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Feature Papers in Human Genomics and Genetic Diseases 2024

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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: closed (25 December 2024) | Viewed by 18820

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Prof. Dr. Mariarosa Anna Beatrice Melone

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1. Department of Medical and Surgical Advanced Sciences, Second Division of Neurology , Center for Rare Neurological and Neuromuscular Diseases & Inter University Center for Research in Neurosciences, University of Campania Luigi Vanvitelli, Naples , Italy
2. Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
Interests: genetics of rare neurologic and neuromuscular diseases; translational neurogenetics; clinical & molecular neurogenetics; applied stem cell biology; systems neuroscience; neuropathology and experimental neurobiology; nanotechnology in nutraceuticals and functional fods; roles of autophagy in neurodegenerative diseases; clinical neurology of adults and children
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Dear Colleagues,

This Special Issue, entitled “Feature Papers in Human Genomics and Genetic Diseases 2024”, aims to collect high-quality review articles or research articles on all aspects of human health and disease, as well as the diagnosis, treatment, and prognosis of genetic disorders, and heritable or acquired cancers. It is dedicated to recent advances in the research area of genomics and genetics and comprises a selection of exclusive papers from the Editorial Board Members (EBMs) of the Human Genomics and Genetic Section, as well as invited papers from relevant experts. We also welcome senior experts in the field to contribute to this Special Issue. We aim to represent our Section as an attractive open access publishing platform for genomics and genetic research.

Prof. Dr. Mariarosa Anna Beatrice Melone
Guest Editor

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Keywords

genetics of monogenic diseases and complex diseases
genotype–phenotype relationships
population genomics and genetic epidemiology
precision medicine
pharmacogenetics and pharmacogenomics
targeted genome editing
gene therapy and delivery systems
genetically engineered cell therapy
RNA- and small nucleic acid-based therapeutics
genetic testing and molecular diagnostics, biomarker development and application
genome-wide association studies
epigenetic therapy
developmental genetics, epigenetics, and epigenomics

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Published Papers (11 papers)

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Research

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8 pages, 217 KiB

Open AccessArticle

Association of +67 G/A and -426 T/C Polymorphism in Eotaxin (CCL11) Gene with Psoriasis Phenotypes

by Vladimír Vašků, Adam Fiala and Anna Vašků

Genes 2025, 16(3), 288; https://doi.org/10.3390/genes16030288 - 27 Feb 2025

Viewed by 432

Abstract

Background/Objectives: Several gene targets were identified for psoriasis. Some are currently being explored as potential therapeutic targets, including CCL11. Our task was to prove a possible association of single-nucleotide polymorphisms +67 G/A and -426 T/C in the eotaxin gene (CCL11, 17q 21.3) with the development and clinical aspects of psoriasis as an immune-based dermatological disease and evaluate its relationship to potential comorbidities. Material and Methods: In total, 460 patients with psoriasis were included in the case–control and genotype–phenotype study together with 167 control persons of similar age and sex distributions without a personal and/or family history of chronic disease of the skin. Two eotaxin gene polymorphisms were detected from isolated DNA via standard PCR, restriction analysis methods, and horizontal electrophoresis. Results: No significant case–control differences in the frequency of the CCL11 genotype in both polymorphisms were observed. In polymorphism +67 G/A, a significant increase in the AA genotype in patients with psoriasis guttata compared to plaque psoriasis was found (p = 0.006). A significant association of the A allele in psoriatic patients with a personal history of allergy was found (p = 0.02). The A alle was also significantly associated with a family history of psoriasis (p = 0.00008). In men, a higher risk of a delayed start of psoriasis (later than 40 years) associated with the T allele of -426 T/C polymorphism (p = 0.0007) was found. When double genotypes of both polymorphisms were evaluated, we observed significant differences in double genotype distribution between men with and without a family history of allergy (Pdg = 0.0005) and between those with and without affected siblings (Pdg = 0.03). In women with psoriasis, a higher risk of the TT genotype of -426 T/C polymorphism in patients with a personal history of diabetes (p = 0.001) as well as in patients with both a personal history of cardiovascular disease and diabetes (p = 0.00005) was proved. When double genotypes of both polymorphisms were evaluated, the significance of double genotype difference between those with and without personal history of diabetes was very high (Pdg = 0.0002). Similarly, the significance of the double genotype difference between those with and without personal history of cardiovascular diseases and diabetes was very high (Pdg = 0.000001). Conclusions: CCL11 is considered one of the basic chemokines responsible for the origin and development of immune-based reactions. Based on our results, we suggest that the +67 G/A CCL11 polymorphism should be considered as a gene modulator of psoriasis in specific subgroups of patients. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2024)

12 pages, 1785 KiB

Open AccessArticle

Sleep Abnormalities in SLC13A5 Citrate Transporter Disorder

by Raegan M. Adams, Can Ozlu, Lauren E. Bailey, Rayann M. Solidum, Sydney Cooper, Carrie R. Best, Jennifer Elacio, Brian C. Kavanaugh, Tanya L. Brown, Kimberly Nye, Judy Liu, Brenda E. Porter, Kimberly Goodspeed and Rachel M. Bailey

Genes 2024, 15(10), 1338; https://doi.org/10.3390/genes15101338 - 18 Oct 2024

Viewed by 2058

Abstract

Background: SLC13A5 Citrate Transporter Disorder is a rare pediatric neurodevelopmental disorder. Patients have epilepsy, developmental disability, and impaired mobility. While sleep disorders are common in children with neurodevelopmental disorders, sleep abnormalities have not been reported in SLC13A5 patients. Methods: Here, we assessed sleep disturbances in patients through caregiver reported surveys and in a transgenic mouse model of SLC13A5 deficiency. A total of 26 patients were evaluated with the Sleep Disturbance Scale for Children three times over a one-year span. Sleep and wake activities were assessed in the SLC13A5 knock-out (KO) mice using wireless telemetry devices. Results: A high burden of clinically significant sleep disturbances were reported in the patients, with heterogeneous symptoms that remained stable across time. While sleep disturbances were common, less than 30% of patients were prescribed medications for sleep. Comparatively, in SLC13A5 KO mice using EEG recordings, significant alterations were found during light cycles, when rodents typically sleep. During the sleep period, SLC13A5 mice had increased activity, decreased paradoxical sleep, and changes in absolute power spectral density, indicating altered sleep architecture in the mouse model. Conclusions: Our results demonstrate a significant component of sleep disturbances in SLC13A5 patients and mice, highlighting a potential gap in patient care. Further investigation of sleep dysfunction and the underlying etiologies of sleep disturbances in SLC13A5 citrate transporter disorder is warranted. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2024)

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11 pages, 824 KiB

Open AccessArticle

APOBR Is Downregulated in EBV+ Tonsils of Children with Obstructive Sleep-Disordered Breathing

by Regie Lyn P. Santos-Cortez, Helen Z. Gomez, Christina L. Elling, Landen Mayher, Obinna R. Diala, Colin Gardner, Kiera Willford, Valerie C. Zamora, Ashley Agyepong, Nam K. Lee, Katherine K. Green, Owen A. Darr, Todd M. Wine, Christian R. Francom, Eric D. Larson, Sarah A. Gitomer, Amy E. Schell, Daniel N. Frank, Norman R. Friedman and Brian W. Herrmann

Genes 2024, 15(10), 1324; https://doi.org/10.3390/genes15101324 - 14 Oct 2024

Viewed by 1660

Abstract

Background: Obstructive sleep-disordered breathing (oSDB) is a heterogeneous phenotype that is increasing in prevalence worldwide and has many potential comorbidities that could severely affect quality of life. There is a need to identify biomarkers for oSDB and its comorbidities to improve clinical management, particularly in children. Methods: We performed bulk mRNA-sequencing, differential expression analysis, and qPCR replication of selected differentially expressed genes (DEGs) using RNA samples extracted from tonsils of children with oSDB. Two variables were used as classifier, namely, detection of Epstein–Barr virus (EBV) in tonsils and need for continuous positive airway pressure (CPAP) treatment. Standard statistical tests were used to determine associations across clinical, EBV, and DEG variables. Results: Nineteen genes were dysregulated in tonsils that are EBV+ or from children needing CPAP. Of these genes, APOBR was downregulated in both EBV+ and CPAP+ tonsils, and this downregulation was replicated by qPCR in an independent set of pediatric samples. In the tonsils of adult patients with oSDB, APOBR was positively correlated with age, and potentially with diastolic blood pressure. Conclusions: Taken together, APOBR and DEGs in tonsillar tissues may be useful as potential biomarkers of oSDB severity and comorbidity across the lifespan, with APOBR levels being dependent on latent EBV infection. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2024)

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21 pages, 2018 KiB

Open AccessArticle

Activation of the CDK7 Gene, Coding for the Catalytic Subunit of the Cyclin-Dependent Kinase (CDK)-Activating Kinase (CAK) and General Transcription Factor II H, by the Trans-Activator Protein Tax of Human T-Cell Leukemia Virus Type-1

by Mashiro Shirasawa, Rinka Nakajima, Yaxuan Zhou, Lin Zhao, Mariana Fikriyanti, Ritsuko Iwanaga, Andrew P. Bradford, Kenta Kurayoshi, Keigo Araki and Kiyoshi Ohtani

Genes 2024, 15(8), 1080; https://doi.org/10.3390/genes15081080 - 15 Aug 2024

Viewed by 1410

Abstract

Human T-cell leukemia virus type-1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL). The trans-activator protein Tax of HTLV-1 plays crucial roles in leukemogenesis by promoting proliferation of virus-infected cells through activation of growth-promoting genes. However, critical target genes are yet to be elucidated. We show here that Tax activates the gene coding for cyclin-dependent kinase 7 (CDK7), the essential component of both CDK-activating kinase (CAK) and general transcription factor TFIIH. CAK and TFIIH play essential roles in cell cycle progression and transcription by activating CDKs and facilitating transcriptional initiation, respectively. Tax induced CDK7 gene expression not only in human T-cell lines but also in normal peripheral blood lymphocytes (PHA-PBLs) along with increased protein expression. Tax stimulated phosphorylation of CDK2 and RNA polymerase II at sites reported to be mediated by CDK7. Tax activated the CDK7 promoter through the NF-κB pathway, which mainly mediates cell growth promotion by Tax. Knockdown of CDK7 expression reduced Tax-mediated induction of target gene expression and cell cycle progression. These results suggest that the CDK7 gene is a crucial target of Tax-mediated trans-activation to promote cell proliferation by activating CDKs and transcription. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2024)

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10 pages, 3509 KiB

Open AccessArticle

Simultaneous Detection of Common Founder Mutations Using a Cost-Effective Deep Sequencing Panel

by Sapir Shalom, Mor Hanany, Avital Eilat, Itay Chowers, Tamar Ben-Yosef, Samer Khateb, Eyal Banin and Dror Sharon

Genes 2024, 15(5), 646; https://doi.org/10.3390/genes15050646 - 20 May 2024

Cited by 1 | Viewed by 1490

Abstract

Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of diseases which cause visual loss due to Mendelian mutations in over 250 genes, making genetic diagnosis challenging and time-consuming. Here, we developed a new tool, CDIP (Cost-effective Deep-sequencing IRD Panel) in which a simultaneous sequencing of common mutations is performed. CDIP is based on simultaneous amplification of 47 amplicons harboring common mutations followed by next-generation sequencing (NGS). Following five rounds of calibration of NGS-based steps, CDIP was used in 740 IRD samples. The analysis revealed 151 mutations in 131 index cases. In 54 (7%) of these cases, CDIP identified the genetic cause of disease (the remaining were single-heterozygous recessive mutations). These include a patient that was clinically diagnosed with retinoschisis and found to be homozygous for NR2E3-c.932G>A (p.R311Q), and a patient with RP who is hemizygous for an RPGR variant, c.292C>A (p.H98N), which was not included in the analysis but is located in proximity to one of these mutations. CDIP is a cost-effective deep sequencing panel for simultaneous detection of common founder mutations. This protocol can be implemented for additional populations as well as additional inherited diseases, and mainly in populations with strong founder effects. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2024)

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20 pages, 4800 KiB

Open AccessEditor’s ChoiceArticle

Single-Cell Transcriptomic Profiling Identifies Molecular Phenotypes of Newborn Human Lung Cells

by Soumyaroop Bhattacharya, Jacquelyn A. Myers, Cameron Baker, Minzhe Guo, Soula Danopoulos, Jason R. Myers, Gautam Bandyopadhyay, Stephen T. Romas, Heidie L. Huyck, Ravi S. Misra, Jennifer Dutra, Jeanne Holden-Wiltse, Andrew N. McDavid, John M. Ashton, Denise Al Alam, S. Steven Potter, Jeffrey A. Whitsett, Yan Xu, Gloria S. Pryhuber and Thomas J. Mariani

Genes 2024, 15(3), 298; https://doi.org/10.3390/genes15030298 - 26 Feb 2024

Cited by 6 | Viewed by 3781

Abstract

While animal model studies have extensively defined the mechanisms controlling cell diversity in the developing mammalian lung, there exists a significant knowledge gap with regards to late-stage human lung development. The NHLBI Molecular Atlas of Lung Development Program (LungMAP) seeks to fill this gap by creating a structural, cellular and molecular atlas of the human and mouse lung. Transcriptomic profiling at the single-cell level created a cellular atlas of newborn human lungs. Frozen single-cell isolates obtained from two newborn human lungs from the LungMAP Human Tissue Core Biorepository, were captured, and library preparation was completed on the Chromium 10X system. Data was analyzed in Seurat, and cellular annotation was performed using the ToppGene functional analysis tool. Transcriptional interrogation of 5500 newborn human lung cells identified distinct clusters representing multiple populations of epithelial, endothelial, fibroblasts, pericytes, smooth muscle, immune cells and their gene signatures. Computational integration of data from newborn human cells and with 32,000 cells from postnatal days 1 through 10 mouse lungs generated by the LungMAP Cincinnati Research Center facilitated the identification of distinct cellular lineages among all the major cell types. Integration of the newborn human and mouse cellular transcriptomes also demonstrated cell type-specific differences in maturation states of newborn human lung cells. Specifically, newborn human lung matrix fibroblasts could be separated into those representative of younger cells (n = 393), or older cells (n = 158). Cells with each molecular profile were spatially resolved within newborn human lung tissue. This is the first comprehensive molecular map of the cellular landscape of neonatal human lung, including biomarkers for cells at distinct states of maturity. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2024)

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10 pages, 242 KiB

Open AccessReview

Genetics of Gallstones

by Agnieszka Pęczuła, Adam Czaplicki and Adam Przybyłkowski

Genes 2025, 16(3), 256; https://doi.org/10.3390/genes16030256 - 22 Feb 2025

Viewed by 961

Abstract

Gallstone disease (GSD) is a common gastrointestinal disorder affecting approximately 10–20% of the global adult population, characterized by the presence of gallstones, predominantly cholesterol-based, in the gallbladder and/or biliary ducts. While many patients remain asymptomatic, more than 20% develop clinical symptoms such as abdominal pain, nausea, vomiting, jaundice, and anorexia, potentially leading to severe complications like acute cholecystitis and biliary pancreatitis. GSD has a significant genetic predisposition, with the variable prevalence of the disease according to ethnicity being highest in American and European countries and lowest in Asian and African populations. Numerous genes encoding membrane transporters involved in bile metabolism are associated with GSD, including in particular members of ATP-binding cassette transporters and others, which affect bile lithogenicity and contribute to the development of gallstones. Specific mutations in these genes are linked to an increased risk of gallstone formation, especially in individuals with certain hereditary conditions such as hemolytic diseases, thyroid disorders, and hyperparathyroidism. Advances in genetic studies have identified new variants that influence the risk of cholelithiasis, although the exact mechanisms remain partially understood in many cases. This review briefly summarizes the genetic causes of cholelithiasis, highlighting various pathogenetic mechanisms. It presents the currently used treatments and the potential implications of widely applied genetic diagnostics. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2024)

18 pages, 878 KiB

Open AccessReview

Integrating Machine Learning-Based Approaches into the Design of ASO Therapies

by Jamie Leckie and Toshifumi Yokota

Genes 2025, 16(2), 185; https://doi.org/10.3390/genes16020185 - 2 Feb 2025

Cited by 1 | Viewed by 2420

Abstract

Rare diseases impose a significant burden on affected individuals, caregivers, and healthcare systems worldwide. Developing effective therapeutics for these small patient populations presents substantial challenges. Antisense oligonucleotides (ASOs) have emerged as a promising therapeutic approach that targets the underlying genetic cause of disease at the RNA level. Several ASOs have gained FDA approval for the treatment of genetic conditions, including use in personalized N-of-1 trials. However, despite their potential, ASOs often exhibit limited clinical efficacy, and optimizing their design is a complex process influenced by numerous factors. Machine learning-based platforms, including eSkip-Finder and ASOptimizer, have been developed to address these challenges by predicting optimal ASO sequences and chemical modifications to enhance efficacy. eSkip-Finder focuses on exon-skipping applications, while ASOptimizer aims to optimize ASOs for RNA degradation. Preliminary in vitro results have demonstrated the promising predictive power of these platforms. However, limitations remain, including their generalizability to alternative targets and gaps in their consideration of all factors influencing ASO efficacy and safety. Continued advancements in machine learning models, alongside efforts to incorporate additional features affecting ASO efficacy and safety, hold significant promise for the field. These platforms have the potential to streamline ASO development, reduce associated costs, and improve clinical outcomes, positioning machine learning as a key tool in the future of ASO therapeutics. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2024)

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33 pages, 462 KiB

Open AccessReview

Hereditary Neuromuscular Disorders in Reproductive Medicine

by Agnese Luglio, Elena Maggi, Francesco Nicola Riviello, Alessandro Conforti, Ugo Sorrentino and Daniela Zuccarello

Genes 2024, 15(11), 1409; https://doi.org/10.3390/genes15111409 - 30 Oct 2024

Viewed by 1650

Abstract

Neuromuscular disorders (NMDs) encompass a broad range of hereditary and acquired conditions that affect motor units, significantly impacting patients’ quality of life and reproductive health. This narrative review aims to explore in detail the reproductive challenges associated with major hereditary NMDs, including Charcot–Marie–Tooth disease (CMT), dystrophinopathies, Myotonic Dystrophy (DM), Facioscapulohumeral Muscular Dystrophy (FSHD), Spinal Muscular Atrophy (SMA), Limb–Girdle Muscular Dystrophy (LGMD), and Amyotrophic Lateral Sclerosis (ALS). Specifically, it discusses the stages of diagnosis and genetic testing, recurrence risk estimation, options for preimplantation genetic testing (PGT) and prenatal diagnosis (PND), the reciprocal influence between pregnancy and disease, potential obstetric complications, and risks to the newborn. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2024)

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12 pages, 635 KiB

Open AccessCase Report

The Arg99Gln Substitution in HNRNPC Is Associated with a Distinctive Clinical Phenotype Characterized by Facial Dysmorphism and Ocular and Cochlear Anomalies

by Luigi Chiriatti, Manuela Priolo, Roberta Onesimo, Mattia Carvetta, Chiara Leoni, Alessandro Bruselles, Francesca Clementina Radio, Camilla Cappelletti, Marco Ferilli, Daniela Ricci, Marcello Niceta, Viviana Cordeddu, Andrea Ciolfi, Cecilia Mancini, Giuseppe Zampino and Marco Tartaglia

Genes 2025, 16(2), 176; https://doi.org/10.3390/genes16020176 - 1 Feb 2025

Viewed by 754

Abstract

Background/Objectives: Heterozygous variants in the heterogeneous nuclear ribonucleoprotein C gene (HNRNPC) have recently been reported to cause intellectual developmental disorder-74 (MRD74), a neurodevelopmental disorder with no recurrent diagnostic handles. Affected individuals show variable, non-specific, and subtle dysmorphic features. The degree of developmental delay (DD)/intellectual disability (ID) is also wide, ranging from mild to severe. The mutational spectrum is relatively broad with exon deletions and splice site and frameshift variants distributed along the entire length of the gene leading to HNRNPC loss of function. Only two missense changes located within the RNA-binding motif (RBM) and adjacent linker region of the more abundant isoform (Arg64Trp and Arg99Gln) have been described. Notably, the Arg99Gln amino acid substitution was reported in a subject presenting with a more complex and unique clinical phenotype characterized by distinctive facial features, DD/ID, cochlear aplasia, and bilateral colobomatous microphthalmia, suggesting the possible occurrence of phenotypic heterogeneity. Results: Here, we report the second individual carrying the Arg99Gln change in HNRNPC and having clinical features with a significant overlap with the peculiar phenotype of the previously described subject, supporting the occurrence of a genotype–phenotype correlation. Conclusions: Due to the concomitant occurrence of ocular and cochlear involvement as recognizable diagnostic handles, we propose that the HNRNPC^Arg99Gln-related phenotype should be considered as a potential differential diagnosis in subjects with ID and major signs of CHARGE syndrome not fulfilling the minimum criteria for a clinical diagnosis. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2024)

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10 pages, 3337 KiB

Open AccessCase Report

Typical Clinical Presentation of an Autosomal Dominant Polycystic Kidney Disease Patient with an Atypical Genetic Pattern

by Nenzi Marzano, Carlotta Caprara, Thiago Reis, Diego Pomarè Montin, Sofia Maria Pretto, Matteo Rigato, Anna Giuliani, Fiorella Gastaldon, Barbara Mancini, Claudio Ronco, Monica Zanella, Daniela Zuccarello and Valentina Corradi

Genes 2025, 16(1), 39; https://doi.org/10.3390/genes16010039 - 30 Dec 2024

Viewed by 1036

Abstract

Background: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is mainly characterized by renal involvement with progressive bilateral development of renal cysts and volumetric increase in the kidneys, causing a loss of renal function, chronic kidney disease (CKD), and kidney failure. The occurrence of mosaicism may modulate the clinical course of the disease. Mosaicism is characterized by a few cell populations with different genomes. In these special cases, a genetic diagnosis could be challenging. Methods: Herein, we describe the case of a 47-year-old woman presenting with typical ultrasound and computed tomography features of ADPKD. She had stage 3b CKD and hypertension. There was no family history of ADPKD, prompting an investigation with a genetic test. Target next-generation sequencing (NGS) did not detect the presence of any genomic variants. Therefore, we carried out second-level genetic analysis to investigate the presence of a large rearrangement through a multiple ligation-dependent probe amplification (MLPA) analysis of PKD1 and PKD2 genes. Results: MLPA showed a large deletion (portion including exons 2–34 of PKD1) present in the heterozygosis with a percentage of cells close to the resolution limits of the technique used (<25–30%). We concluded that the large deletion identified was mosaicism. This variant is not reported in major ADPKD databases, but due to the type of mutation and the patient’s clinical picture, it should be considered as likely pathogenic. Conclusions: A stepwise genetic approach might be useful in those cases where standard methods do not allow one to reach a definitive diagnosis. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2024)

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