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Genetic and Genomic Diagnostics for Rare Diseases
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Genetic and Genomic Diagnostics for 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 (31 July 2025) | Viewed by 1408

Special Issue Editor

Dr. Antonella La Russa

E-Mail Website
Guest Editor
Department of Health Sciences, Magna Graecia University, 88100 Catanzaro, Italy
Interests: genetics; X-linked disease; kidney disease; rare diseases

Special Issue Information

Dear Colleagues,

Genomic technologies such as targeted, exome and short-read genome sequencing have revolutionized the care of patients with rare genetic diseases. However, more than half of patients remain undiagnosed. Rare diseases are heterogeneous, life-threatening or severely debilitating conditions that affect < 1 in 2000 individuals. Emerging research-based approaches such as long-read genome sequencing and optical genome mapping promise to improve the identification of disease-causing genetic variants. In addition, new omics technologies that measure the transcriptome, epigenome, proteome or metabolome are showing great potential for variant interpretation. With the rapid expansion of genetic testing options, the clinical community needs to be aware of their individual strengths and limitations, as well as remaining challenges, in order to select the appropriate diagnostic test, correctly interpret results, and drive innovation to fill research gaps. 

This Special Issue aims to understand whether these multi-omics approaches are actually being integrated into clinical research and how these technologies are improving the interpretive power of genetic and genomic diagnostics for rare diseases.

Dr. Antonella La Russa
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 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

  • genome sequencing
  • molecular diagnosis
  • rare diseases
  • multi-omics
  • next-generation sequencing
  • long-read RNA-Seq

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Published Papers (3 papers)

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14 pages, 2368 KiB  
Article
Beyond the Known: Expanding the Clinical and Genetic Spectrum of Rare RPL13-Related Spondyloepimetaphyseal Dysplasia
by Daria Gorodilova, Elena Dadali, Vladimir Kenis, Evgenii Melchenko, Daria Akimova, Maria Bulakh, Anna Orlova, Maria Orlova, Olga Shatokhina, Evgeniya Melnik, Marc Baud’huin, Mikhail Skoblov, Sergey Kutsev and Tatiana Markova
Int. J. Mol. Sci. 2025, 26(14), 6982; https://doi.org/10.3390/ijms26146982 - 20 Jul 2025
Viewed by 351
Abstract
Spondyloepimetaphyseal dysplasia type Isidor-Toutain (RPL13-SEMD) is an autosomal dominant skeletal dysplasia caused by heterozygous pathogenic variants in the RPL13 gene, encoding the ribosomal protein eL13. To date, 13 pathogenic variants in RPL13 have been reported, all clustering within intron 5 and exon 6, [...] Read more.
Spondyloepimetaphyseal dysplasia type Isidor-Toutain (RPL13-SEMD) is an autosomal dominant skeletal dysplasia caused by heterozygous pathogenic variants in the RPL13 gene, encoding the ribosomal protein eL13. To date, 13 pathogenic variants in RPL13 have been reported, all clustering within intron 5 and exon 6, suggesting this hotspot region is critical for the function of ribosomes in skeletal tissues. Here, we present clinical and radiological characteristics of seven individuals, five children and two adults, from four unrelated families with RPL13-SEMD caused by two novel variants (c.477+5G>C and c.539_541del) and two previously reported variants (c.477+1G>C and c.548G>A) in RPL13. RNA analysis demonstrated that c.477+5G>C leads to a 54-nucleotide extension of exon 5, resulting in an 18-amino acid insertion. The phenotypic spectrum ranged from mild manifestations, such as Blount-like tibial deformity without significant short stature or Perthes-like femoral epiphyseal changes, to severe skeletal deformities with disproportionate short stature, accompanied by extraskeletal features (e.g., penoscrotal hypospadias, coccygeal abnormalities). For the first time, we describe Blount-like tibial deformity as a feature of this dysplasia, which resolves with age. Our study provides additional insights into the clinical, radiological, and genotypic features of RPL13-SEMD through detailed analysis of patients and their affected relatives. Full article
(This article belongs to the Special Issue Genetic and Genomic Diagnostics for Rare Diseases)
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26 pages, 5665 KiB  
Article
A New GlyT2 Variant Associated with Hyperekplexia
by Jorge Sarmiento-Jiménez, Raquel Felipe, Enrique Núñez, Alejandro Ferrando-Muñoz, Cristina Benito-Muñoz, Federico Gago, Jesús Vázquez, Emilio Camafeita, Emma Clement, Brian Wilson and Beatriz López-Corcuera
Int. J. Mol. Sci. 2025, 26(14), 6753; https://doi.org/10.3390/ijms26146753 - 14 Jul 2025
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Abstract
Hyperekplexia (OMIM 149400), a sensorimotor syndrome of perinatal clinical relevance, causes newborns to display an energic startle reflex in response to certain trivial stimuli. This condition can be lethal due to apnea episodes. The disease is caused by a blockade of glycinergic neurotransmission. [...] Read more.
Hyperekplexia (OMIM 149400), a sensorimotor syndrome of perinatal clinical relevance, causes newborns to display an energic startle reflex in response to certain trivial stimuli. This condition can be lethal due to apnea episodes. The disease is caused by a blockade of glycinergic neurotransmission. Glycinergic interneurons preserve their identity by the activity of the surface glycine transporter GlyT2, which supplies glycine to presynaptic terminals to maintain glycine content in synaptic vesicles. Loss-of-function mutations in the GlyT2 gene (SLC6A5) cause a presynaptic form of human hyperekplexia. Here, we describe a new GlyT2 variant found in an infantile patient diagnosed with hyperekplexia. A missense mutation in the open reading frame of the GlyT2 gene inherited in homozygosity caused the substitution G449E in a residue highly conserved across the phylogenetic scale. The sequences of the glycine receptor genes GLRA1 and GLRB did not show abnormalities. We expressed the recombinant GlyT2 variant in heterologous cells and analyzed its pathogenic mechanism. The transporter was totally inactive, behaving as a bona fide loss-of-function mutant. Furthermore, the mutation promoted the abnormal insertion of the protein into the membrane, leading to its large incorporation into lipid rafts. However, there was no apparent alteration of wild-type trafficking upon mutant coexpression, as the mutant was prematurely degraded from the endoplasmic reticulum. Rescue with chemical chaperones was not possible for this mutant. Proteomics demonstrated that the expression of the mutant induced the unfolded protein response and interfered with raft-dependent processes. Therefore, the new variant causes a loss of function regarding GlyT2 activity but a gain of function as a cell proteostasis disturber. Full article
(This article belongs to the Special Issue Genetic and Genomic Diagnostics for Rare Diseases)
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Other

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9 pages, 1313 KiB  
Case Report
Potential Pathogenetic Role of the D313Y Mutation in the GLA Gene in Anderson Fabry Disease: Two Case Reports
by Antonella La Russa, Antonio Siniscalchi, Ardito Bonaventura, Domenico Di Noia, Teresa Valsania, Giovanni Stallone, Luciano Tartaglia, Concetta Chiapparino, Giovanni Di Rienzo, Giuseppe Coppolino, Davide Bolignano, Teresa Faga, Ashour Michael, Alberto Montesanto, Raffaele Serra and Michele Andreucci
Int. J. Mol. Sci. 2025, 26(9), 4400; https://doi.org/10.3390/ijms26094400 - 6 May 2025
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Abstract
Anderson Fabry disease (AFD) is an X-linked hereditary lysosomal abnormality that causes the accumulation of glycosphingolipids in body fluids and tissues, leading to progressive organ damage and a shortened life span. More than 1000 mutations in the GLA gene have been identified, promoting [...] Read more.
Anderson Fabry disease (AFD) is an X-linked hereditary lysosomal abnormality that causes the accumulation of glycosphingolipids in body fluids and tissues, leading to progressive organ damage and a shortened life span. More than 1000 mutations in the GLA gene have been identified, promoting many different clinical pictures. For this reason, diagnosing AFD can be difficult, especially because of the great diversity of atypical clinical presentations that can simulate the disease. Some of these variants of the GLA gene have been described as non-pathogenic. For example, the D313Y variant is one of the most controversial, even if there are several case reports of D313Y patients presenting with signs and symptoms consistent with AFD without any other etiological explanation. This work aimed to clarify whether the presence of the D313Y variant affects α-Gal A activity and causes AFD symptoms and organ involvement in two patients from different families. The presence of the D313Y variant resulted in clinical manifestations of AFD in both patients and a decrease in alpha-galactosidase activity in the male patient. Two patients (one female and one male) from two unrelated families were examined. Sequencing of all seven GLA exons and the adjacent 5′ and 3′ exon–intron boundaries identified the D313Y variant in exon 6, as well as the genetic variation g.1170C>T in the flanking 5′ UTR in patient 1 only. Our results suggest that the D313Y variant is causative for the disease and that the clinical phenotype can be enhanced by the presence of other variants modulating protein expression. Full article
(This article belongs to the Special Issue Genetic and Genomic Diagnostics for Rare Diseases)
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