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Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances: 2nd Edition
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Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances: 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: 30 November 2026 | Viewed by 4993

Editors

Dr. Judit Bene

E-Mail Website
Guest Editor
Department of Medical Genetics, Medical School, University of Pécs, 7624 Pécs, Hungary
Interests: molecular genetics and genomics; next generation sequencing; rare diseases; genetic testing; neurocutaneous syndromes; copy number variations
Special Issues, Collections and Topics in MDPI journals
Dr. Kinga Hadzsiev

E-Mail Website
Guest Editor
Department of Medical Genetics, Medical School, University of Pécs, Pecs, Hungary
Interests: autism spectrum disorders; genomic disorders; epilepsy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This is a continuation to our series of Special Issue “Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances”.

Rare diseases, defined as life-threatening, chronically debilitating conditions, represent a substantial public health burden as they affect ca. 2–6% of the population. Currently, there are around 5000–8000 different rare diseases, and these numbers are continuing to increase. Despite intensive research, the genetic etiology and pathomechanisms of the majority of rare diseases are still unclear, and most of them do not yet have an approved therapy. Their diagnostics and care pathways are also challenging due to their rarity, heterogeneous manifestations, multisystem involvement and the often-observed incomplete penetrance. In addition, patients with undiagnosed genetic diseases often face a diagnostic odyssey that lasts for an average of eight years; moreover, a certain number of patients receive a misdiagnosis.

However, due to new sophisticated technologies, such as high-throughput sequencing and mass spectrometry, an increasing amount of genomic and metabolomic data for various rare disorders have recently become available. These data could help us to understand biological mechanisms, identify new genes, determine causative mutations, discover biomarkers and ultimately develop novel therapeutics and diagnostic methods.

The aim of this Special Issue is to collect original and review articles that provide cutting-edge knowledge related to genetic, genomic and metabolomic investigations in rare disorders.

Dr. Judit Bene
Dr. Kinga Hadzsiev
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-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

  • rare diseases
  • genotype–phenotype analyses
  • NGS
  • mass spectrometry
  • biomarker discovery
  • molecular targeted therapy

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Published Papers (3 papers)

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12 pages, 961 KB  
Article
Mutation Spectrum of ADAMTS13 Gene in Patients with Upshaw–Schulman Syndrome (USS) in Russia
by Julia Poznyakova, Olesya Pshenichnikova, Elizaveta Klebanova, Gennadiy Galstyan and Vadim Surin
Int. J. Mol. Sci. 2026, 27(10), 4643; https://doi.org/10.3390/ijms27104643 - 21 May 2026
Viewed by 913
Abstract
Upshaw–Schulman syndrome (USS) is a rare inherited autosomal recessive thrombotic microangiopathy affecting less than 1/1,000,000 individuals. It is a congenital form of thrombotic thrombocytopenic purpura (TTP) caused by ADAMTS13 protease deficiency because of mutations in the ADAMTS13 gene. USS is characterized by the [...] Read more.
Upshaw–Schulman syndrome (USS) is a rare inherited autosomal recessive thrombotic microangiopathy affecting less than 1/1,000,000 individuals. It is a congenital form of thrombotic thrombocytopenic purpura (TTP) caused by ADAMTS13 protease deficiency because of mutations in the ADAMTS13 gene. USS is characterized by the formation of platelet thrombi in the microcirculation, accompanied by hemolytic anemia, thrombocytopenia, and clinical and laboratory signs of renal and neurological failure. The aim of this study was to describe the ADAMTS13 gene mutation spectrum in the Russian population. We analyzed the ADAMTS13 gene in 45 unrelated patients with TTP of unknown origin. DNA was extracted from blood cells using the phenol-chlorophorm method, and all exons of the gene were investigated using Sanger sequencing. In 15 out of 45 patients, we identified 20 different variants associated with USS, including two frameshift, two variants affecting the splice site, one nonsense and fifteen missense mutations. Eight out of those mutations were previously undescribed. Tree variants were revealed more than once: p.Arg1060Trp (7 patients), p.Glu1326ArgfsTer6 (7 patients) and p.Cys1067SerfsTer30 (3 patients). Variants (p.Arg1060Trp) and p.Glu1326ArgfsTer6 prevailed in the global population; however, p.Cys1067SerfsTer30 was not previously described in the European population. Our results expand the existing knowledge of the molecular basis of USS and may contribute to improved genetic diagnostics in Russia. Full article
(This article belongs to the Special Issue Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances: 2nd Edition)
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22 pages, 2108 KB  
Article
Untargeted Metabolomic Study for Urinary Characterization of Adult Patients with Phenylketonuria
by Arnau Gonzalez-Rodriguez, Blanca Barrau-Martinez, Adriana Pané, Rosa Maria López Galera, Ester Tobias, Cristina Montserrat-Carbonell, Mariona Guitart-Mampel, Olga Jáuregui, Regina Roca-Vives, Judit Garcia-Villoria, Jose Cesar Milisenda, Ana Matas-Garcia, Maria de Talló Forga Visa, Pedro Juan Moreno Lozano, Gloria Garrabou, Mireia Urpi-Sarda and Rafael Llorach
Int. J. Mol. Sci. 2025, 26(24), 11808; https://doi.org/10.3390/ijms262411808 - 6 Dec 2025
Cited by 2 | Viewed by 1973
Abstract
Phenylketonuria (PKU) is a rare inherited metabolic disorder caused by phenylalanine hydroxylase deficiency, leading to phenylalanine (Phe) accumulation and neurological dysfunction if untreated. While metabolomics holds promise for biomarker discovery in PKU, few studies have examined urinary metabolites using untargeted approaches. This study [...] Read more.
Phenylketonuria (PKU) is a rare inherited metabolic disorder caused by phenylalanine hydroxylase deficiency, leading to phenylalanine (Phe) accumulation and neurological dysfunction if untreated. While metabolomics holds promise for biomarker discovery in PKU, few studies have examined urinary metabolites using untargeted approaches. This study applied untargeted metabolomics using HPLC-QTOF-MS to analyze urine from 36 adult patients with PKU and 34 healthy controls. Biomarker Analysis was performed with MetaboAnalyst 6.0. A total of 73 significant metabolites (FDR < 0.05; VIP > 1) were identified, with 29 upregulated and 44 downregulated in PKU. A 23% of these metabolites were related to Phe metabolism, while 77% were associated with alterations across more than 10 metabolic pathways, including leucine and tryptophan metabolism, acylcarnitines, vitamins, and diet- or microbiota-derived compounds, among others. Specifically, upregulated metabolites with an AUC > 0.9 included several Phe-derived compounds, the nucleoside 8-hydroxy-7-methylguanine, and indole compounds (1H-indole-3-carboxaldehyde). Conversely, downregulated metabolites with an AUC > 0.9 included N-acetyl(iso)leucine and a heptenoylcarnitine isomer. The Random Forest-based model demonstrated enhanced predictive performance when integrating 10 metabolites, supporting their potential utility as biomarkers for PKU. These findings improve the biological understanding of metabolic disturbances beyond Phe, and may support the development of new therapeutic and dietary strategies. Full article
(This article belongs to the Special Issue Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances: 2nd Edition)
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12 pages, 1684 KB  
Case Report
Biparental and Androgenetic Somatic Mosaicism with Presentation of Non-Syndromic Severe Neonatal Hyperinsulinemia
by Miguel Angel Alcántara-Ortigoza, Marcela Vela-Amieva, Ariadna González-del Angel, Miriam Erandi Reyna-Fabián, Liliana Fernández-Hernández, Bernardette Estandía-Ortega, Sara Guillén-López, Lizbeth López-Mejía, Isabel Ibarra-González, María de la Luz Ruiz-Reyes, Raúl Calzada-de León, Mauricio Rojas-Maruri, Flora Zárate-Mondragón, Go Hun-Seo, Hane Lee and Cynthia Fernández-Lainez
Int. J. Mol. Sci. 2025, 26(16), 7985; https://doi.org/10.3390/ijms26167985 - 19 Aug 2025
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Abstract
Genome-wide paternal uniparental isodisomy mosaicism (GWpUPIDM) is an extremely rare condition characterized by varying proportions of an androgenetic cell line across different tissues. It is primarily associated with severe congenital hyperinsulinism (CHI), Beckwith–Wiedemann syndrome (BWS) stigmata, a high risk (69–79%) of developing neoplasia [...] Read more.
Genome-wide paternal uniparental isodisomy mosaicism (GWpUPIDM) is an extremely rare condition characterized by varying proportions of an androgenetic cell line across different tissues. It is primarily associated with severe congenital hyperinsulinism (CHI), Beckwith–Wiedemann syndrome (BWS) stigmata, a high risk (69–79%) of developing neoplasia and, in some cases, additional manifestations of multilocus paternal imprinting disorders (MPIDs). We herein report the first Mexican/Latin American female patient GWpUPIDM presenting with non-syndromic CHI requiring subtotal pancreatectomy and persistent but unexplained asymptomatic diffuse hepatopathy. When she was 8.5 years old, whole-exome sequencing (WES) in blood revealed an unexpectedly high (~92%) proportion of regions of homozygosity. DNA profiling confirmed a single haploid set of paternal chromosomes in both biparental and androgenetic cell lines, with varying proportions of the androgenetic lineage in leukocytes (84%), resected pancreas (74%), buccal cells (47%), and hair follicles (0.7%). Additional WES trio analysis using gDNA from the patient’s buccal cells and blood samples from both parents revealed an allelic frequency of ~75% for the paternally inherited variant NM_000158.4(GBE1):c.555+1G>T [ClinVar:632422; dbSNP:rs759707498]. At age 8.5, the patient exhibited no clinical features of BWS, MPIDs, or neoplasia. However, she presented persistent hepatic abnormalities that warrant further investigation to rule out an unmasked glycogen storage disease type IV (OMIM#232500). Our findings emphasize the critical need for early diagnosis of GWpUPIDM using SNP-based microarray or WES with further confirmation through DNA profiling in patients presenting with CHI, placental mesenchymal dysplasia, BWS stigmata, or other MPID-related conditions, including neoplasia, to facilitate timely cancer surveillance and management. Full article
(This article belongs to the Special Issue Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances: 2nd Edition)
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