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New Sights: Genetic Advances and Challenges in Rare Diseases
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New Sights: Genetic Advances and Challenges in 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: closed (20 November 2024) | Viewed by 14222

Special Issue Editor

Dr. Luisa M. Botella

E-Mail Website
Guest Editor
Centro de Investigaciones Biológicas, Margarita Salas (CSIC), 28040 Madrid, Spain
Interests: genetics; TGF-β; vascular disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is a pleasure to introduce this Special Issue.  

Rare diseases (RDs) have lower incidence rates. Typically, RDs are mostly underdiagnosed, with a few active studies, and lack therapeutic options. Eighty percent of the RDs are genetic. RDs cover a broad range of disorders, with more than 7000 different ones. Around 6–8% of the world population is affected by some RD. The advent of Genetics Advances has sped up early diagnosis and family screening processes, contributing to appropriate patient follow-ups and preventing undesired outcomes. Thus, Genetics is a major tool for diagnosis and clinical prevention. Genetic Advances empower researchers to apply a personalized approach to the diagnosis and molecular basis of these diseases. Knowing that the genes/pathways are altered, we can search for targeted therapies in a precise/personalized manner. Some undiagnosed diseases need Genetic Advances to identify the cause of the pathology. Rare tumors have also a genetic basis. This Special Issue aims to highlight the current Genetic Advances and how they are improving the diagnosis of RD and the molecular basis of diseases to search for tailored therapies. Thus, in vitro and in vivo results on therapeutic targets will be also a highly appreciated.

Dr. Luisa M. Botella
Guest Editor

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Keywords

  • rare diseases
  • cavernomas
  • NGS
  • exome/genome
  • epigenome, undiagnosed rare diseases
  • phenotype–genotype correlations
  • transcription regulation
  • biomarkers
  • personalized medicine, precision medicine

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Published Papers (7 papers)

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Research

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21 pages, 8603 KiB  
Article
Cellular and Molecular Effects of the Bruck Syndrome-Associated Mutation in the PLOD2 Gene
by Olga I. Bolshakova, Evgenia M. Latypova, Artem E. Komissarov, Alexandra D. Slobodina, Elena V. Ryabova, Elena Yu. Varfolomeeva, Olga E. Agranovich, Sergey F. Batkin and Svetlana V. Sarantseva
Int. J. Mol. Sci. 2024, 25(24), 13379; https://doi.org/10.3390/ijms252413379 - 13 Dec 2024
Viewed by 928
Abstract
Bruck syndrome is a rare autosomal recessive disorder characterized by increased bone fragility and joint contractures similar to those in arthrogryposis and is known to be associated with mutations in the FKBP10 (FKBP prolyl isomerase 10) and PLOD2 (Procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase [...] Read more.
Bruck syndrome is a rare autosomal recessive disorder characterized by increased bone fragility and joint contractures similar to those in arthrogryposis and is known to be associated with mutations in the FKBP10 (FKBP prolyl isomerase 10) and PLOD2 (Procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 2) genes. These genes encode endoplasmic reticulum proteins that play an important role in the biosynthesis of type I collagen, which in turn affects the structure and strength of connective tissues and bones in the body. Mutations are associated with disturbances in both the primary collagen chain and its post-translational formation, but the mechanism by which mutations lead to Bruck syndrome phenotypes has not been determined, not only because of the small number of patients who come to the attention of researchers but also because of the lack of disease models. In our work, we investigated the cellular effects of two forms of the wild-type PLOD2 gene, as well as the PLOD2 gene with homozygous mutation c.1885A>G (p.Thr629Ala). The synthesized genetic constructs were transfected into HEK293 cell line and human skin fibroblasts (DF2 line). The localization of PLOD2 protein in cells and the effects caused by the expression of different isoforms—long, short, and long with mutation—were analyzed. In addition, the results of the transcriptome analysis of a patient with Bruck syndrome, in whom this mutation was detected, are presented. Full article
(This article belongs to the Special Issue New Sights: Genetic Advances and Challenges in Rare Diseases)
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12 pages, 679 KiB  
Article
Investigation of the Genetic Determinants of Telangiectasia and Solid Organ Arteriovenous Malformation Formation in Hereditary Hemorrhagic Telangiectasia (HHT)
by Kevin J. Whitehead, Doruk Toydemir, Whitney Wooderchak-Donahue, Gretchen M. Oakley, Bryan McRae, Angelica Putnam, Jamie McDonald and Pinar Bayrak-Toydemir
Int. J. Mol. Sci. 2024, 25(14), 7682; https://doi.org/10.3390/ijms25147682 - 12 Jul 2024
Cited by 3 | Viewed by 1408
Abstract
Telangiectases and arteriovenous malformations (AVMs) are the characteristic lesions of Hereditary Hemorrhagic Telangiectasia (HHT). Somatic second-hit loss-of-function variations in the HHT causative genes, ENG and ACVRL1, have been described in dermal telangiectasias. It is unclear if somatic second-hit mutations also cause the [...] Read more.
Telangiectases and arteriovenous malformations (AVMs) are the characteristic lesions of Hereditary Hemorrhagic Telangiectasia (HHT). Somatic second-hit loss-of-function variations in the HHT causative genes, ENG and ACVRL1, have been described in dermal telangiectasias. It is unclear if somatic second-hit mutations also cause the formation of AVMs and nasal telangiectasias in HHT. To investigate the genetic mechanism of AVM formation in HHT, we evaluated multiple affected tissues from fourteen individuals. DNA was extracted from fresh/frozen tissue of 15 nasal telangiectasia, 4 dermal telangiectasia, and 9 normal control tissue biopsies, from nine unrelated individuals with HHT. DNA from six formalin-fixed paraffin-embedded (FFPE) AVM tissues (brain, lung, liver, and gallbladder) from five individuals was evaluated. A 736 vascular malformation and cancer gene next-generation sequencing (NGS) panel was used to evaluate these tissues down to 1% somatic mosaicism. Somatic second-hit mutations were identified in three in four AVM biopsies (75%) or half of the FFPE (50%) samples, including the loss of heterozygosity in ENG in one brain AVM sample, in which the germline mutation occurred in a different allele than a nearby somatic mutation (both are loss-of-function mutations). Eight of nine (88.9%) patients in whom telangiectasia tissues were evaluated had a somatic mutation ranging from 0.68 to 1.96% in the same gene with the germline mutation. Six of fifteen (40%) nasal and two of four (50%) dermal telangiectasia had a detectable somatic second hit. Additional low-level somatic mutations in other genes were identified in several telangiectasias. This is the first report that nasal telangiectasias and solid organ AVMs in HHT are caused by very-low-level somatic biallelic second-hit mutations. Full article
(This article belongs to the Special Issue New Sights: Genetic Advances and Challenges in Rare Diseases)
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12 pages, 2131 KiB  
Article
Pilot Study by Liquid Biopsy in Gastrointestinal Stromal Tumors: Analysis of PDGFRA D842V Mutation and Hypermethylation of SEPT9 Presence by Digital Droplet PCR
by Rocío Olivera-Salazar, Gabriel Salcedo Cabañas, Luz Vega-Clemente, David Alonso-Martín, Víctor Manuel Castellano Megías, Peter Volward, Damián García-Olmo and Mariano García-Arranz
Int. J. Mol. Sci. 2024, 25(12), 6783; https://doi.org/10.3390/ijms25126783 - 20 Jun 2024
Cited by 1 | Viewed by 1409
Abstract
Tissue biopsy remains the standard for diagnosing gastrointestinal stromal tumors (GISTs), although liquid biopsy is emerging as a promising alternative in oncology. In this pilot study, we advocate for droplet digital PCR (ddPCR) to diagnose GIST in tissue samples and explore its potential [...] Read more.
Tissue biopsy remains the standard for diagnosing gastrointestinal stromal tumors (GISTs), although liquid biopsy is emerging as a promising alternative in oncology. In this pilot study, we advocate for droplet digital PCR (ddPCR) to diagnose GIST in tissue samples and explore its potential for early diagnosis via liquid biopsy, focusing on the PDGFRA D842V mutation and SEPT9 hypermethylated gene. We utilized ddPCR to analyze the predominant PDGFRA mutation (D842V) in surgical tissue samples from 15 GIST patients, correlating with pathologists’ diagnoses. We expanded our analysis to plasma samples to compare DNA alterations between tumor tissue and plasma, also investigating SEPT9 gene hypermethylation. We successfully detected the PDGFRA D842V mutation in GIST tissues by ddPCR. Despite various protocols to enhance mutation detection in early-stage disease, it remained challenging, likely due to the low concentration of DNA in plasma samples. Additionally, the results of Area Under the Curve (AUC) for the hypermethylated SEPT9 gene, analyzing concentration, ratio, and abundance were 0.74 (95% Confidence Interval (CI): 0.52 to 0.97), 0.77 (95% CI: 0.56 to 0.98), and 0.79 (95% CI: 0.59 to 0.99), respectively. As a rare disease, the early detection of GIST through such biomarkers is particularly crucial, offering significant potential to improve patient outcomes. Full article
(This article belongs to the Special Issue New Sights: Genetic Advances and Challenges in Rare Diseases)
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14 pages, 4323 KiB  
Article
Molecular and Cellular Characterization of Primary Endothelial Cells from a Familial Cavernomatosis Patient
by Laura Lorente-Herraiz, Angel M. Cuesta, Jaime Granado, Lucía Recio-Poveda, Luisa-María Botella and Virginia Albiñana
Int. J. Mol. Sci. 2024, 25(7), 3952; https://doi.org/10.3390/ijms25073952 - 2 Apr 2024
Cited by 1 | Viewed by 4265
Abstract
Cerebral cavernous malformation (CCM) or familial cavernomatosis is a rare, autosomal dominant, inherited disease characterized by the presence of vascular malformations consisting of blood vessels with an abnormal structure in the form of clusters. Based on the altered gene (CCM1/Krit1, CCM2 [...] Read more.
Cerebral cavernous malformation (CCM) or familial cavernomatosis is a rare, autosomal dominant, inherited disease characterized by the presence of vascular malformations consisting of blood vessels with an abnormal structure in the form of clusters. Based on the altered gene (CCM1/Krit1, CCM2, CCM3) and its origin (spontaneous or familial), different types of this disease can be found. In this work we have isolated and cultivated primary endothelial cells (ECs) from peripheral blood of a type 1 CCM patient. Differential functional and gene expression profiles of these cells were analyzed and compared to primary ECs from a healthy donor. The mutation of the familial index case consisted of a heterozygous point mutation in the position +1 splicing consensus between exons 15 and 16, causing failure in RNA processing and in the final protein. Furthermore, gene expression analysis by quantitative PCR revealed a decreased expression of genes involved in intercellular junction formation, angiogenesis, and vascular homeostasis. Cell biology analysis showed that CCM1 ECs were impaired in angiogenesis and cell migration. Taken together, the results obtained suggest that the alterations found in CCM1 ECs are already present in the heterozygous condition, suffering from vascular impairment and somewhat predisposed to vascular damage. Full article
(This article belongs to the Special Issue New Sights: Genetic Advances and Challenges in Rare Diseases)
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Review

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15 pages, 1035 KiB  
Review
Advances in Gene Therapy for Rare Diseases: Targeting Functional Haploinsufficiency Through AAV and mRNA Approaches
by Nuria Bara-Ledesma, Adrian Viteri-Noel, Monica Lopez Rodriguez, Konstantinos Stamatakis, Martin Fabregate, Almudena Vazquez-Santos and Vicente Gomez del Olmo
Int. J. Mol. Sci. 2025, 26(2), 578; https://doi.org/10.3390/ijms26020578 - 11 Jan 2025
Cited by 3 | Viewed by 2746
Abstract
Most rare diseases (RDs) encompass a diverse group of inherited disorders that affect millions of people worldwide. A significant proportion of these diseases are driven by functional haploinsufficiency, which is caused by pathogenic genetic variants. Currently, most treatments for RDs are limited to [...] Read more.
Most rare diseases (RDs) encompass a diverse group of inherited disorders that affect millions of people worldwide. A significant proportion of these diseases are driven by functional haploinsufficiency, which is caused by pathogenic genetic variants. Currently, most treatments for RDs are limited to symptom management, emphasizing the need for therapies that directly address genetic deficiencies. Recent advancements in gene therapy, particularly with adeno-associated viruses (AAVs) and lipid nanoparticle-encapsulated messenger RNA (mRNA), have introduced promising therapeutic approaches. AAV vectors offer durable gene expression, extensive tissue tropism, and a safety profile that makes them a leading choice for gene delivery; however, limitations remain, including packaging size and immune response. In contrast, mRNA therapeutics, formulated in LNPs, facilitate transient protein expression without the risk of genomic integration, supporting repeated dosing and pharmacokinetic control, though with less long-term expression than AAVs. This review analyzes the latest developments in AAV and mRNA technologies for rare monogenic disorders, focusing on preclinical and clinical outcomes, vector design, and delivery challenges. We also address key regulatory and immunological considerations impacting therapeutic success. Together, these advancements in AAV and mRNA technology underscore a new era in RD treatment, providing innovative tools to target the genetic root of these diseases and expanding therapeutic approaches for patients who currently face limited medical options. Full article
(This article belongs to the Special Issue New Sights: Genetic Advances and Challenges in Rare Diseases)
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Other

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11 pages, 2592 KiB  
Case Report
Duchenne Muscular Dystrophy in Two Half-Brothers Due to Inherited 306 Kb Inverted Insertion of 10p15.1 into Intron 44 of the Dp427m Transcript of the DMD Gene
by Wayne M. Jepsen, Andrew Fazenbaker, Keri Ramsey, Anna Bonfitto, Marcus Naymik, Bryce Turner, Jennifer Sloan, Nishant Tiwari, Saunder M. Bernes, Derek E. Neilson, Meredith Sanchez-Castillo, Matt J. Huentelman and Vinodh Narayanan
Int. J. Mol. Sci. 2024, 25(22), 11922; https://doi.org/10.3390/ijms252211922 - 6 Nov 2024
Viewed by 1257
Abstract
Duchenne muscular dystrophy (DMD) is a rare genetic disorder caused by the absence of a fully functional dystrophin protein in myocytes. In skeletal muscle, the lack of dystrophin ultimately results in muscle wasting and the replacement of myocytes with fatty or fibrous tissues. [...] Read more.
Duchenne muscular dystrophy (DMD) is a rare genetic disorder caused by the absence of a fully functional dystrophin protein in myocytes. In skeletal muscle, the lack of dystrophin ultimately results in muscle wasting and the replacement of myocytes with fatty or fibrous tissues. In the heart, cardiomyocytes eventually fail and cause fatal cardiomyopathy. We present a case of a male patient and his younger brother with a maternally inherited inverted insertion of approximately 306 kb of chromosome 10 in the deep intronic region between exons 44 and 45 of the DMD gene, leading to Duchenne muscular dystrophy. Chromosomal microarray, comprehensive muscular dystrophy genetic testing, and whole exome sequencing were negative. Targeted transcriptome RNA sequencing at an external lab showed no aberrant splicing. Research whole genome sequencing identified the copy number gain and insertion. Subsequent reanalysis of the RNA sequencing data showed possible aberrant splicing involving DMD exons 44–45, and research RNA sequencing revealed a fusion between the DMD gene on the minus strand of chromosome X and the PFKFB3 gene on the plus strand of chromosome 10. We demonstrate that whole genome sequencing can be valuable for identifying intronic events in the DMD gene previously undetected or not reported by traditional clinical testing. Full article
(This article belongs to the Special Issue New Sights: Genetic Advances and Challenges in Rare Diseases)
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17 pages, 2461 KiB  
Case Report
Genomic Insights into Idiopathic Granulomatous Mastitis through Whole-Exome Sequencing: A Case Report of Eight Patients
by Seeu Si Ong, Peh Joo Ho, Alexis Jiaying Khng, Benita Kiat Tee Tan, Qing Ting Tan, Ern Yu Tan, Su-Ming Tan, Thomas Choudary Putti, Swee Ho Lim, Ee Ling Serene Tang, Jingmei Li and Mikael Hartman
Int. J. Mol. Sci. 2024, 25(16), 9058; https://doi.org/10.3390/ijms25169058 - 21 Aug 2024
Viewed by 1476
Abstract
Idiopathic granulomatous mastitis (IGM) is a rare condition characterised by chronic inflammation and granuloma formation in the breast. The aetiology of IGM is unclear. By focusing on the protein-coding regions of the genome, where most disease-related mutations often occur, whole-exome sequencing (WES) is [...] Read more.
Idiopathic granulomatous mastitis (IGM) is a rare condition characterised by chronic inflammation and granuloma formation in the breast. The aetiology of IGM is unclear. By focusing on the protein-coding regions of the genome, where most disease-related mutations often occur, whole-exome sequencing (WES) is a powerful approach for investigating rare and complex conditions, like IGM. We report WES results on paired blood and tissue samples from eight IGM patients. Samples were processed using standard genomic protocols. Somatic variants were called with two analytical pipelines: nf-core/sarek with Strelka2 and GATK4 with Mutect2. Our WES study of eight patients did not find evidence supporting a clear genetic component. The discrepancies between variant calling algorithms, along with the considerable genetic heterogeneity observed amongst the eight IGM cases, indicate that common genetic drivers are not readily identifiable. With only three genes, CHIT1, CEP170, and CTR9, recurrently altering in multiple cases, the genetic basis of IGM remains uncertain. The absence of validation for somatic variants by Sanger sequencing raises further questions about the role of genetic mutations in the disease. Other potential contributors to the disease should be explored. Full article
(This article belongs to the Special Issue New Sights: Genetic Advances and Challenges in Rare Diseases)
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