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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: 15 October 2026 | Viewed by 5699

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Dr. Giorgia Girotto

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1. Institute for Maternal and Child Health—IRCCS, Burlo Garofolo, 34127 Trieste, Italy
2. Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149 Trieste, Italy
Interests: clinical and molecular genetics; hereditary and multifactorial hearing loss; rare diseases
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Special Issue Information

Dear Colleagues,

We would like to invite you to contribute to the following Genes Special Issue: “Diagnosis, Management and Therapy of Rare Diseases”.

More than 8500 rare diseases have been described to this date, and the advances in genomic analyses have substantially improved the chance of achieving a genetic diagnosis of these disorders. Of note, only approximately 5% of these conditions recognize an approved tailored treatment, limiting the possibilities to provide truly personalized management.

This Special Issue aims at focusing on the role of clinical and molecular genetics in clinically complex cases, solved by applying the most advanced sequencing technologies, for which molecular diagnosis deeply modified the treatment and care of patients.

In particular, this Special Issue includes, but it is not limited to, the following topics:

Molecular mechanisms behind rare and ultrarare genetic diseases;
Diagnosis, clinical features, and expansion of the phenotypic spectrum of rare and ultrarare genetic diseases;
The clinical and molecular characterization of family members;
Ethnic variability in rare and ultrarare genetic diseases;
Gene-tailored therapeutic options (including pharmacogenomics);
Clinical trials with which to develop new treatments.

We look forward to receiving your contributions.

Dr. Giorgia Girotto
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 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. Genes 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

rare and ultrarare genetic diseases
genetic mechanisms
gene-tailored management
personalized therapeutic approaches

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Published Papers (7 papers)

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Research

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16 pages, 1911 KB

Open AccessArticle

by Ralyath Balogoun, Margaux Serey-Gaut, Véronique Pingault, Isabelle Lemiere, Geneviève Lina-Granade, Geoffroy Delplancq, Anne Marie Guerrot, Annick Toutain, Delphine Dupin-Deguine, Marine Legendre, Estelle Colin, Natalie Loundon, Laurence Jonard and Sandrine Marlin

Genes 2026, 17(5), 588; https://doi.org/10.3390/genes17050588 - 21 May 2026

Viewed by 462

Abstract

Objectives: To characterize heterozygous pathogenic COCH variants in a French cohort with non-syndromic sensorineural hearing loss (NSHL) and assess genotype–phenotype correlations in autosomal dominant NSHL (DFNA9). Setting: National Reference Center for Genetic Hearing Loss, Necker–Enfants Malades Hospital, Paris, France. Methods: This retrospective observational study included 69 individuals from 20 unrelated families diagnosed with DFNA9 (2005–2025). All individuals underwent clinical and audiological evaluations and genetic testing via targeted COCH Sanger sequencing or next-generation sequencing (NGS) panels. Variants were interpreted according to ACMG guidelines. Audiometric profiles and vestibular data were collected. Results: Seven known pathogenic COCH variants were found in ten families, and ten novel likely pathogenic variants in the others. Variants in vWFA domains were associated with early or late onset, progressive, bilateral and symmetrical hearing loss. Three variants (p.Gln410Arg, p.Ile450Val, p.Cys542Arg) were associated with congenital or prelingual onset, an atypical DFNA9 presentation. Variants in the LCCL domain were associated with later-onset hearing loss and more frequent vestibular dysfunction. Vestibular abnormalities were observed in about half of early-onset cases. Conclusions:COCH-related hearing loss is a rare cause of autosomal dominant NSHL, with only 20 families identified over two decades within the French network. This study expands the mutational spectrum of COCH by reporting ten novel variants and supports a domain-specific genotype–phenotype correlation. These findings improve the understanding of DFNA9 variability and have direct implications for clinical diagnosis, prognosis, and genetic counseling. Full article

(This article belongs to the Special Issue Diagnosis, Management and Therapy of Rare Diseases)

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16 pages, 2108 KB

Open AccessArticle

Infantile-Onset Glutaric Acidemia Type I with Mild Hepatopathy: Clinical, Biochemical, and Molecular Characterization of an Iranian Pediatric Cohort

by Zahra Beyzaei, Bita Geramizadeh, Seyed Mohsen Dehghani, Sorour Inaloo and Ralf Weiskirchen

Genes 2026, 17(4), 481; https://doi.org/10.3390/genes17040481 - 18 Apr 2026

Viewed by 604

Abstract

Background: Glutaric acidemia type 1 (GA1) is an autosomal recessive neurometabolic disorder caused by pathogenic variants in glutaryl-CoA dehydrogenase (GCDH), with variable clinical severity despite early biochemical detectability. Population-specific mutational spectra and genotype–phenotype correlations remain insufficiently defined in infantile-onset disease. Therefore, this study aimed to define the GCDH variant spectrum in GA1 patients with mild hepatopathy and assess genotype–phenotype correlations. Methods: We performed integrated clinical, biochemical, and molecular characterization of 15 unrelated patients with infantile-onset GA1. Whole-exome sequencing (WES) was performed for all participants, and the resulting data were compared with the reference sequence of the GCDH gene. Results: All patients presented within the first 6 months of life with macrocephaly, seizures, dystonia, and feeding difficulties. Neurological impairment and mild hepatopathy were variably observed, and one patient developed an acute encephalopathic crisis. Six homozygous GCDH variants were identified, predominantly missense. A common variant, c.541G>C (p.Glu181Gln), accounted for 73.3% of cases and defined a consistent phenotype of early macrocephaly and movement disorder with frequent mild hepatic involvement, suggesting regional enrichment and raising the possibility of a founder effect that warrants confirmation in future haplotype studies. A truncating variant, c.382C>T (p.Arg128Ter), was associated with severe early encephalopathy. Exon 6 represented a mutational hotspot. Biochemically, all patients showed elevated urinary glutaric and 3-hydroxyglutaric acids, increased glutarylcarnitine, and low-to-normal free carnitine, with higher metabolite levels in clinically more severe cases. All variants were pathogenic or likely pathogenic and extremely rare in population databases. Conclusions: This cohort reveals a striking predominance of the GCDH c.541G>C variant and establishes a clear biochemical signature with genotype-associated clinical patterns in infantile-onset GA1. These findings support a population-specific mutational spectrum, refine genotype–phenotype correlations, and underscore the importance of early molecular diagnosis to guide targeted neurological and hepatic monitoring as well as regional screening strategies. Full article

(This article belongs to the Special Issue Diagnosis, Management and Therapy of Rare Diseases)

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12 pages, 1000 KB

Open AccessArticle

SINEUP-Mediated Overexpression of Endogenous α-Amylase as a Therapeutic Approach in Lafora Disease

by Lorenzo Allegri, Federica Baldan, Catia Mio, Valentina Imperatore, Cinzia Costa, Paolo Prontera, Francesca Bisulli, Lorenzo Muccioli and Giuseppe Damante

Genes 2026, 17(3), 321; https://doi.org/10.3390/genes17030321 - 16 Mar 2026

Viewed by 716

Abstract

Background/Objectives: Lafora disease is a fatal and progressive neurodegenerative disorder characterized by the accumulation of insoluble polyglucosan inclusions, known as Lafora bodies, due to impaired glycogen metabolism. Therapeutic strategies aimed at reducing intracellular glycogen accumulation represent a promising approach to mitigating disease progression. This study aimed to evaluate the feasibility of promoting Lafora body degradation by increasing the protein levels of human pancreatic amylase, a glycogen-degrading enzyme, through the SINEUP approach. Methods: Two SINEUP constructs specifically targeting human pancreatic amylase were designed and tested in continuous tumor-derived cell lines of central nervous system origin, as well as in primary fibroblasts obtained from a patient with Lafora disease. Human pancreatic amylase protein and mRNA levels were assessed to determine the specificity of SINEUP-mediated regulation. Enzymatic activity assays were performed to evaluate functional protein upregulation, and intracellular glycogen content was measured in patient-derived fibroblasts. Results: Both SINEUP constructs significantly increased human pancreatic amylase protein expression without affecting mRNA levels, confirming a post-transcriptional mechanism of action. The elevated protein levels were associated with a significant increase in enzymatic activity. In primary fibroblasts derived from a Lafora disease patient, enhanced amylase expression correlated with a marked reduction in intracellular glycogen content. Conclusions: These findings provide proof of concept that SINEUP-mediated upregulation of glycogen-degrading enzymes may represent a viable therapeutic strategy to counteract Lafora body accumulation. Further studies are warranted to assess the efficacy, safety, and translational potential of this approach, particularly in relevant animal models of Lafora disease. Full article

(This article belongs to the Special Issue Diagnosis, Management and Therapy of Rare Diseases)

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22 pages, 1432 KB

Open AccessArticle

Fifteen Years of Myotonic Dystrophy Type 1 in Mexico: Clinical, Molecular, and Socioeconomic Insights from a National Reference Cohort

by César M. Cerecedo-Zapata, Araceli Guerra-Grajeda, Luz C. Márquez-Quiróz, Paola Arciga-Portela, Rosa E. Escobar-Cedillo, Guadalupe E. Jiménez-Gutiérrez, Óscar A. Pérez-Méndez, Jorge S. Velasco-Flores, Blanca A. Barredo-Prieto, Norberto Leyva-García, Bulmaro Cisneros, Nadia M. Murillo-Melo and Jonathan J. Magaña

Genes 2025, 16(12), 1515; https://doi.org/10.3390/genes16121515 - 17 Dec 2025

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Abstract

Background/Objectives: Myotonic dystrophy type 1 (DM1) is a rare, multisystemic disorder caused by an expanded (CTG)n repeat in the DMPK gene. Although DM1 has been studied in several populations, access to molecular diagnosis and comprehensive care remains limited in many low- and middle-income countries. This study provides an updated overview of DM1 in Mexico, from diagnostic implementation to patient management, describing key clinical and genetic findings. Methods: We conducted a nationwide, 15-year prospective study at Mexico’s National Reference Center for neuromuscular diseases. A total of 853 individuals at risk were subjected to clinical and molecular evaluation using PCR, TP-PCR, and SP-PCR, encompassing symptomatic, pre-symptomatic, prenatal, and preimplantation genetic diagnosis. Socioeconomic, clinical, and molecular variables were analyzed. Results: A total of 488 individuals were confirmed as DM1 carriers, with the most prevalent phenotypes being classic (36.5%) and juvenile (28.5%). Genomic analysis revealed a correlation between CTG tract sizes and phenotypes. Intriguingly, interrupted CTG repeat tracts were identified in 2.8% of DM1 carriers, who exhibited milder clinical phenotypes and a reduced degree of somatic and intergenerational instability. Survival analysis revealed a reduction in symptom-free survival in patients with larger expansions, while interrupted CTG tracts were associated with delayed onset. Conclusions: The centralization of diagnostic services in Mexico resulted in regional disparities, impacting early diagnosis and family planning. This study highlights the clinical and molecular diversity of DM1 in a Latin American population and underscores the urgent need for decentralized diagnostic services, integrated care models, and tailored prognostic tools in underserved settings. Full article

(This article belongs to the Special Issue Diagnosis, Management and Therapy of Rare Diseases)

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26 pages, 5255 KB

Open AccessReview

Molecular Diagnosis to Individualized Therapies in Rare Genetic Diseases: New Approach Methodologies, RNA Therapeutics, and the Case for a Human-First Filter

by Saeed Anwar and Toshifumi Yokota

Genes 2026, 17(7), 780; https://doi.org/10.3390/genes17070780 - 3 Jul 2026

Viewed by 230

Abstract

Rare genetic diseases are heterogeneous across mechanisms, trajectories, and treatment responses. To date, approved therapies remain available for only a small proportion of rare genetic diseases. Oligonucleotide-based RNA therapeutics, particularly antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), offer a promising therapeutic avenue for rare genetic diseases with sequence-level precision. However, traditional preclinical paths may mis-predict human outcomes when disease biology diverges from animal models. New approach methodologies (NAMs), including patient-derived induced pluripotent stem cells (iPSCs), organoid models, and clinical-trials-in-a-dish (CTiD), aim to bring human biology earlier into the translational pipeline. NAMs enable variant-to-function studies, efficacy screening, and safety triage at clinically relevant speed and scale. While critics argue that NAMs are unvalidated and cannot replace preclinical animal models, proponents report that they are increasingly able to recapitulate human phenotypes and predict clinical liabilities, although their predictive validity remains context-dependent. Here, a front-loaded human filter refers to the use of human-derived systems early in development to support mechanistic interpretation, candidate prioritization, and early liability assessment before broader nonclinical evaluation. Recent studies pairing NAMs with ASOs support rapid, patient-specific preclinical screening in selected settings, while also showing the need for broader evidence on delivery, pharmacology, safety, and clinical relevance. This review places these developments within the translational realities of oligonucleotide-based therapeutics, including model fidelity, ASO chemistry and optimization, delivery challenges, pharmacology, regulatory pathways for individualized ASOs, and accessibility. We also propose a pragmatic validation framework to assess the scientific and translational credibility of NAMs across rare genetic diseases. Full article

(This article belongs to the Special Issue Diagnosis, Management and Therapy of Rare Diseases)

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21 pages, 781 KB

Open AccessReview

Building CRISPR-Based Gene-Editing Platforms for Personalized Medicine: The Next Step in Interventional Genetics

by Sebastian Hernandez Rodriguez and Toshifumi Yokota

Genes 2026, 17(6), 631; https://doi.org/10.3390/genes17060631 - 30 May 2026

Viewed by 1245

Abstract

Recent advances in CRISPR technology have expanded beyond traditional double-strand break–based genome editing to include base editors and prime editors, enabling precise and programmable sequence modifications. This evolution marks a shift from conventional mutation correction toward platform-based therapeutic systems capable of targeting a broad spectrum of pathogenic variants. Such versatility holds promise for addressing a substantial proportion of known disease-causing mutations in rare monogenic disorders. This review discusses the technological progression of CRISPR systems, highlighting the principles, applications, and limitations of emerging editing modalities. We will explore their translation into personalized gene therapies, emphasizing delivery challenges, off-target safety, and the need for regulatory innovation. The paper will also introduce the concept of interventional genetics, an emerging medical framework linking genomic diagnosis directly to therapeutic intervention through adaptive gene-editing platforms. Finally, we will outline strategies for establishing unified, scalable, and regulatory-ready editing platforms that can accelerate the clinical implementation of individualized therapies for rare diseases. Full article

(This article belongs to the Special Issue Diagnosis, Management and Therapy of Rare Diseases)

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Other

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12 pages, 3084 KB

Open AccessCase Report

Identification and Functional Characterization of a Novel De Novo SATB1 Frameshift Variant in a Patient with Epilepsy-Dominant Neurodevelopmental Disorders

by Mingchao Xu, Rui Zhang, Shiqi Fan, Miao Sun and Xue Zhang

Genes 2026, 17(5), 565; https://doi.org/10.3390/genes17050565 - 15 May 2026

Viewed by 455

Abstract

Background/Objectives: As a global chromatin organizer, SATB1 is increasingly implicated in neurodevelopmental disorders (NDDs). This study aims to delineate the clinical and molecular characteristics of a novel de novo SATB1 variant in a patient presenting with epilepsy-dominant NDDs phenotypes. Methods: Triggered by the onset of seizures, trio-based whole-exome sequencing (Trio-WES) was performed to identify the genetic etiology. Subsequent sleep electroencephalogram (EEG) and magnetic resonance imaging (MRI) were then conducted to further characterize the patient’s clinical phenotypes. Pathogenicity was assessed through structural modeling and functional characterization. Nonsense-mediated mRNA decay (NMD) status, protein expression profiles, and subcellular localization were determined by reverse-transcription quantitative PCR (RT-qPCR), Western blotting, and immunofluorescence staining. The transcriptional regulatory impacts of the variant were quantified using dual-luciferase reporter system targeting known downstream regulatory elements. Clinical responses to antiepileptic intervention was also monitored. Results: We identified a novel de novo heterozygous pathogenic frameshift variant in SATB1 (NM_002971.5: c.1718_1719insCA; p.Val574Argfs*134) in a patient presenting with early-onset epilepsy, mild intellectual developmental disorder (IDD), speech delay, and dental anomalies. Functional assays demonstrated that the variant-derived transcript escaping NMD, yielding a truncated protein that forms irregular punctate aggregates within nuclei. Dual-luciferase assays revealed significantly increased transcriptional activity, indicating a loss of the protein’s innate transcriptional regulatory capacity. Clinically, treatment with sodium valproate (VPA) successfully stabilized seizures of the patient, markedly reducing both frequency and intensity. Conclusions: The study reports a novel SATB1 frameshift variant that exerts pathogenicity significant functional impairment by disrupting protein localization and transcriptional regulation. These findings expand the genetic spectrum of SATB1-related NDDs and underscore the efficacy of targeted antiepileptic management in genetic diseases. Full article

(This article belongs to the Special Issue Diagnosis, Management and Therapy of Rare Diseases)

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