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Genes and Variants in Human Rare Genetic Diseases
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Genes and Variants in Human Rare Genetic Diseases

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

Deadline for manuscript submissions: closed (20 November 2024) | Viewed by 8053

Special Issue Editor

Dr. Edoardo Errichiello

E-Mail Website
Guest Editor
1. Department of Molecular Medicine, University of Pavia, Pavia, Italy
2. IRCCS Mondino Foundation, Pavia, Italy
Interests: molecular genetics; clinical genetics; next generation sequencing (NGS); molecular karyotyping; prenatal diagnosis; neurogenomics; oncogenomics; bioinformatics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Rare diseases (RDs) affect more than 300–400 million people worldwide, often causing chronic illness, severe disability, and premature death. In a large portion of cases, people with an undiagnosed disease incur in the so-called “diagnostic odyssey”. An accurate diagnosis of an RD can result in better clinical management, the identification of potential therapeutics, and the avoidance of unnecessary treatments that may have non-negligible side effects. In the last decade, the advent of NGS (next-generation sequencing) and omics sciences, such as genomics, transcriptomics, and methylomics, has completely revolutionized the approach to RDs.

This Special Issue aims to highlight the contribution of these novel approaches to unravel the pathogenetic mechanisms, discover novel disease genes, and depict the genetic architecture underlying RDs. Original articles, case series, reviews, and descriptions of new methodologies in the field of RDs are welcome to contribute to this Special Issue. Potential topics include, but are not limited to, the following: novel diagnostic approaches, genotype–phenotype correlations, disease gene discovery, multi-omics data integration, genetic pleiotropy, and phenotypic expansion.

We look forward to receiving your contributions.

Dr. Edoardo Errichiello
Guest Editor

Manuscript Submission Information

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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. 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 disease
  • multi-omics
  • exome
  • genome
  • transcriptome
  • methylome
  • next-generation sequencing

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Published Papers (5 papers)

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Research

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12 pages, 532 KiB  
Communication
CTLA4 Alteration and Neurologic Manifestations: A New Family with Large Phenotypic Variability and Literature Review
by Edoardo Genio, Mauro Lecca, Rachele Ciccocioppo and Edoardo Errichiello
Genes 2025, 16(3), 306; https://doi.org/10.3390/genes16030306 - 3 Mar 2025
Viewed by 906
Abstract
Cytotoxic-T-lymphocyte-antigen-4 (CTLA-4), a member of the immunoglobulin superfamily, is an essential negative regulator of immune responses that is constitutively expressed on both regulatory (Treg) and activated T cells. To date, heterozygous germline variants in CTLA4, leading to haploinsufficiency, have been associated with [...] Read more.
Cytotoxic-T-lymphocyte-antigen-4 (CTLA-4), a member of the immunoglobulin superfamily, is an essential negative regulator of immune responses that is constitutively expressed on both regulatory (Treg) and activated T cells. To date, heterozygous germline variants in CTLA4, leading to haploinsufficiency, have been associated with several immunological disorders, including hypogammaglobulinemia, multi-organ autoimmunity, lymphoproliferative disorders, and enlarged lymphoid organs. Indeed, CTLA4 carriers display highly heterogeneous clinical manifestations with a phenotypic spectrum ranging from asymptomatic carrier status to fatal autoimmunity. Here, we describe a family with autoimmune phenotypes (Hashimoto thyroiditis, psoriasiform dermatitis, celiac disease/inflammatory bowel disease, and rheumatoid arthritis), segregating across three different generations due to a recurrent missense variant [c.436G>A, p.(Gly146Arg)] in the CTLA4 gene. Interestingly, the proband showed prominent neurological manifestations, including seizures, hydrocephalus, and demyelination, which are less frequently reported in individuals with pathogenic variants in CTLA4. A detailed literature review of neurologic features that have been reported so far in CTLA4 carriers is also provided. Full article
(This article belongs to the Special Issue Genes and Variants in Human Rare Genetic Diseases)
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11 pages, 2480 KiB  
Article
Expanding the Genotypic and Phenotypic Spectrum of OFD1-Related Conditions: Three More Cases
by Tatiana Kyian, Artem Borovikov, Inga Anisimova, Oksana Ryzhkova, Maria Bulakh, Elizabeth Bragina, Maria Avakyan, Anna Demchenko, Victoria Zabnenkova, Victor Kovalev, Artem Bukhonin, Elena Kondratyeva and Sergey Kutsev
Genes 2024, 15(12), 1633; https://doi.org/10.3390/genes15121633 - 20 Dec 2024
Cited by 1 | Viewed by 1450
Abstract
Introduction: Pathogenic variants in the OFD1 gene are linked to a spectrum of syndromes that exhibit partial clinical overlap. Hemizygous loss-of-function variants are considered lethal in males, while heterozygous loss-of-function variants generally result in oro-facial-digital syndrome type 1. A reported phenotype, Simpson–Golabi–Behmel syndrome [...] Read more.
Introduction: Pathogenic variants in the OFD1 gene are linked to a spectrum of syndromes that exhibit partial clinical overlap. Hemizygous loss-of-function variants are considered lethal in males, while heterozygous loss-of-function variants generally result in oro-facial-digital syndrome type 1. A reported phenotype, Simpson–Golabi–Behmel syndrome type 2, was published once but remains controversial, with many specialists questioning its validity and arguing about its continued listing in the OMIM database. Methods: To investigate the genetic and phenotypic characteristics of the patients, we performed clinical exome sequencing, family-based genetic analysis, X-inactivation studies, electron microscopy, and detailed clinical assessments. Results: Three patients from unrelated families carrying loss-of-function variants in the OFD1 gene were identified, emphasizing the diverse phenotypic spectrum of OFD1-associated disorders. The first patient, a female with a heterozygous frameshift variant p.(Gln398LeufsTer2), was diagnosed with oro-facial-digital syndrome type 1. The second patient, a male with a heterozygous nonsense variant p.(Gln892Ter), presented with features resembling Simpson–Golabi–Behmel syndrome type 2, as previously reported under this diagnosis. The third patient, a male with another heterozygous nonsense variant p.(Glu879Ter), exhibited isolated primary ciliary dyskinesia without any syndromic features. Conclusions: This study contributes to the growing body of evidence on the expanding phenotypic spectrum of OFD1-associated disorders. It underscores the need for further investigation into the molecular mechanisms underlying the diverse presentations and the necessity of re-evaluating diagnostic classifications for conditions such as SGBS2 in the context of variants in the OFD1 gene. Full article
(This article belongs to the Special Issue Genes and Variants in Human Rare Genetic Diseases)
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Review

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12 pages, 1345 KiB  
Review
Genetic Insights and Clinical Implications of NEU1 Mutations in Sialidosis
by Mei-Ling Peng, Siu-Fung Chau, Jia-Ying Chien, Peng-Yeong Woon, Yu-Chen Chen, Wai-Man Cheang, Hsien-Yang Tsai and Shun-Ping Huang
Genes 2025, 16(2), 151; https://doi.org/10.3390/genes16020151 - 25 Jan 2025
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Abstract
Sialidosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the NEU1 gene, resulting in deficient neuraminidase-1 activity and the subsequent accumulation of sialylated compounds in lysosomes. This review comprehensively analyzes the genetic and clinical heterogeneity associated with sialidosis, emphasizing [...] Read more.
Sialidosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the NEU1 gene, resulting in deficient neuraminidase-1 activity and the subsequent accumulation of sialylated compounds in lysosomes. This review comprehensively analyzes the genetic and clinical heterogeneity associated with sialidosis, emphasizing the distinction between the milder type I form and the more severe type II form. Over 90 pathogenic NEU1 variants, predominantly missense mutations, have been identified, highlighting significant phenotypic diversity. Advancements in genomic sequencing technologies have facilitated the identification of known and novel mutations, with population-specific insights elucidating ethnic variability in symptomatology and genetic profiles. Recent case studies, including a novel compound heterozygous variant, further illustrate the complexity of the genotype–phenotype correlations. Emerging therapeutic approaches, such as enzyme replacement therapy and adeno-associated virus-mediated gene therapy, demonstrate promising potential for restoring neuraminidase-1 function and improving outcomes in preclinical models. This review emphasizes the critical role of genetic analysis in diagnosis and management while advocating for continued research into the molecular mechanisms underlying sialidosis to enable the development of targeted, personalized treatments. Full article
(This article belongs to the Special Issue Genes and Variants in Human Rare Genetic Diseases)
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Other

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14 pages, 5679 KiB  
Case Report
Identification of a Novel Indel Variant in the DARS2 Gene in Russian Patients with Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation
by Fatima M. Bostanova, Polina G. Tsygankova, Elena A. Larshina, Ilya O. Nagornov, Yulia V. Evseeva, Irina L. Krutikhina, Marina E. Dzhentemirova, Marina N. Kashlakova, Marina S. Petukhova, Inna V. Sharkova and Ekaterina Y. Zakharova
Genes 2024, 15(5), 615; https://doi.org/10.3390/genes15050615 - 11 May 2024
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Abstract
Background: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is an inherited disease caused by pathogenic biallelic variants in the gene DARS2, which encodes mitochondrial aspartyl-tRNA synthetase. This disease is characterized by slowly progressive spastic gait, cerebellar symptoms, and leukoencephalopathy [...] Read more.
Background: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is an inherited disease caused by pathogenic biallelic variants in the gene DARS2, which encodes mitochondrial aspartyl-tRNA synthetase. This disease is characterized by slowly progressive spastic gait, cerebellar symptoms, and leukoencephalopathy with brainstem and spinal cord involvement. Case Presentation: Peripheral blood samples were collected from four patients from four unrelated families to extract genomic DNA. All patients underwent partial exon analysis of the DARS2 gene using Sanger sequencing, which detected the c.228-21_228-20delinsC variant in a heterozygous state. Further DNA from three patients was analyzed using a next-generation sequencing-based custom AmpliSeq™ panel for 59 genes associated with leukodystrophies, and one of the patients underwent whole genome sequencing. We identified a novel pathogenic variant c.1675-1256_*115delinsGCAACATTTCGGCAACATTCCAACC in the DARS2 gene. Three patients (patients 1, 2, and 4) had slowly progressive cerebellar ataxia, and two patients (patients 1 and 2) had spasticity. In addition, two patients (patients 2 and 4) showed signs of axonal neuropathy, such as decreased tendon reflexes and loss of distal sensitivity. Three patients (patients 1, 2, and 3) also had learning difficulties. It should be noted the persistent presence of characteristic changes in brain MRI in all patients, which emphasizes its importance as the main diagnostic tool for suspicion and subsequent confirmation of LBSL. Conclusions: We found a novel indel variant in the DARS2 gene in four patients with LBSL and described their clinical and genetic characteristics. These results expand the mutational spectrum of LBSL and aim to improve the laboratory diagnosis of this form of leukodystrophy. Full article
(This article belongs to the Special Issue Genes and Variants in Human Rare Genetic Diseases)
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15 pages, 3590 KiB  
Case Report
Characterization of a New Variant in ARHGAP31 Probably Involved in Adams–Oliver Syndrome in a Family with a Variable Phenotypic Spectrum
by Carlo Santaniello, Alice Faversani, Luigi Corsaro, Giulia Melloni, Silvia Motta, Elena Mandorino, Davide Sacco, Sabine Stioui, Fulvio Ferrara, Davide Barteselli, Dario De Vita, Debora Manuelli and Lucy Costantino
Genes 2024, 15(5), 536; https://doi.org/10.3390/genes15050536 - 24 Apr 2024
Viewed by 1654
Abstract
Adams–Oliver syndrome is a rare inherited condition characterized by scalp defects and limb abnormalities. It is caused by variants in different genes such as ARHGAP31. Here, we used an interdisciplinary approach to study a family with lower limb anomalies. We identified a [...] Read more.
Adams–Oliver syndrome is a rare inherited condition characterized by scalp defects and limb abnormalities. It is caused by variants in different genes such as ARHGAP31. Here, we used an interdisciplinary approach to study a family with lower limb anomalies. We identified a novel variant in the ARHGAP31 gene that is predicted to result in a truncated protein with a constitutively activated catalytic site due to the loss of 688 amino acids involved in the C-terminal domain, essential for protein auto-inhibition. Pathogenic variants in ARHGAP31 exon 12, leading to a premature protein termination, are associated with Adams–Oliver syndrome. Bioinformatic analysis was useful to elucidate the impact of the identified genetic variant on protein structure. To better understand the impact of the identified variant, 3D protein models were predicted for the ARHGAP31 wild type, the newly discovered variant, and other pathogenetic alterations already reported. Our study identified a novel variant probably involved in Adams–Oliver syndrome and increased the evidence on the phenotypic variability in patients affected by this syndrome, underlining the importance of translational research, including experimental and bioinformatics analyses. This strategy represents a successful model to investigate molecular mechanisms involved in syndrome occurrence. Full article
(This article belongs to the Special Issue Genes and Variants in Human Rare Genetic Diseases)
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