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Optical Genome Mapping: A New Tool for Cytogenomic Analysis -
Genomic Regions Associated with Respiratory Disease in Holstein Calves in the Southern United States -
ABCC6 Involvement in Cerebral Small Vessel Disease: Potential Mechanisms and Associations -
Increased Prevalence of Psychiatric Disorders in Children with RASopathies: Comparing NF1, Noonan Syndrome Spectrum Disorder, and the General Population -
Identification of Key Genes Associated with Overall Survival in Glioblastoma Multiforme Using TCGA RNA-Seq Expression Data
Journal Description
Genes
Genes
is a peer-reviewed, open access journal of genetics and genomics published monthly online by MDPI. The Spanish Society for Nitrogen Fixation (SEFIN) is affiliated with Genes and their members receive discounts on the article processing charges.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
- High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, MEDLINE, PMC, Embase, PubAg, and other databases.
- Journal Rank: JCR - Q2 (Genetics and Heredity) / CiteScore - Q2 (Genetics (clinical))
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 14.6 days after submission; acceptance to publication is undertaken in 2.5 days (median values for papers published in this journal in the first half of 2025).
- Recognition of Reviewers: Reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
Impact Factor:
2.8 (2024);
5-Year Impact Factor:
3.2 (2024)
Latest Articles
Molecular Characterization and Functional Effect on Canine Peripheral Blood Mononuclear Cells of an Uncharacterized Major Egg Antigen EGR-01664 from Echinococcus granulosus
Genes 2025, 16(11), 1384; https://doi.org/10.3390/genes16111384 - 14 Nov 2025
Abstract
Background: Cystic echinococcosis (CE) is a globally distributed zoonosis triggered by the larval stage of Echinococcus granulosus (E. granulosus), impacting humans and an extensive array of mammalian intermediate hosts. EGR-01664 is the major egg antigen of E. granulosus, but almost
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Background: Cystic echinococcosis (CE) is a globally distributed zoonosis triggered by the larval stage of Echinococcus granulosus (E. granulosus), impacting humans and an extensive array of mammalian intermediate hosts. EGR-01664 is the major egg antigen of E. granulosus, but almost nothing is currently known about the function of EGR-01664 from E. granulosus. Methods: This study aimed to investigate the E. granulosus EGR-01664 gene (GenBank ID: 36337379), and the recombinant EGR-01664 protein was expressed successfully. Next, the transcription of the EGR-01664 gene across various developmental stages of E. granulosus was analyzed. Its spatial expression patterns in adult worms and protoscoleces were characterized using both quantitative PCR (qPCR) and immunofluorescence assays. Furthermore, the immunomodulatory effects of rEGR-01664 on cell proliferation, nitric oxide production, and cytokine secretion were examined by co-culturing the recombinant protein with canine PBMCs. Results: The rEGR-01664 could be recognized by sera from dogs infected with E. granulosus. Immunofluorescence assay (IFA) localization revealed the protein’s presence in the epidermis of protoscoleces, the adult epidermis, and some parenchymal tissues. qPCR revealed that EGR-01664 mRNA levels were significantly higher in protoscoleces compared to adults (p < 0.0001). At a concentration of 20 μg/mL, rEGR-01664 could significantly activate the transcription and expression of IL-10, TGF-β1, IL-17A, and Bax in canine PBMCs. However, with an increase in concentration, it inhibited the expression of IFN-γ, Bcl-2, GSDMD, IL-18, and IL-1β. These results suggest that the EGR-01664 gene plays a crucial role in the development, parasitism, and reproduction of E. granulosus. In vitro studies have shown that rEGR-01664 protein regulates the immune regulation function of canine PBMCs, suggesting its potential as a vaccine adjuvant or immunotherapy target. Conclusions: EGR-01664 may modulate canine PBMC functions to regulate host immune responses, thereby facilitating our understanding of how E. granulosus EGR-01664 contributes to the mechanism of parasitic immune evasion.
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(This article belongs to the Section Animal Genetics and Genomics)
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Open AccessArticle
Genome-Wide Association Study and Candidate Gene Analysis of Seed Shattering Trait in Psathyrostachys juncea
by
Yuru Lv, Lan Yun, Yixin Mu, Bohua Li, Xiaodi Jia and Miaomiao Jia
Genes 2025, 16(11), 1383; https://doi.org/10.3390/genes16111383 - 14 Nov 2025
Abstract
Background: Seed shattering enhances ecological adaptation in perennial grasses but severely limits harvestable seed yield in forage crops. Psathyrostachys juncea is an important perennial forage species in arid and cold regions, yet the genetic basis of its seed shattering remains largely unknown. Here
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Background: Seed shattering enhances ecological adaptation in perennial grasses but severely limits harvestable seed yield in forage crops. Psathyrostachys juncea is an important perennial forage species in arid and cold regions, yet the genetic basis of its seed shattering remains largely unknown. Here we asked which genomic regions and biological pathways underlie natural variation in seed shattering in P. juncea, and whether cellulose synthase (CESA)-mediated cell-wall formation contributes to abscission-zone strength. Results: We evaluated seed shattering in a diverse association panel of P. juncea across four environment–-year combinations and performed a genome-wide association study (GWAS) using genotyping-by-sequencing single-nucleotide polymorphism (SNP) markers. The analysis identified 36 significant SNP loci distributed on multiple chromosomes, consistent with a highly polygenic and environment-responsive architecture. Candidate-gene annotation highlighted pathways related to cell-wall biosynthesis, hormone signaling and sugar transport. Notably, in the BT23SHT environment a cluster of association signals on chromosome 3D co-localized with several genes annotated as cellulose synthase (CESA). Abscission-zone transcriptome profiling and qRT-PCR at 7, 14, 21 and 28 days after heading revealed that CESA genes, including TraesCS3D02G010100.1 located near the lead SNP Chr3D_3539055, showed higher early expression in low-shattering lines and a decline toward baseline in high-shattering lines. Comparative analyses placed P. juncea CESA proteins within a broadly conserved but lineage-divergent framework among grasses. Conclusion: Together, these results define the genetic landscape of seed shattering in P. juncea and nominate cellulose-biosynthetic genes on chromosome 3D as promising targets for marker-assisted selection of low-shattering, high-seed-yield forage cultivars.
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(This article belongs to the Section Molecular Genetics and Genomics)
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Open AccessArticle
A Plot Twist: When RNA Yields Unexpected Findings in Paired DNA-RNA Germline Genetic Testing
by
Heather Zimmermann, Terra Brannan, Colin Young, Jesus Ramirez Castano, Carolyn Horton, Alexandra Richardson, Bhuvan Molparia and Marcy E. Richardson
Genes 2025, 16(11), 1382; https://doi.org/10.3390/genes16111382 - 13 Nov 2025
Abstract
Background: Germline genetic variants impacting splicing are a frequent cause of disease. The clinical interpretation of such variants is challenging for many reasons including the immense complexity of splicing mechanisms. While recent advances in splicing algorithms have improved the accuracy of splice prediction,
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Background: Germline genetic variants impacting splicing are a frequent cause of disease. The clinical interpretation of such variants is challenging for many reasons including the immense complexity of splicing mechanisms. While recent advances in splicing algorithms have improved the accuracy of splice prediction, predicting the nature and abundance of aberrant splicing remains challenging. As RNA testing becomes more mainstream in the clinical diagnostic setting, the complexities of interpretation are coming to light. Methods: Data from patients undergoing concurrent DNA and RNA testing were retrospectively reviewed for unusual splicing impacts to underscore some of these complexities and serve as exemplars in how to avoid pitfalls in the interpretation of sequence variants. Results: Seven rare variants with unusual splicing impacts are presented: a variant at a consensus donor nucleotide position lacking a splice impact (NF1 c.888+2T>C); a mid-exonic missense variant creating a novel donor site and a cryptic acceptor site resulting in pseudo-intronization (BRIP1 c.727A<G p.Ile243Val); one variant creating a spliceosome switch from U12 to U2 (LZTR1 c.2232G>A p.Ala744Ala); two variants that would be expected to result in nonsense-mediated-mRNA-decay triggering splicing impacts that obviated nonsense-mediated-decay (APC c.1042C>T p.Arg348Ter and BRCA2 c.6762del; c.6816_6841+1534del); and two variants causing splicing impacts through pyrimidine tract optimization (NF1 c.5750-184_5750-178dup and ATM c.3480G>T p.Val1160Val). Conclusions: Paired DNA and RNA testing revealed unexpected splice events altering variant interpretation, expanding our knowledge of clinically important splicing mechanisms and highlighting the benefit of RNA testing.
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(This article belongs to the Special Issue From Genetic Mechanisms Discovery to Patient-Centered Care: The Expanse of Genomics Research)
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Open AccessCase Report
Clinical and Molecular Clues to Diagnosing Hereditary Hyperferritinemia-Cataract Syndrome: Case Report and Literature Review
by
Barbora Ludikova, Lucie Sochorcova, Damjan Jaksic, Katarina Hlusickova Kapralova and Monika Horvathova
Genes 2025, 16(11), 1381; https://doi.org/10.3390/genes16111381 - 13 Nov 2025
Abstract
Background: Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare autosomal dominant disorder characterized by persistently elevated serum ferritin and early-onset bilateral cataracts in the absence of systemic iron overload. It is caused by pathogenic variants in the iron-responsive element (IRE) of the FTL
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Background: Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare autosomal dominant disorder characterized by persistently elevated serum ferritin and early-onset bilateral cataracts in the absence of systemic iron overload. It is caused by pathogenic variants in the iron-responsive element (IRE) of the FTL gene, leading to dysregulated L-ferritin synthesis. Methods: We evaluated a 12-year-old Czech girl with markedly elevated serum ferritin identified incidentally during workup for abdominal pain. Clinical assessment included biochemical, radiological, ophthalmological, and genetic testing of the proband and available family members. Results: Magnetic resonance imaging excluded systemic iron overload, while ophthalmological evaluation revealed bilateral cataracts. Family history indicated multiple affected relatives across three generations. Genetic testing confirmed a heterozygous FTL c.-168G>C variant. Additional screening for common HFE variants revealed heterozygous H63D in several family members, with no impact on ferritin or hepcidin levels. Beyond this case, we provide a comprehensive review of HHCS, including molecular mechanisms, an updated overview of reported FTL mutations, and ophthalmological features that distinguish HHCS cataracts from other congenital cataracts. Conclusions: This report underscores the translational relevance of combining molecular diagnostics, clinical evaluation, and family screening to improve recognition and management of HHCS, and to prevent misdiagnosis and unnecessary iron-depletion therapy.
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(This article belongs to the Section Genetic Diagnosis)
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Open AccessArticle
SLC30A3 as a Zinc Transporter-Related Biomarker and Potential Therapeutic Target in Alzheimer’s Disease
by
Ruyu Bai, Zhiyun Cheng and Yong Diao
Genes 2025, 16(11), 1380; https://doi.org/10.3390/genes16111380 - 13 Nov 2025
Abstract
Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with unclear pathogenic mechanisms. Dysregulated zinc metabolism contributes to AD pathology. This study aimed to identify zinc metabolism-related hub genes to provide potential biomarkers and therapeutic targets for AD. Methods: We performed an integrative
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Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with unclear pathogenic mechanisms. Dysregulated zinc metabolism contributes to AD pathology. This study aimed to identify zinc metabolism-related hub genes to provide potential biomarkers and therapeutic targets for AD. Methods: We performed an integrative analysis of multiple transcriptomic datasets from AD patients and normal controls. Differentially expressed genes and weighted gene co-expression network analysis (WGCNA) were combined to identify hub genes. We then conducted Gene Set Enrichment Analysis (GSEA), immune cell infiltration analysis (CIBERSORT), and receiver operating characteristic (ROC) curve analysis to assess the hub gene’s biological function, immune context, and diagnostic performance. Drug-gene interactions were predicted using the DrugBank database. Results: We identified a single key zinc transporter–related hub gene, SLC30A3, which was significantly downregulated in AD and demonstrated potential diagnostic value (AUC 0.70–0.80). Lower SLC30A3 expression was strongly associated with impaired synaptic plasticity (long-term potentiation, long-term depression, calcium signaling pathway, and axon guidance), mitochondrial dysfunction (the citrate cycle and oxidative phosphorylation), and pathways common to major neurodegenerative diseases (Parkinson’s disease, AD, Huntington’s disease, and amyotrophic lateral sclerosis). Furthermore, SLC30A3 expression correlated with specific immune infiltrates, particularly the microglia-related chemokine CX3CL1. Zinc chloride and zinc sulfate were identified as potential pharmacological modulators. Conclusions: Our study systematically identifies SLC30A3 as a novel biomarker in AD, linking zinc dyshomeostasis to synaptic failure, metabolic impairment, and neuroimmune dysregulation. These findings offer a new basis for developing targeted diagnostic and therapeutic strategies for AD.
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(This article belongs to the Section Neurogenomics)
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Open AccessArticle
Inflammation-Mediated Lipid Metabolism in Endocrine Autoimmune Diseases: A Genetic Distance-Based PRS Approach Integrating HLA Region
by
Fenghuixue Liu, Yifei Ren, Wenhua Liu, Qi Chen, Ping Yin and Peng Wang
Genes 2025, 16(11), 1379; https://doi.org/10.3390/genes16111379 - 12 Nov 2025
Abstract
Background: Endocrine autoimmune diseases (AIDs) exhibit special polygenic characteristics in human leucocyte antigen (HLA) region. Current understanding of their association with lipid metabolism remains constrained by imprecise polygenic risk score (PRS) modeling. Advanced analytical approaches are needed to elucidate the association between
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Background: Endocrine autoimmune diseases (AIDs) exhibit special polygenic characteristics in human leucocyte antigen (HLA) region. Current understanding of their association with lipid metabolism remains constrained by imprecise polygenic risk score (PRS) modeling. Advanced analytical approaches are needed to elucidate the association between genetic susceptibility and lipid metabolic dysregulation. Methods: We proposed a genetic distance-based clumping gPRS to account for linkage disequilibrium in the HLA region. gPRS and pathway gPRS were constructed for individuals diagnosed with type I diabetes (T1D), Graves’ disease (GD), Hashimoto thyroiditis (HT) and Addison’s disease (AD) in the UK Biobank, with sex considered as a stratification factor. Latent correlations between gPRS and phenotypes were explored using Kendall’s tau test, two-trait LD score regression (LDSC) and gene annotation. Results: Lipid metabolism served an important function through immune and inflammatory biomarkers across multiple traits. Males with low genetic risk tended to have lower high-density lipoprotein cholesterol level, while the correlation presented the opposite pattern in females. Increased genetic susceptibility to AIDs was associated with elevated levels of low-density lipoprotein cholesterol, triglycerides in low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) across all traits. Moreover, levels of polyunsaturated fatty acids, including omega-3 and omega-6, decreased with higher PRS in males and females, while those of monounsaturated fatty acids exhibited an increasing trend. Conclusion: Our study constructed more precise polygenic risk scores of AIDs, highlighting inflammation-mediated lipid metabolism as a potential pathogenic mechanism in endocrine AIDs, offering valuable insights into shared etiology for future comprehensive investigations.
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(This article belongs to the Section Human Genomics and Genetic Diseases)
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Open AccessArticle
The G Allele and GG Genotype of the Junctional Cadherin 5 Associated (JCAD) Is a Biomarker Predicting Myocardial Infarction in Slovenian Subjects with Type 2 Diabetes Mellitus
by
Miha Tibaut and Danijel Petrovič
Genes 2025, 16(11), 1378; https://doi.org/10.3390/genes16111378 - 11 Nov 2025
Abstract
Background: Patients with type 2 diabetes mellitus (T2DM) have a two- to fourfold higher risk of myocardial infarction (MI), yet genetic determinants of this excess risk remain incompletely defined. The JCAD (junctional cadherin 5 associated; formerly KIAA1462) locus has been implicated in
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Background: Patients with type 2 diabetes mellitus (T2DM) have a two- to fourfold higher risk of myocardial infarction (MI), yet genetic determinants of this excess risk remain incompletely defined. The JCAD (junctional cadherin 5 associated; formerly KIAA1462) locus has been implicated in coronary artery disease through genome-wide association studies, but data in diabetic populations are scarce. Objectives: To assess whether the rs3739998 polymorphism of JCAD is associated with MI in Slovenian subjects with T2DM and to explore its relationship with coronary disease burden and coronary artery calcium (CAC). Methods: We performed a retrospective cross-sectional association study of 1471 Slovenian subjects with T2DM: 387 with prior MI and 1084 without clinical evidence of coronary artery disease. Genotyping for JCAD rs3739998 was performed using a fluorescence-based competitive allele-specific PCR (KASPar). A coronary computed tomographic angiography (CCTA) substudy (n = 146) evaluated the number of diseased coronary arteries, stenosis severity, and CAC score. Results: The GG genotype was more frequently observed in MI cases compared to controls in unadjusted analysis (OR 1.37; p = 0.05) but association was lost with adjustment for confounders (GG vs. CC, aOR 1.63, p = 0.09). The G allele was also more prevalent among cases (OR 1.18; p = 0.05, unadjusted analysis). In the CCTA substudy, no significant associations were observed between rs3739998 and the number of diseased vessels, stenosis grade, or CAC. Conclusions: In a Slovenian T2DM cohort, the JCAD rs3739998 G allele and GG genotype showed a nominal association with prior MI that did not persist after multivariable adjustment. There was no clear relationship with anatomic disease burden or CAC, underscoring the need for replication in larger cohorts and functional studies to clarify the mechanism and clinical utility.
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(This article belongs to the Section Human Genomics and Genetic Diseases)
Open AccessSystematic Review
Genetic Assessment and Clinical Correlates in Severe Hypertriglyceridemia: A Systematic Review
by
Carmine De Luca, Paola Ciciola, Guido D’Errico, Maria Donata Di Taranto, Giuliana Fortunato, Carina Gross, Jonathan Garn, Gabriella Iannuzzo, Matteo Di Minno and Ilenia Calcaterra
Genes 2025, 16(11), 1377; https://doi.org/10.3390/genes16111377 - 11 Nov 2025
Abstract
Background: Severe hypertriglyceridemia (SHTG) is associated with acute pancreatitis, metabolic dysfunction, and increased cardiovascular risk. Its genetic architecture ranges from rare biallelic variants causing familial chylomicronemia syndrome (FCS) to more prevalent polygenic or multifactorial chylomicronemia syndromes (MCS). Methods: We systematically reviewed
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Background: Severe hypertriglyceridemia (SHTG) is associated with acute pancreatitis, metabolic dysfunction, and increased cardiovascular risk. Its genetic architecture ranges from rare biallelic variants causing familial chylomicronemia syndrome (FCS) to more prevalent polygenic or multifactorial chylomicronemia syndromes (MCS). Methods: We systematically reviewed scientific literature up to 2025 for studies reporting genetic data, clinical features, or therapeutic outcomes in adults with triglycerides (TG) ≥ 500 mg/dL. Extracted data were synthesized for genotype, polygenic risk score (PRS), TG levels, metabolic comorbidities, hepatic steatosis, pancreatitis, and treatment response. Results: Ten studies (n = 2521) were included. FCS due to biallelic LPL, APOC2, GPIHBP1, or LMF1 variants accounted for <5% of cases and showed extreme TG elevations (>2800 mg/dL) with pancreatitis prevalence (>70%). APOA5, APOC3, and APOB variants were associated with intermediate TG levels and high rates of metabolic dysfunction-associated steatotic liver disease (MASLD). Polygenic hypertriglyceridemia represented ~70–80% of cases, with TG ≈ 2200 mg/dL and pancreatitis prevalence 15–20%, largely modulated by metabolic triggers. MASLD was present in >70% of polygenic cases, supporting a “two-hit” model where hepatic overproduction of TG-rich lipoproteins amplifies TG excess. Interventional trials demonstrated TG reductions with APOC3 antisense therapy (70–80%) and ANGPTL3 inhibition (50–55%), while GLP-1RA significantly reduced hepatic fat (30–35%) and resolved NASH in up to 59% of patients. Conclusions: SHTG displays a genotype–phenotype gradient: FCS is linked to recurrent pancreatitis, whereas polygenic/MCS forms are closely associated with MASLD and metabolic dysfunction. These findings support a precision-medicine approach integrating genetic testing and PRS-guided strategies—prioritizing APOC3/ANGPTL3 inhibitors for FCS and combined TG-lowering plus metabolic therapies for MCS—to reduce pancreatitis recurrence and liver disease.
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(This article belongs to the Section Genetic Diagnosis)
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Open AccessArticle
Genome-Wide Screening for MYB Transcription Factors Involved in Flavonoid Glycoside Biosynthesis in Carthamus tinctorius L.
by
Xiaohan Yu, Bin Xian, Lijun Peng, Xunjian Wu, Juncheng Zhang, Yuanyuan Li, Yueying Hu and Jiang Chen
Genes 2025, 16(11), 1376; https://doi.org/10.3390/genes16111376 - 11 Nov 2025
Abstract
Background: Safflower (Carthamus tinctorius L.) is a multipurpose crop with both medicinal and economic values. Flavonoid glycosides are the core bioactive components of this species for preventing and treating cardiovascular and cerebrovascular diseases, yet their specific regulatory mechanisms remain insufficiently systematically elucidated.
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Background: Safflower (Carthamus tinctorius L.) is a multipurpose crop with both medicinal and economic values. Flavonoid glycosides are the core bioactive components of this species for preventing and treating cardiovascular and cerebrovascular diseases, yet their specific regulatory mechanisms remain insufficiently systematically elucidated. Methods: Based on the whole-genome data of Carthamus tinctorius L., key MYB transcription factors regulating the flavonoid glycoside biosynthesis pathway in safflower were screened and verified via MeJA treatment. Results: A total of 202 MYB transcription factors were identified, and 18 candidate genes were screened out. Further analysis showed that four genes (HH_019113, HH_009268, HH_009443 and HH_029380) were extremely significantly positively correlated with flavonid glycoside biosynthesis genes. After MeJA treatment, RT-qPCR analysis showed that their expression levels were significantly different. Conclusions: With the objective of elucidating the biosynthesis mechanism of flavonoid glycosides in safflower and exploring key regulatory genes, this study identified four MYB transcription factors that regulate flavonoid glycoside biosynthesis, providing new insights into elucidating the biosynthesis mechanism of flavonoid glycosides in safflower and offering targets for the construction of its molecular regulatory network and the improvement of medicinal quality and molecular breeding technology
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(This article belongs to the Section Plant Genetics and Genomics)
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Open AccessReview
Analysis of Human Degraded DNA in Forensic Genetics
by
Irena Zupanič Pajnič
Genes 2025, 16(11), 1375; https://doi.org/10.3390/genes16111375 - 11 Nov 2025
Abstract
Upon an organism’s death, enzymatic DNA repair ceases, exposing the genome to destructive factors such as free cellular nucleases and proliferating microorganisms, which can cause DNA loss. DNA preservation is highly dependent on environmental conditions, and less favorable environments accelerate degradation. Despite this,
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Upon an organism’s death, enzymatic DNA repair ceases, exposing the genome to destructive factors such as free cellular nucleases and proliferating microorganisms, which can cause DNA loss. DNA preservation is highly dependent on environmental conditions, and less favorable environments accelerate degradation. Despite this, advanced extraction and analytical methods now enable the study of poorly preserved and degraded DNA. DNA typing is a foundation of forensic genomics, enabling the identification of individuals and the individualization of biological evidence through the generation of unique genetic profiles. Although DNA is relatively stable, environmental exposure initiates its degradation into progressively shorter fragments, complicating analysis. The extent of DNA preservation in biological evidence depends on numerous factors, and this review focuses on the environmental factors—including temperature, humidity, ultraviolet radiation, pH, chemical agents, and microbial activity—as the most influential variables. In samples with degraded DNA, the maximum amplicon length achievable through polymerase chain reaction (PCR) is inherently limited. This review discusses genetic markers and analytical strategies improvements that enable the examination of highly degraded samples, particularly when conventional short tandem repeat (STR) typing fails. In these situations, successful identification requires targeting short DNA fragments, which are more likely to persist. Single-nucleotide polymorphisms (SNPs) are a valuable alternative, as their high allelic variability and short amplicon requirements make them more amenable to amplification from fragmented templates than STRs. Advances in next-generation sequencing (NGS) technologies have further enhanced this capacity by enabling high-resolution SNP profiling, thereby improving outcomes in challenging forensic cases.
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(This article belongs to the Special Issue Advances and Challenges in Forensic Genetics)
Open AccessArticle
Transcript Patterns of Bovine CYP21A2 and Its Pseudogene in Adrenal and Ovarian Tissues
by
Jakub Wozniak, Monika Stachowiak, Marek Switonski and Joanna Nowacka-Woszuk
Genes 2025, 16(11), 1374; https://doi.org/10.3390/genes16111374 - 11 Nov 2025
Abstract
Background: The cytochrome P450 family 21 subfamily A member 2 gene (CYP21A2) encodes 21-hydroxylase, a key enzyme in adrenal steroid biosynthesis. Despite its physiological importance, the diversity of CYP21A2 transcript variants and their tissue-specific expression in domestic animals, including cattle, remains
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Background: The cytochrome P450 family 21 subfamily A member 2 gene (CYP21A2) encodes 21-hydroxylase, a key enzyme in adrenal steroid biosynthesis. Despite its physiological importance, the diversity of CYP21A2 transcript variants and their tissue-specific expression in domestic animals, including cattle, remains largely unexplored. This study aimed to characterize CYP21A2 transcription in adrenal glands and ovaries and assess the potential transcriptional activity of its pseudogene, CYP21A1P. Methods: CYP21A2 transcription was investigated in adrenal and ovarian tissues of 12 healthy cows using semi-quantitative PCR and Sanger sequencing. Real-time PCR was performed to confirm expression levels. Melting curve analysis and electrophoresis were used to validate distinct amplicons corresponding to different transcript variants. Extended amplicons were sequenced to identify transcripts corresponding to reference sequences and potential pseudogene products. Results: A single transcript variant (NM_001013596.1) was consistently detected in adrenal glands, whereas ovaries expressed two variants: NM_001013596.1 and XM_024983378.2. Semi-quantitative analysis showed significantly higher CYP21A2 expression in adrenal glands compared to ovaries (p < 0.01). In ovarian samples, the NM_001013596.1 variant was more abundant than the XM_024983378.2 (p < 0.01). Sanger sequencing revealed two products matching CYP21A2 reference transcripts and an additional, longer product containing sequence motifs specific to the pseudogene CYP21A1P, indicating its transcriptional activity. Conclusions: These results provide the first evidence of tissue-specific expression and differential abundance of CYP21A2 transcript variants in cattle and suggest the transcription of the CYP21A1P pseudogene. The findings reveal the complexity of CYP21A2 expression in steroidogenic tissues and suggest potential regulatory roles for transcript and pseudogene variants in bovine physiology.
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(This article belongs to the Section Animal Genetics and Genomics)
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Open AccessSystematic Review
Human Breast Milk miRNAs: Investigation of Association Between Breastfeeding Children and Maternal Obesity in Obesity Development in Offspring
by
Marina Chondrogianni, Maria Lithoxopoulou, Athina Ververi, Alexandros Lampropoulos, Alexandros Sotiriadis and Eystratios Kolibianakis
Genes 2025, 16(11), 1373; https://doi.org/10.3390/genes16111373 - 11 Nov 2025
Abstract
Background/Objectives: Human breast milk is a mammary gland secretion with a dynamic composition, containing important bioactive factors for infant growth. Epigenetic factors, like microRNAs, are found in breast milk and can regulate gene expression and, thus, infant growth. Obesity is, among others, a
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Background/Objectives: Human breast milk is a mammary gland secretion with a dynamic composition, containing important bioactive factors for infant growth. Epigenetic factors, like microRNAs, are found in breast milk and can regulate gene expression and, thus, infant growth. Obesity is, among others, a major global health concern with long-term consequences, making its prevention during early life a public health priority. Maternal lifestyle factors, including diet and body weight status, may influence infant growth patterns and susceptibility to obesity. The aim of this review is to explore the hypothesis that miRNA content in breast milk might be influenced by maternal obesity, eventually affecting the obesity risk in offspring. Methods: This systematic review was carried out in line with the PRISMA 2020 statement and included observational (cohort) studies that met the inclusion criteria and compare the expression of miRNAs in OW/OB lactating mothers and associate this to the obesity development in the offspring. Results: According to the included studies, the most common miRNAs are miR-148a, miR-30 family, and miR-let7 family, with miR-30b and miR-let7a among the most discussed that participate in adipogenesis. Some of these miRNAs secreted in breast milk pass on a genetic predisposition for obesity to the next generation, while others provide a protective role against obesity in the offspring. Conclusions: Eventually, even though individual miRNAs may fluctuate, the overall miRNA profile remains stable. The findings underscore the importance of balanced maternal nutrition and optimal health during lactation, both for supporting healthy infant development and for potentially reducing the risk of obesity later in life.
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(This article belongs to the Section RNA)
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Open AccessArticle
Pharmacogenetic Analysis of TPMT and NUDT15 in a European Pediatric Cohort with IBD and Autoimmune Diseases: Frequency Data and Clinical Relevance
by
Anna Pau, Ilaria Galliano, Alice Ponte, Anna Clemente, Maddalena Dini, Cristina Calvi, Paola Montanari, Antonio Pizzol, Stefano Gambarino, Pier Luigi Calvo and Massimiliano Bergallo
Genes 2025, 16(11), 1372; https://doi.org/10.3390/genes16111372 - 11 Nov 2025
Abstract
Background/Objectives: Thiopurines remain a cornerstone in the management of inflammatory bowel disease (IBD) and gastrointestinal immune diseases but are associated with significant interindividual variability in efficacy and toxicity, mainly influenced by polymorphisms in Thiopurine S-methyltransferase TPMT and Nudix Hydrolase 15 NUDT15. This study
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Background/Objectives: Thiopurines remain a cornerstone in the management of inflammatory bowel disease (IBD) and gastrointestinal immune diseases but are associated with significant interindividual variability in efficacy and toxicity, mainly influenced by polymorphisms in Thiopurine S-methyltransferase TPMT and Nudix Hydrolase 15 NUDT15. This study aimed to assess the frequency of TPMT and NUDT15 variants in a pediatric cohort and evaluate their clinical impact to support a pharmacogenetic-guided approach to thiopurine therapy. Methods: Eighty-three pediatric patients with IBD and other autoimmune diseases were genotyped for clinically relevant TPMT and NUDT15 variants using two HRM-PCR assays and were confirmed with sequencing. Variant frequencies were compared to expected population data, and clinical records were reviewed to assess thiopurine dosing, tolerance, and adverse events. Results: Among the cohort, six carried heterozygous TPMT variants *1/*3A, while 2 carried the NUDT15 *1/*9 diplotype, with frequencies higher than expected. Among patients with TPMT variant alleles, some needed dose reductions or treatment discontinuation due to adverse effects, while others tolerated standard dosing without significant issues. Notably, no significant differences in adverse reactions were observed between NUDT15 *1/*9 carriers and wild-type patients. Conclusions: Our results confirm the clinical relevance of TPMT and NUDT15 genotyping to personalize thiopurine therapy in pediatric IBD. Routine implementation of rapid genetic testing, combined with therapeutic drug monitoring and a structured management algorithm, may optimize treatment outcomes and minimize preventable toxicity.
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(This article belongs to the Section Human Genomics and Genetic Diseases)
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Open AccessArticle
Germline Variant Call Accuracy in Whole Genome Sequence Data from Canine Formalin-Fixed Paraffin-Embedded Tissue Samples
by
Vidhya Jagannathan and Tosso Leeb
Genes 2025, 16(11), 1371; https://doi.org/10.3390/genes16111371 - 11 Nov 2025
Abstract
Background/Objectives: Fresh frozen (FF) samples are routinely used to isolate high-molecular-weight intact genomic DNA. However, when FF samples are not available, archived formalin-fixed paraffin-embedded (FFPE) tissue samples often represent the only available material in clinical research. Due to formaldehyde-induced degradation of nucleic acids
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Background/Objectives: Fresh frozen (FF) samples are routinely used to isolate high-molecular-weight intact genomic DNA. However, when FF samples are not available, archived formalin-fixed paraffin-embedded (FFPE) tissue samples often represent the only available material in clinical research. Due to formaldehyde-induced degradation of nucleic acids they pose special challenges for genetic investigations. In this study we compare whole-genome sequencing results on intact DNA versus fragmented DNA derived from FFPE samples of three dogs. Methods: We prepared matched libraries from FF and FFPE samples of three dogs affected by an inherited disease, EFNB3-related congenital mirror movement disorder 1 (CMM1). Paired-end short-read sequencing data were obtained on an Illumina sequencer and analyzed with adapted workflows for FF or FFPE data, respectively. Results: The data between FF and FFPE samples were largely consistent. FF data showed a superior variant call accuracy, as expected. However, the data quality from the FFPE samples was sufficient to correctly identify the causal variant in EFNB3. Conclusions: This pilot study demonstrates the feasibility of using FFPE samples from dogs for whole-genome sequencing and the detection of germline variants. Using FFPE samples in the analysis of suspected inherited diseases in domestic animals may represent a valuable approach in veterinary genetics if no other samples are available.
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(This article belongs to the Special Issue Advances in Veterinary Genetics and Genomics)
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Open AccessArticle
Canine Neuronal Ceroid Lipofuscinosis-like Disorder Associated with Sequence Variants in AP3B1 and TRAPPC9
by
Alexander Then, Rebecca Welly, Garrett Bullock, Lucie Chevallier and Martin L. Katz
Genes 2025, 16(11), 1370; https://doi.org/10.3390/genes16111370 - 11 Nov 2025
Abstract
Background/Objectives: A Petit Bleu de Gascogne (PBDG) dog presented with a progressive neurological disorder characterized by hind-limb weakness, anxiety and hallucinatory episodes, lip smacking, progressive vision loss, muscle atrophy, and ataxia. Magnetic resonance imaging revealed diffuse brain atrophy. The dog was euthanized at
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Background/Objectives: A Petit Bleu de Gascogne (PBDG) dog presented with a progressive neurological disorder characterized by hind-limb weakness, anxiety and hallucinatory episodes, lip smacking, progressive vision loss, muscle atrophy, and ataxia. Magnetic resonance imaging revealed diffuse brain atrophy. The dog was euthanized at approximately 23 months of age due to the progression of neurological signs. A study was undertaken to identify the molecular genetic basis of the disorder in this dog. Methods: Microscopic analyses were performed to characterize the disease pathology and whole-genome sequencing was performed to identify the molecular genetic basis of the disorder. Results: The proband exhibited pronounced accumulations of autofluorescent intracellular inclusions in the brain, retina, and heart with ultrastructural appearances similar to those of lysosomal storage bodies that accumulate in the neuronal ceroid lipofuscinosis (NCLs), a group of progressive neurodegenerative disorders. Whole-genome sequence analysis of DNA from the proband identified homozygous missense variants in AP3B1 and TRAPPC9 that encode proteins involved in sorting and transport of proteins through the Golgi apparatus to lysosomes. Screening of unaffected PBDGs for these variants identified dogs that were homozygous for either variant, but no other dogs that were homozygous for both. Conclusions: These findings raise the possibility that the disease involves the combined influence of the two variants, and that the proteins encoded by these genes interact within the Golgi apparatus to mediate protein sorting and transport to lysosomes. An alteration in this interaction could underlie the NCL-like lysosomal storage disorder observed in the proband.
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(This article belongs to the Special Issue 15th Anniversary of Genes: Feature Papers in “Neurogenetics and Neurogenomics”)
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Open AccessArticle
Dystrophin-Deficient Muscular Dystrophy in a Family of Shiba Inu Dogs with a Complex Deletion Encompassing DMD Exon 5
by
Laura Mcleay, Simone Hardinge, Katie M. Minor, Steven G. Friedenberg, Jonah N. Cullen, Ling T. Guo and G. Diane Shelton
Genes 2025, 16(11), 1369; https://doi.org/10.3390/genes16111369 - 11 Nov 2025
Abstract
Background: Two Shiba Inu littermates presented for investigation of marked and persistent elevation of creatine kinase activities. Method and Results: Histopathology of muscle biopsy samples revealed a dystrophic phenotype and immunostaining confirmed an absence of dystrophin protein in both cases. Whole genome sequencing
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Background: Two Shiba Inu littermates presented for investigation of marked and persistent elevation of creatine kinase activities. Method and Results: Histopathology of muscle biopsy samples revealed a dystrophic phenotype and immunostaining confirmed an absence of dystrophin protein in both cases. Whole genome sequencing of one affected dog revealed a complex deletion in the DMD gene encompassing exon 5. Screening of 27 related dogs confirmed an X-linked inheritance. The variant was identified in three related male dogs. One littermate died from cardiac arrest and the other littermate had no clinical myopathic signs at the time of the manuscript’s preparation. An additional related male dog reportedly died suddenly during grooming. Conclusion: This study adds a new breed to the canine dystrophinopathy spectrum having a ~17 kb deletion that encompasses exon 5 of DMD. This same exon 5 deletion has been identified in human dystrophin-deficient muscular dystrophy patients.
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(This article belongs to the Special Issue Hereditary Traits and Diseases in Companion Animals)
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Open AccessReview
Nutrigenomics and Epigenetics in the Dietary Management of Inflammatory Bowel Diseases
by
Patrycja Musz, Gabriela Ryś, Weronika Fic, Aneta Sokal-Dembowska and Sara Jarmakiewicz-Czaja
Genes 2025, 16(11), 1368; https://doi.org/10.3390/genes16111368 - 11 Nov 2025
Abstract
Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic diseases with complex aetiology involving genetic, immunological, and environmental factors and intestinal microbiota disorders. Mutations in genes such as NOD2, ATG16L1, IRGM, TLR4, and IL23R disrupt the functioning of
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Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic diseases with complex aetiology involving genetic, immunological, and environmental factors and intestinal microbiota disorders. Mutations in genes such as NOD2, ATG16L1, IRGM, TLR4, and IL23R disrupt the functioning of the intestinal barrier and the immune response, increasing susceptibility to chronic inflammation. Recent studies indicate that interactions between diet, gene expression, and epigenetic mechanisms play a key role in modulating the course of IBD, e.g., DNA methylation, histone modifications, and microRNA activity. The use of bioactive dietary components in combination with epigenome modulation is a promising tool in the treatment of IBD, enabling the reduction in chronic inflammation, improving intestinal barrier function, and supporting the immune response.
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(This article belongs to the Section Epigenomics)
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Open AccessReview
Curing Sickle Cell Disease by Allogeneic Hematopoietic Stem Cell (HSC) Transplantation Toward In Vivo HSC Gene Therapy
by
Rina Kansal
Genes 2025, 16(11), 1367; https://doi.org/10.3390/genes16111367 - 11 Nov 2025
Abstract
Sickle cell disease comprises a group of prevalent inherited disorders defined by an underlying sickle cell allele that forms sickle hemoglobin. The incidence of this disease is rising, with more than 500,000 children born with it globally. The disease carries significant morbidity and
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Sickle cell disease comprises a group of prevalent inherited disorders defined by an underlying sickle cell allele that forms sickle hemoglobin. The incidence of this disease is rising, with more than 500,000 children born with it globally. The disease carries significant morbidity and mortality. Its only curative treatment was an allogeneic hematopoietic stem cell (HSC) transplant (HSCT) until late 2023, when two one-time gene therapies were approved for treating patients aged 12 years or older with severe sickle cell disease. This work aims to inform readers about these two gene therapies: one lentiviral-based and the other nonviral. The latter is based on the Nobel Prize-winning discovery of clustered, regularly interspaced, short, palindromic repeats (CRISPR)/CRISPR-associated (Cas)9 proteins and single-guide RNA (sgRNA)-based genome editing. Both approved gene therapies require an autologous HSCT with ex vivo genetically edited autologous hematopoietic stem and progenitor cells. Therefore, access to these gene therapies is limited to specialized centers with expertise in HSCTs. This review is meant for students, researchers, and clinical practitioners. It explains the basis for both approved gene therapies, their mechanisms of action, differences, risks, and other lentiviral-based and CRISPR-Cas9-based ex vivo gene therapies for sickle cell disease in clinical development. Additionally, it discusses the current state of preclinical studies for in vivo HSC gene therapy for sickle cell disease, which utilize advanced genome editing technologies developed after CRISPR-Cas9-sgRNA-based genome editing. In vivo HSC gene therapy, after it is clinically developed, would eliminate the need for an HSCT in receiving gene therapy and vastly increase access for numerous patients worldwide, even in low-income countries with the most significant disease burden.
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(This article belongs to the Special Issue Progress in Hematology: Non-Malignant, Pre-Malignant, and Malignant Disorders, and Genetically Based Therapies)
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Open AccessArticle
Genomic Characterization of Predominant Delta Variant (B.1.617.2 and AY.120 Sub-Lineages) SARS-CoV-2 Detected from AFI Patients in Ethiopia During 2021–2022
by
Musse Tadesse Chekol, Dejenie Shiferaw Teklu, Adamu Tayachew, Wolde Shura, Admikew Agune, Aster Hailemariam, Aynalem Alemu, Mesfin Wossen, Abdulhafiz Hassen, Melaku Gonta, Neamin Tesfay, Tesfu Kasa and Nigatu Kebede
Genes 2025, 16(11), 1366; https://doi.org/10.3390/genes16111366 - 11 Nov 2025
Abstract
Background: The Delta variant of SARS-CoV-2 virus, one of the alarming variants of concern (VOC) with a distinct mutation characteristic, was immensely detrimental and a significant cause of the prolonged pandemic waves. This study aimed to analyze the genetic characteristics of the
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Background: The Delta variant of SARS-CoV-2 virus, one of the alarming variants of concern (VOC) with a distinct mutation characteristic, was immensely detrimental and a significant cause of the prolonged pandemic waves. This study aimed to analyze the genetic characteristics of the predominant Delta variant in acute febrile illness (AFI) patients in Ethiopia. Method: Nasopharyngeal swab samples were collected from AFI patients in four hospitals from February 2021 to June 2022 and tested for SARS-CoV-2 by using RT-qPCR. Of 101 positive samples, 48 stored specimens were re-tested, and 26 with sufficient RNA quality (Ct < 30) were sequenced using whole-genome sequencing to identify variants of concern, specific virus lineages and mutation features. Result: Delta variants (21J clade) were found predominant among all the sequenced SARS-CoV-2 isolate (80.8%, 21/26). AY.120 (46.2%) and B.1.617.2 (26.9%) were the predominant sub-lineages of the Delta variant. Omicron (21k, Pango BA.1.1/BA.1.17/BA.1) and Alpha (20I, Pango B.1.1.7) variants accounted for 11.5% and 7.7% of the total sequenced samples. Phylogenetic analysis showed evidence of local transmission and possible multiple introductions of SARS-CoV-2 VOCs in Ethiopia. The number of mutations increases dramatically from Alpha (~35 avg) to Delta (~42 avg) to Omicron (~56 avg). The Delta variant revealed a spike mutation on L452R and T478K and P681R, and was characterized by the double deletion E156-F157- in Spike protein. Conclusions: The findings are indicative of a gradual change in the genetic coding of the virus underscoring the importance of ongoing genomic surveillance to track the evolution and spread of SARS-CoV-2 and other emerging virus.
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(This article belongs to the Section Microbial Genetics and Genomics)
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Open AccessCase Report
Prenatal Diagnosis of 6q Terminal Deletion Associated with Coffin–Siris Syndrome: Phenotypic Delineation and Review
by
Christian Peña-Padilla, David Alejandro Martínez-Ceccopieri, Evelin Montserrat García-Hernández, Lucina Bobadilla-Morales and Jorge Román Corona-Rivera
Genes 2025, 16(11), 1365; https://doi.org/10.3390/genes16111365 - 10 Nov 2025
Abstract
Chromosome 6q deletion syndrome is a rare entity that has a highly variable clinical presentation and size of deletions. The most frequent manifestations of 6q terminal deletion are intellectual disability, facial dysmorphism, brain structural anomalies, and congenital heart defects. The phenotype is not
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Chromosome 6q deletion syndrome is a rare entity that has a highly variable clinical presentation and size of deletions. The most frequent manifestations of 6q terminal deletion are intellectual disability, facial dysmorphism, brain structural anomalies, and congenital heart defects. The phenotype is not clinically recognizable, except in those who harbor a terminal 6q deletion that includes the ARID1B gene, in whom features similar to Coffin–Siris syndrome (CSS) can be observed. We report the case of a female newborn with a prenatal diagnosis of a terminal deletion on 6q25.1q27, which encompasses the ARID1B gene, and who was diagnosed with CSS during the neonatal period. From our review, we found that facial gestalt, hypertrichosis, and fifth fingernail aplasia/hypoplasia, along with other features, such as vertebral defects and cystic hygroma (or webbed neck), correlated with the presence of a CSS causally related to 6q25.3 small deletions that include the ARID1B gene.
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(This article belongs to the Section Genetic Diagnosis)
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