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Genomic Research of Rare Diseases
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Genomic Research of Rare Diseases

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: 20 July 2025 | Viewed by 4790

Special Issue Editors

Dr. Shira Rockowitz

E-Mail Website
Guest Editor
Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Interests: genomics; rare disease; bioinformatics; epigenomics
Dr. Piotr Sliz

E-Mail Website
Guest Editor
Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Interests: genomics; rare disease; mechanistic and structural biology; bioinformatics

Special Issue Information

Dear Colleagues,

There are over 7000 rare diseases impacting over 300 million people worldwide. The ubiquity of whole exome and genome sequencing has transformed rare disease research and shortened lengthy diagnostic odysseys and are leading to changes in disease management, yet 60–70% of rare disease patients remain undiagnosed after genomic testing. Furthermore, the validation of variants of uncertain significance in candidate genes remains a tedious and lengthy process. Increasingly, the integration of multi-omics data, the reanalysis of prior genomic testing, emerging technologies, and computational approaches are contributing to rare disease diagnostics and enabling precision medicine.

This Special Issue aims to highlight the latest research and innovation in rare diseases, in particular, in the areas of genomic and multi-omics approaches as well as mechanistic research that aims to validate genomic findings. We invite original research, innovative methodologies, case studies, up-to-date reviews, meta-analyses, and discussions about therapeutic implications of genomic findings.

Dr. Shira Rockowitz
Dr. Piotr Sliz
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. 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

  • rare disease ontology
  • variants of uncertain significance
  • candidate genes
  • whole genome sequencing
  • long read whole genome sequencing
  • machine learning
  • multi-omics

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Published Papers (5 papers)

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Research

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16 pages, 5907 KiB  
Article
Long-Read Whole-Genome Sequencing as a Tool for Variant Detection in Inherited Retinal Dystrophies
by Cristina Rodilla, Gonzalo Núñez-Moreno, Yolanda Benitez, Marta Rodríguez de Alba, Fiona Blanco-Kelly, Aroa López-Alcojor, Lidia Fernández-Caballero, Irene Perea-Romero, Marta Del Pozo-Valero, Gema García-García, Mar Balanzá, Cristina Villaverde, Olga Zurita, Claire Jubin, Cedric Fund, Marc Delepine, Aurelie Leduc, Jean-François Deleuze, José M. Millán, Pablo Minguez, Marta Corton and Carmen Ayusoadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2025, 26(8), 3825; https://doi.org/10.3390/ijms26083825 - 18 Apr 2025
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Abstract
Advances in whole-genome sequencing (WGS) have significantly enhanced our ability to detect genomic variants underlying inherited diseases. In this study, we performed long-read WGS on 24 patients with inherited retinal dystrophies (IRDs) to validate the utility of nanopore sequencing in detecting genomic variations. [...] Read more.
Advances in whole-genome sequencing (WGS) have significantly enhanced our ability to detect genomic variants underlying inherited diseases. In this study, we performed long-read WGS on 24 patients with inherited retinal dystrophies (IRDs) to validate the utility of nanopore sequencing in detecting genomic variations. We confirmed the presence of all previously detected variants and demonstrated that this approach allows for the precise refinement of structural variants (SVs). Furthermore, we could perform genotype phasing by sequencing only the probands, confirming that the variants were inherited in trans. Moreover, nanopore sequencing enables the detection of complex variants, such as transposon insertions and structural rearrangements. This comprehensive assessment illustrates the power of long-read sequencing in capturing diverse forms of genomic variation and in improving diagnostic accuracy in IRDs. Full article
(This article belongs to the Special Issue Genomic Research of Rare Diseases)
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10 pages, 5405 KiB  
Article
Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss
by Nikoletta Nagy, Ágnes Szalenko-Tőkés, Margit Pál, Barbara Anna Bokor, Roland Nagy, János András Jarabin, László Róvó and Márta Széll
Int. J. Mol. Sci. 2025, 26(4), 1583; https://doi.org/10.3390/ijms26041583 - 13 Feb 2025
Viewed by 527
Abstract
Autosomal dominant non-syndromic hearing loss (ADNSHL) is a genetically heterogenic condition. The transformation/transcription domain associated protein (TRRAP) gene has been recently associated with ADNSHL, and only four variants of the gene have so far been reported in this disease. Here, we [...] Read more.
Autosomal dominant non-syndromic hearing loss (ADNSHL) is a genetically heterogenic condition. The transformation/transcription domain associated protein (TRRAP) gene has been recently associated with ADNSHL, and only four variants of the gene have so far been reported in this disease. Here, we report on a Hungarian ADNSHL family in which the affected individuals exhibited sensorineural hearing loss with similar clinical symptoms, including initial impaired high frequencies that subsequently affected speech and lower frequencies. Whole exome sequencing and screening of the shared genetic variants of the affected individuals was performed. Our results revealed a novel heterozygous missense variant (NM_001244580.2, c.5360A>G, p.Lys1787Arg) in the TRRAP gene. This variant is completely co-segregated with hearing impairment. It is present in a heterozygous form in the affected mother and daughter but not carried by any unaffected family members. This study highlights the importance of elucidating the germline genetic background of ADNSHL, which may help to predict individual risk and the risk of family members. This will improve prevention, screening, and therapeutic measures for each patient and hearing loss-prone families. Full article
(This article belongs to the Special Issue Genomic Research of Rare Diseases)
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11 pages, 2266 KiB  
Article
Erythropoiesis and Gene Expression Analysis in Erythroid Progenitor Cells Derived from Patients with Hemoglobin H/Constant Spring Disease
by Narawich Wongkhammul, Pinyaphat Khamphikham, Siripong Tongjai, Adisak Tantiworawit, Kanda Fanhchaksai, Somsakul Pop Wongpalee, Alisa Tubsuwan, Supawadee Maneekesorn and Pimlak Charoenkwan
Int. J. Mol. Sci. 2024, 25(20), 11246; https://doi.org/10.3390/ijms252011246 - 19 Oct 2024
Viewed by 1064
Abstract
Hemoglobin H/Constant Spring (Hb H/CS) disease represents a form of non-deletional Hb H disease characterized by chronic hemolytic anemia that ranges from moderate to severe and may lead to transfusion-dependent thalassemia. To study the underlying mechanisms of this disease, we conducted an analysis [...] Read more.
Hemoglobin H/Constant Spring (Hb H/CS) disease represents a form of non-deletional Hb H disease characterized by chronic hemolytic anemia that ranges from moderate to severe and may lead to transfusion-dependent thalassemia. To study the underlying mechanisms of this disease, we conducted an analysis of erythropoiesis and gene expression in erythroid progenitor cells derived from CD34+ hematopoietic stem/progenitor cells from patients with Hb H/CS disease and normal controls. Twelve patients with Hb H/CS disease and five normal controls were enrolled. Peripheral blood samples were collected to isolate CD34+ hematopoietic stem/progenitor cells for the analysis of cell proliferation and differentiation. Six samples from patients with Hb H/CS disease and three controls were subsequently studied for gene expression by next generation sequencing analysis. Erythroid progenitor cells derived from patients with Hb H/CS disease exhibited a trend towards increased rates of erythroid proliferation and decreased cell viability compared to those from controls. Moreover, erythroid progenitor cells derived from patients with Hb H/CS disease demonstrated delayed terminal differentiation. Gene expression profiling revealed elevated levels of genes encoding molecular chaperones, including the heat shock protein genes (HSPs) and the chaperonin containing TCP-1 subunit genes (CCTs) in the Hb H/CS disease group. In summary, erythroid progenitor cells derived from patients with Hb H/CS disease exhibit a trend towards heightened erythroid proliferation, diminished cell viability, and delayed terminal differentiation. Additionally, the increased expression of genes encoding molecular chaperones was observed, providing information on potential underlying pathophysiological mechanisms. Full article
(This article belongs to the Special Issue Genomic Research of Rare Diseases)
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Review

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12 pages, 1487 KiB  
Review
Expanding Upon Genomics in Rare Diseases: Epigenomic Insights
by Jia W. Tan, Emily J. Blake, Joseph D. Farris and Eric W. Klee
Int. J. Mol. Sci. 2025, 26(1), 135; https://doi.org/10.3390/ijms26010135 - 27 Dec 2024
Viewed by 984
Abstract
DNA methylation is an essential epigenetic modification that plays a crucial role in regulating gene expression and maintaining genomic stability. With the advancement in sequencing technology, methylation studies have provided valuable insights into the diagnosis of rare diseases through the various identification of [...] Read more.
DNA methylation is an essential epigenetic modification that plays a crucial role in regulating gene expression and maintaining genomic stability. With the advancement in sequencing technology, methylation studies have provided valuable insights into the diagnosis of rare diseases through the various identification of episignatures, epivariation, epioutliers, and allele-specific methylation. However, current methylation studies are not without limitations. This mini-review explores the current understanding of DNA methylation in rare diseases, highlighting the key mechanisms and diagnostic potential, and emphasizing the need for advanced methodologies and integrative approaches to enhance the understanding of disease progression and design more personable treatment for patients, given the nature of rare diseases. Full article
(This article belongs to the Special Issue Genomic Research of Rare Diseases)
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Other

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23 pages, 1191 KiB  
Perspective
Estimating the Number of Polygenic Diseases Among Six Mutually Exclusive Entities of Non-Tumors and Cancer
by C. I. Edvard Smith, Jan A. Burger and Rula Zain
Int. J. Mol. Sci. 2024, 25(22), 11968; https://doi.org/10.3390/ijms252211968 - 7 Nov 2024
Viewed by 1356
Abstract
In the era of precision medicine with increasing amounts of sequenced cancer and non-cancer genomes of different ancestries, we here enumerate the resulting polygenic disease entities. Based on the cell number status, we first identified six fundamental types of polygenic illnesses, five of [...] Read more.
In the era of precision medicine with increasing amounts of sequenced cancer and non-cancer genomes of different ancestries, we here enumerate the resulting polygenic disease entities. Based on the cell number status, we first identified six fundamental types of polygenic illnesses, five of which are non-cancerous. Like complex, non-tumor disorders, neoplasms normally carry alterations in multiple genes, including in ‘Drivers’ and ‘Passengers’. However, tumors also lack certain genetic alterations/epigenetic changes, recently named ‘Goners’, which are toxic for the neoplasm and potentially constitute therapeutic targets. Drivers are considered essential for malignant transformation, whereas environmental influences vary considerably among both types of polygenic diseases. For each form, hyper-rare disorders, defined as affecting <1/108 individuals, likely represent the largest number of disease entities. Loss of redundant tumor-suppressor genes exemplifies such a profoundly rare mutational event. For non-tumor, polygenic diseases, pathway-centered taxonomies seem preferable. This classification is not readily feasible in cancer, but the inclusion of Drivers and possibly also of epigenetic changes to the existing nomenclature might serve as initial steps in this direction. Based on the detailed genetic alterations, the number of polygenic diseases is essentially countless, but different forms of nosologies may be used to restrict the number. Full article
(This article belongs to the Special Issue Genomic Research of Rare Diseases)
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