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Breaking the Code: How Genome Sequencing Is Revolutionizing the Diagnosis...
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Breaking the Code: How Genome Sequencing Is Revolutionizing the Diagnosis of Rare Diseases

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Genetics and Genomics".

Deadline for manuscript submissions: closed (6 November 2025) | Viewed by 313

Special Issue Editors

Dr. Massimiliano Chetta

E-Mail
Guest Editor
U.O.C. Genetica Medica e di Laboratorio, A.O.R.N. Antonio Cardarelli, Via Antonio Cardarelli, 9, 80131 Naples, NA, Italy
Interests: human genetics and genomics; bioinformatics; cytogenetics and cytogenomics
Prof. Dr. Nenad Bukvic

E-Mail Website
Guest Editor
Laboratorio di Genetica Medica, Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari, 70124 Bari, Italy
Interests: clinical genetics; medical genetics; human genetics and genomics; cytogenetics and cytogenomics

Special Issue Information

Dear Colleagues,

Recent advances in genomic sequencing are transforming rare disease diagnosis and comprehension, giving patients and their families new hope around the world.

More than 300 million people worldwide are affected by uncommon diseases, many of which are genetically based. Accurate and prompt diagnosis is still a major obstacle. Whole genome sequencing (WGS), next-generation sequencing (NGS), and other advanced genomic technologies have made it possible to identify disease-causing gene variations more quickly and accurately, opening the door to more targeted therapies and enhanced clinical outcomes.

Original research and reviews examining the most recent developments in rare disease genome sequencing are requested for this Special Issue. We are looking for submissions on a variety of subjects, such as new diagnostic techniques, developments in bioinformatics, and the practical implications of genomic results. 

This Special Issue aims to highlight the revolutionary potential of genome sequencing in rare disease research and patient treatment by bringing together a variety of viewpoints from genetics, bioinformatics, and clinical practice.

Dr. Massimiliano Chetta
Prof. Dr. Nenad Bukvic
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 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-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Life 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

  • genomics
  • bioinformatics
  • genetics
  • cytogenetics

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Published Papers (1 paper)

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Research

22 pages, 2802 KB  
Article
Alteplase and Angioedema: Can Clinical Exome Sequencing Redefine the Paradigm?
by Marina Tarsitano, Maurizio Russo, Vincenzo Andreone, Maria Bova, Francesco Palestra, Paolo Candelaresi, Giovanna Servillo, Anne Lise Ferrara, Gilda Varricchi, Luigi Ferrara, Stefania Loffredo and Massimiliano Chetta
Life 2026, 16(2), 200; https://doi.org/10.3390/life16020200 (registering DOI) - 26 Jan 2026
Abstract
Intravenous thrombolysis with recombinant tissue-type plasminogen activator (tPA) remains a keystone of acute ischemic stroke treatment but in a subset of patients is complicated by angioedema, a potentially life-threatening adverse event largely mediated by bradykinin signaling. The unpredictable and idiosyncratic nature of this [...] Read more.
Intravenous thrombolysis with recombinant tissue-type plasminogen activator (tPA) remains a keystone of acute ischemic stroke treatment but in a subset of patients is complicated by angioedema, a potentially life-threatening adverse event largely mediated by bradykinin signaling. The unpredictable and idiosyncratic nature of this reaction has long suggested an underlying genetic contribution, yet its molecular architecture has remained poorly characterized. We hypothesized that alteplase-associated angioedema represents a multigenic susceptibility phenotype, arising from the convergence of rare genetic variants across multiple interacting physiological systems rather than from a single causal variant. To explore this hypothesis, we performed clinical exome sequencing in a cohort of 11 patients who developed angioedema following alteplase administration. Rather than identifying a shared pathogenic variant, we observed distinct yet convergent patterns of genetic vulnerability, allowing patients to be grouped according to dominant, but overlapping, biological axes. These included alterations affecting bradykinin regulation (e.g., ACE, SERPING1, XPNPEP2), endothelial structure and hemostasis (e.g., VWF, COL4A1), neurovascular and calcium signaling (e.g., SCN10A, RYR1), and vascular repair or remodeling pathways (e.g., PSEN2, BRCA2). Notably, many of the identified variants were classified as Variant of Uncertain Significance (VUS) or likely benign significance in isolation. However, when considered within an integrated, pathway-based framework, these variants can be interpreted as capable of contributing cumulatively to system level fragility, a phenomenon best described as “contextual pathogenicity”. Under the acute biochemical and proteolytic stress imposed by thrombolysis, this reduced physiological reserve may allow otherwise compensated vulnerabilities to become clinically manifest. Together, these findings support a model in which severe alteplase-associated angioedema appears as an emergent property of interacting genetic networks, rather than a monogenic disorder. This systems level perspective underscores the limitations of gene centric interpretation for adverse drug reactions and highlights the potential value of pathway informed, multi-genic approaches to risk stratification. Such frameworks may ultimately contribute to safer, more personalized thrombolytic decision, while providing a conceptual foundation for future functional and translational studies. Full article
(This article belongs to the Special Issue Breaking the Code: How Genome Sequencing Is Revolutionizing the Diagnosis of Rare Diseases)
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