle damage can result from injury, exercise, or disease, necessitating a highly coordinated repair process to restore normal strength and function. Resident satellite cells are activated, differentiate, and fuse with the damaged tissue to facilitate this repair. This overview emphasizes the importance of muscle differentiation in the pathogenesis of myopathies with diverse etiologies and a broad range of underlying molecular mechanisms. These insights highlight differentiation as a potential convergent therapeutic target. Full article
(This article belongs to the Special Issue Molecular Progression of Genome-Related Diseases: 2nd Edition)
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43 pages, 2326 KB  
Review
NGS Approaches in Clinical Diagnostics: From Workflow to Disease-Specific Applications
by Desiree Brancato, Simone Treccarichi, Francesca Bruno, Elvira Coniglio, Mirella Vinci, Salvatore Saccone, Francesco Calì and Concetta Federico
Int. J. Mol. Sci. 2025, 26(19), 9597; https://doi.org/10.3390/ijms26199597 - 1 Oct 2025
Cited by 20 | Viewed by 12185
Abstract
Next-Generation Sequencing (NGS) techniques have become a cornerstone of molecular diagnostics, enabling high-throughput, parallel analysis of multiple disease-associated genes. Their targeted design allows streamlined interpretation and optimised diagnostic yield, especially in disorders with known genetic heterogeneity. In this review, we provide a comprehensive [...] Read more.
Next-Generation Sequencing (NGS) techniques have become a cornerstone of molecular diagnostics, enabling high-throughput, parallel analysis of multiple disease-associated genes. Their targeted design allows streamlined interpretation and optimised diagnostic yield, especially in disorders with known genetic heterogeneity. In this review, we provide a comprehensive overview of the clinical application of NGS techniques—targeted gene panels, whole exome sequencing (WES) and whole genome sequencing (WGS)—detailing the methodological workflow and the critical steps involved in their implementation. Particular emphasis is placed on the genes identified through NGS that are implicated in neurodevelopmental, neurodegenerative, psychiatric, neuromuscular, cardiovascular, and metabolic disorders. We also compare the advantages and limitations of panel-based diagnostics versus WES and WGS, and discuss future directions, including the integration of long-read sequencing technologies into multidisciplinary clinical practice. Finally, we consider how these advances may ultimately bridge biomedical research and clinical practise to improve the diagnosis and management of multifactorial diseases. Full article
(This article belongs to the Special Issue Molecular Progression of Genome-Related Diseases: 2nd Edition)
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