Genes

Research

14 pages, 1212 KiB

Open AccessArticle

Gene Dosage of F5 c.3481C>T Stop-Codon (p.R1161Ter) Switches the Clinical Phenotype from Severe Thrombosis to Recurrent Haemorrhage: Novel Hypotheses for Readthrough Strategy

by Donato Gemmati, Elisabetta D’Aversa, Bianca Antonica, Miriana Grisafi, Francesca Salvatori, Stefano Pizzicotti, Patrizia Pellegatti, Maria Ciccone, Stefano Moratelli, Maria Luisa Serino and Veronica Tisato

Genes 2024, 15(4), 432; https://doi.org/10.3390/genes15040432 - 29 Mar 2024

Viewed by 1422

Abstract

Inherited defects in the genes of blood coagulation essentially express the severity of the clinical phenotype that is directly correlated to the number of mutated alleles of the candidate leader gene (e.g., heterozygote vs. homozygote) and of possible additional coinherited traits. The F5 [...] Read more.

Inherited defects in the genes of blood coagulation essentially express the severity of the clinical phenotype that is directly correlated to the number of mutated alleles of the candidate leader gene (e.g., heterozygote vs. homozygote) and of possible additional coinherited traits. The F5 gene, which codes for coagulation factor V (FV), plays a two-faced role in the coagulation cascade, exhibiting both procoagulant and anticoagulant functions. Thus, defects in this gene can be predisposed to either bleeding or thrombosis. A Sanger sequence analysis detected a premature stop-codon in exon 13 of the F5 gene (c.3481C>T; p.R1161Ter) in several members of a family characterised by low circulating FV levels and contrasting clinical phenotypes. The propositus, a 29 y.o. male affected by recurrent haemorrhages, was homozygous for the F5 stop-codon and for the F5 c.1691G>A (p.R506Q; FV-Leiden) inherited from the heterozygous parents, which is suggestive of combined cis-segregation. The homozygous condition of the stop-codon completely abolished the F5 gene expression in the propositus (FV:Ag < 1%; FV:C < 1%; assessed by ELISA and PT-based one-stage clotting assay respectively), removing, in turn, any chance for FV-Leiden to act as a prothrombotic molecule. His father (57 y.o.), characterised by severe recurrent venous thromboses, underwent a complete molecular thrombophilic screening, revealing a heterozygous F2 G20210A defect, while his mother (56 y.o.), who was negative for further common coagulation defects, reported fully asymptomatic anamnesis. To dissect these conflicting phenotypes, we performed the ProC^®Global (Siemens Helthineers) coagulation test aimed at assessing the global pro- and anticoagulant balance of each family member, investigating the responses to the activated protein C (APC) by means of an APC-sensitivity ratio (APC-sr). The propositus had an unexpectedly poor response to APC (APC-sr: 1.09; n.v. > 2.25), and his father and mother had an APC-sr of 1.5 and 2.0, respectively. Although ProC^®Global prevalently detects the anticoagulant side of FV, the exceptionally low APC-sr of the propositus and his discordant severe–moderate haemorrhagic phenotype could suggest a residual expression of mutated FV p.506QQ through a natural readthrough or possible alternative splicing mechanisms. The coagulation pathway may be physiologically rebalanced through natural and induced strategies, and the described insights might be able to track the design of novel treatment approaches and rebalancing molecules. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2023)

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15 pages, 1078 KiB

Open AccessArticle

PDE4 Gene Family Variants Are Associated with Response to Apremilast Treatment in Psoriasis

by Kalliopi Liadaki, Efterpi Zafiriou, Themistoklis Giannoulis, Sofia Alexouda, Kleoniki Chaidaki, Polyxeni Gidarokosta, Angeliki-Viktoria Roussaki-Schulze, Sotirios G. Tsiogkas, Athina Daponte, Zissis Mamuris, Dimitrios P. Bogdanos, Nicholas K. Moschonas and Theologia Sarafidou

Genes 2024, 15(3), 369; https://doi.org/10.3390/genes15030369 - 17 Mar 2024

Cited by 1 | Viewed by 2559

Abstract

Moderate-to-severe psoriasis (Ps) treatment includes systemic drugs and biological agents. Apremilast, a small molecule primarily metabolized by cytochrome CYP3A4, modulates the immune system by specifically inhibiting phosphodiesterase type 4 (PDE4) isoforms and is currently used for the treatment of Ps and psoriatic arthritis [...] Read more.

Moderate-to-severe psoriasis (Ps) treatment includes systemic drugs and biological agents. Apremilast, a small molecule primarily metabolized by cytochrome CYP3A4, modulates the immune system by specifically inhibiting phosphodiesterase type 4 (PDE4) isoforms and is currently used for the treatment of Ps and psoriatic arthritis (PsA). Clinical trials and real-world data showed variable efficacy in response among Ps patients underlying the need for personalized therapy. This study implements a candidate-gene and a network-based approach to identify genetic markers associated with apremilast response in forty-nine Greek Ps patients. Our data revealed an association of sixty-four SNPs within or near PDE4 and CYP3A4 genes, four SNPs in ncRNAs ANRIL, LINC00941 and miR4706, which influence the abundance or function of PDE4s, and thirty-three SNPs within fourteen genes whose protein products either interact directly with PDE4 proteins or constitute components of the cAMP signaling pathway which is modulated by PDE4s. Notably, fifty-six of the aforementioned SNPs constitute eQTLs for the respective genes in relevant to psoriasis tissues/cells implying that these variants could be causal. Our analysis provides a number of novel genetic variants that, upon validation in larger cohorts, could be utilized as predictive markers regarding the response of Ps patients to apremilast treatment. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2023)

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10 pages, 259 KiB

Open AccessArticle

Polymorphic Variants of SCN5A Gene (rs41312433 and rs1805124) Associated with Coronary Artery Affliction in Patients with Severe Arrhythmias

by Anna Vašků, Tomáš Novotný and Jindřich Špinar

Genes 2024, 15(2), 200; https://doi.org/10.3390/genes15020200 - 2 Feb 2024

Viewed by 1502

Abstract

Several mutations in this gene for the α subunit of the cardiac sodium channel have been identified in a heterogeneous subset of cardiac rhythm syndromes, including Brugada syndrome, progressive cardiac conduction defect, sick sinus node syndrome, atrial fibrillation and dilated cardiomyopathy. The aim [...] Read more.

Several mutations in this gene for the α subunit of the cardiac sodium channel have been identified in a heterogeneous subset of cardiac rhythm syndromes, including Brugada syndrome, progressive cardiac conduction defect, sick sinus node syndrome, atrial fibrillation and dilated cardiomyopathy. The aim of our study was to associate some SCN5A polymorphic variants directly with confirmed coronary stenoses in patients with non-LQTS ventricular fibrillation/flutter treated by an implantable cardioverter defibrillator. Materials and Methods: A group of 32 unrelated individuals, aged 63 ± 12 years, was included in the study. All the patients were examined, diagnosed and treated with an implantable cardioverter defibrillator at the Department of Internal Cardiology Medicine, Faculty Hospital Brno. The control group included 87 persons of similar age without afflicted coronary circulation, which was confirmed coronagraphically. Genomic DNA was extracted from samples of peripheral blood according to the standard protocol. Two SCN5A polymorphisms—IVS9-3C/A (rs41312433) and A1673G (rs1805124, H558R)—were examined in association with coronary artery stenosis in the patients. Results: In the case–control study, no significant differences in genotype distribution/allelic frequencies were observed for IVS9-3c>a and A1673G gene polymorphisms between patients with severe arrhythmias and healthy persons. The distribution of SCN5A double genotypes was not significantly different among different types of arrhythmias according to their ejection fraction in arrhythmic patients (p = 0.396). The ventricular arrhythmias with an ejection fraction below 40% were found to be 10.67 times more frequent in patients with multiple coronary stenosis with clinically valid sensitivity, specificity and power tests. In the genotype–phenotype study, we observed a significant association of both SCN5A polymorphisms with the stenosis of coronary vessels in the patients with severe arrhythmia. The double genotype of polymorphisms IVS9-3C/A together with A1673G (CCAA) as well as their simple genotypes were associated with significant multiple stenosis of coronary arteries (MVS) with high sensitivity and specificity (p = 0.05; OR = 5 (95% CI 0.99–23.34); sensitivity 0.70; specificity 0.682; power test 0.359) Moreover, when a concrete stenotic coronary artery was associated with SCN5A genotypes, the CCAA double genotype was observed to be five times more frequent in patients with significant stenosis in the right coronary artery (RCA) compared to those without affliction of this coronary artery (p = 0.05; OR = 5 (95% CI 0.99–23.34); sensitivity 0.682; specificity 0.700; power test 0.359). The CCAA genotype was also more frequent in patients without RCA affliction with MVS (p = 0.008); in patients with ACD affliction but without MVS (p = 0.008); and in patients with both ACD affliction and MVS compared to those without ACD affliction and MVS (p = 0.005). Conclusions: Our study presents a highly sensitive and specific association of two polymorphisms in SCN5A with significant coronary artery stenoses in patients with potentially fatal ventricular arrhythmias. At the same time, these polymorphisms were not associated with arrhythmias themselves. Thus, SCN5A gene polymorphic variants may form a part of germ cell gene predisposition to ischemia. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2023)

13 pages, 1321 KiB

Open AccessArticle

Lack of Association between LOXL1 Variants and Pigment Dispersion Syndrome/Pigmentary Glaucoma: A Meta-Analysis

by Shisong Rong and Xinting Yu

Genes 2024, 15(2), 161; https://doi.org/10.3390/genes15020161 - 26 Jan 2024

Cited by 1 | Viewed by 1266

Abstract

The phenotypic similarities between exfoliation syndrome (XFS)/exfoliation glaucoma (XFG) and pigment dispersion syndrome (PDS)/pigmentary glaucoma (PG), particularly their association with material deposition in the eye’s anterior segment, have prompted investigations into genetic commonalities. This study focuses on the LOXL1 gene, conducting a comprehensive [...] Read more.

The phenotypic similarities between exfoliation syndrome (XFS)/exfoliation glaucoma (XFG) and pigment dispersion syndrome (PDS)/pigmentary glaucoma (PG), particularly their association with material deposition in the eye’s anterior segment, have prompted investigations into genetic commonalities. This study focuses on the LOXL1 gene, conducting a comprehensive meta-analysis of three candidate gene association studies. We analyzed three single nucleotide polymorphisms (SNPs) of LOXL1: rs1048661, rs3825942, and rs2165241. Our results reveal nominal significance for the exonic SNPs rs1048661 and rs3825942 (p ≤ 0.01), but show no significant association for the intronic SNP rs2165241 (p = 0.83) with PDS/PG. There was homogeneity across study cohorts (I² = 0), and sensitivity analyses and funnel plots confirmed a lower likelihood of bias in our findings. The lack of a statistically significant association between LOXL1 variants and PDS/PG at p < 0.05 was attributable to the insufficient statistical power of the pooled data, which ranged from 5% to 37% for the three SNPs. This study suggests no association between LOXL1 variants and PDS/PG. Further validation and exploration of XFS/XFG-associated genes in larger and more diverse cohorts would be helpful to determine the genetic correlation or distinctiveness between these conditions. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2023)

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11 pages, 265 KiB

Open AccessArticle

Genetic Variants at the 9p21.3 Locus Are Associated with Risk for Non-Compressible Artery Disease: Results from the ARTPER Study

by Marc Via, Guillem Pera, Rosa Forés, Anna Costa-Garrido, Antonio Heras, José Miguel Baena-Díez, Edurne Pedrosa, Inmaculada C. Clemente, Noemí Lamonja-Vicente, Maria Mataró, Pere Torán-Montserrat and M. Teresa Alzamora

Genes 2024, 15(1), 2; https://doi.org/10.3390/genes15010002 - 19 Dec 2023

Viewed by 1191

Abstract

Peripheral artery disease (PAD) and non-compressible artery disease (NCAD) constitute predictors of subclinical atherosclerosis easily assessed through the ankle brachial index (ABI). Although both diseases show substantial genetic influences, few genetic association studies have focused on the ABI and PAD, and none have [...] Read more.

Peripheral artery disease (PAD) and non-compressible artery disease (NCAD) constitute predictors of subclinical atherosclerosis easily assessed through the ankle brachial index (ABI). Although both diseases show substantial genetic influences, few genetic association studies have focused on the ABI and PAD, and none have focused on NCAD. To overcome these limitations, we assessed the role of several candidate genes on the ABI, both in its continuous distribution and in the clinical manifestations associated to its extreme values: PAD and NCAD. We examined 13 candidate genomic regions in 1606 participants from the ARTPER study, a prospective population-based cohort, with the ABI assessed through ultrasonography. Association analyses were conducted independently for individuals with PAD (ABI < 0.9) or with NCAD (ABI > 1.4) vs. healthy participants. After including potential covariates and correction for multiple testing, minor alleles in the genetic markers rs10757278 and rs1333049, both in the 9p21.3 region, were significantly associated with a decreased risk of NCAD. Associations with the ABI showed limited support to these results. No significant associations were detected for PAD. The locus 9p21.3 constitutes the first genetic locus associated with NCAD, an assessment of subclinical atherosclerosis feasible for implementation in primary healthcare settings that has been systematically neglected from genetic studies. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2023)

12 pages, 2424 KiB

Open AccessArticle

Co-Occurrence of Germline Genomic Variants and Copy Number Variations in Hereditary Breast and Colorectal Cancer Patients

by Luiza Côrtes, Tatiane Ramos Basso, Rolando André Rios Villacis, Jeferson dos Santos Souza, Mads Malik Aagaard Jørgensen, Maria Isabel Achatz and Silvia Regina Rogatto

Genes 2023, 14(8), 1580; https://doi.org/10.3390/genes14081580 - 3 Aug 2023

Cited by 1 | Viewed by 2202

Abstract

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is an autosomal dominant disease associated with a high risk of developing breast, ovarian, and other malignancies. Lynch syndrome is caused by mutations in mismatch repair genes predisposing to colorectal and endometrial cancers, among others. A [...] Read more.

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is an autosomal dominant disease associated with a high risk of developing breast, ovarian, and other malignancies. Lynch syndrome is caused by mutations in mismatch repair genes predisposing to colorectal and endometrial cancers, among others. A rare phenotype overlapping hereditary colorectal and breast cancer syndromes is poorly characterized. Three breast and colorectal cancer unrelated patients fulfilling clinical criteria for HBOC were tested by whole exome sequencing. A family history of colorectal cancer was reported in two patients (cases 2 and 3). Several variants and copy number variations were identified, which potentially contribute to the cancer risk or prognosis. All patients presented copy number imbalances encompassing PMS2 (two deletions and one duplication), a known gene involved in the DNA mismatch repair pathway. Two patients showed gains covering the POLE2 (cases 1 and 3), which is associated with DNA replication. Germline potentially damaging variants were found in PTCH1 (patient 3), MAT1A, and WRN (patient 2). Overall, concurrent genomic alterations were described that may increase the risk of cancer appearance in HBOC patients with breast and colorectal cancers. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2023)

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Graphical abstract

16 pages, 788 KiB

Open AccessArticle

Rare Coding Variants in Patients with Non-Syndromic Vestibular Dysfunction

by Angelo Augusto M. Sumalde, Melissa A. Scholes, Olivia A. Kalmanson, Elizabeth A. Terhune, Lidia Frejo, Cambria I. Wethey, Pablo Roman-Naranjo, Patrick M. Carry, Samuel P. Gubbels, Jose A. Lopez-Escamez, Nancy Hadley-Miller and Regie Lyn P. Santos-Cortez

Genes 2023, 14(4), 831; https://doi.org/10.3390/genes14040831 - 30 Mar 2023

Cited by 2 | Viewed by 2673

Abstract

Vertigo due to vestibular dysfunction is rare in children. The elucidation of its etiology will improve clinical management and the quality of life of patients. Genes for vestibular dysfunction were previously identified in patients with both hearing loss and vertigo. This study aimed [...] Read more.

Vertigo due to vestibular dysfunction is rare in children. The elucidation of its etiology will improve clinical management and the quality of life of patients. Genes for vestibular dysfunction were previously identified in patients with both hearing loss and vertigo. This study aimed to identify rare, coding variants in children with peripheral vertigo but no hearing loss, and in patients with potentially overlapping phenotypes, namely, Meniere’s disease or idiopathic scoliosis. Rare variants were selected from the exome sequence data of 5 American children with vertigo, 226 Spanish patients with Meniere’s disease, and 38 European–American probands with scoliosis. In children with vertigo, 17 variants were found in 15 genes involved in migraine, musculoskeletal phenotypes, and vestibular development. Three genes, OTOP1, HMX3, and LAMA2, have knockout mouse models for vestibular dysfunction. Moreover, HMX3 and LAMA2 were expressed in human vestibular tissues. Rare variants within ECM1, OTOP1, and OTOP2 were each identified in three adult patients with Meniere’s disease. Additionally, an OTOP1 variant was identified in 11 adolescents with lateral semicircular canal asymmetry, 10 of whom have scoliosis. We hypothesize that peripheral vestibular dysfunction in children may be due to multiple rare variants within genes that are involved in the inner ear structure, migraine, and musculoskeletal disease. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2023)

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14 pages, 1406 KiB

Open AccessArticle

Mutational Spectrum of the ABCA12 Gene and Genotype–Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis

by Alrun Hotz, Julia Kopp, Emmanuelle Bourrat, Vinzenz Oji, Kira Süßmuth, Katalin Komlosi, Bakar Bouadjar, Iliana Tantcheva-Poór, Maritta Hellström Pigg, Regina C. Betz, Kathrin Giehl, Fiona Schedel, Lisa Weibel, Solveig Schulz, Dora V. Stölzl, Gianluca Tadini, Emine Demiral, Karin Berggard, Andreas D. Zimmer, Svenja Alter and Judith Fischer Show full author list Hide full author list

Genes 2023, 14(3), 717; https://doi.org/10.3390/genes14030717 - 15 Mar 2023

Cited by 9 | Viewed by 5176

Abstract

Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin. The three major phenotypes are lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. ARCI is caused by biallelic mutations in ABCA12, ALOX12B, [...] Read more.

Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin. The three major phenotypes are lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1. The most severe form of ARCI, harlequin ichthyosis, is caused by mutations in ABCA12. Mutations in this gene can also lead to congenital ichthyosiform erythroderma or lamellar ichthyosis. We present a large cohort of 64 patients affected with ARCI carrying biallelic mutations in ABCA12. Our study comprises 34 novel mutations in ABCA12, expanding the mutational spectrum of ABCA12-associated ARCI up to 217 mutations. Within these we found the possible mutational hotspots c.4541G>A, p.(Arg1514His) and c.4139A>G, p.(Asn1380Ser). A correlation of the phenotype with the effect of the genetic mutation on protein function is demonstrated. Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2023)

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Review

Jump to: Research, Other

25 pages, 2304 KiB

Open AccessReview

Navigating the Complex Landscape of Fibrodysplasia Ossificans Progressiva: From Current Paradigms to Therapeutic Frontiers

by Saeed Anwar and Toshifumi Yokota

Genes 2023, 14(12), 2162; https://doi.org/10.3390/genes14122162 - 30 Nov 2023

Cited by 2 | Viewed by 3842

Abstract

Fibrodysplasia ossificans progressiva (FOP) is an enigmatic, ultra-rare genetic disorder characterized by progressive heterotopic ossification, wherein soft connective tissues undergo pathological transformation into bone structures. This incapacitating process severely limits patient mobility and poses formidable challenges for therapeutic intervention. Predominantly caused by missense [...] Read more.

Fibrodysplasia ossificans progressiva (FOP) is an enigmatic, ultra-rare genetic disorder characterized by progressive heterotopic ossification, wherein soft connective tissues undergo pathological transformation into bone structures. This incapacitating process severely limits patient mobility and poses formidable challenges for therapeutic intervention. Predominantly caused by missense mutations in the ACVR1 gene, this disorder has hitherto defied comprehensive mechanistic understanding and effective treatment paradigms. This write-up offers a comprehensive overview of the contemporary understanding of FOP’s complex pathobiology, underscored by advances in molecular genetics and proteomic studies. We delve into targeted therapy, spanning genetic therapeutics, enzymatic and transcriptional modulation, stem cell therapies, and innovative immunotherapies. We also highlight the intricate complexities surrounding clinical trial design for ultra-rare disorders like FOP, addressing fundamental statistical limitations, ethical conundrums, and methodological advancements essential for the success of interventional studies. We advocate for the adoption of a multi-disciplinary approach that converges bench-to-bedside research, clinical expertise, and ethical considerations to tackle the challenges of ultra-rare diseases like FOP and comparable ultra-rare diseases. In essence, this manuscript serves a dual purpose: as a definitive scientific resource for ongoing and future FOP research and a call to action for innovative solutions to address methodological and ethical challenges that impede progress in the broader field of medical research into ultra-rare conditions. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2023)

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15 pages, 782 KiB

Open AccessReview

Preimplantation Genetic Testing for Genetic Diseases: Limits and Review of Current Literature

by Roberta Giuliano, Anna Maione, Angela Vallefuoco, Ugo Sorrentino and Daniela Zuccarello

Genes 2023, 14(11), 2095; https://doi.org/10.3390/genes14112095 - 17 Nov 2023

Cited by 8 | Viewed by 6152

Abstract

Preimplantation genetic testing (PGT) has emerged as a revolutionary technique in the field of reproductive medicine, allowing for the selection and transfer of healthy embryos, thus reducing the risk of transmitting genetic diseases. However, despite remarkable advancements, the implementation of PGT faces a [...] Read more.

Preimplantation genetic testing (PGT) has emerged as a revolutionary technique in the field of reproductive medicine, allowing for the selection and transfer of healthy embryos, thus reducing the risk of transmitting genetic diseases. However, despite remarkable advancements, the implementation of PGT faces a series of limitations and challenges that require careful consideration. This review aims to foster a comprehensive reflection on the constraints of preimplantation genetic diagnosis, encouraging a broader discussion about its utility and implications. The objective is to inform and guide medical professionals, patients, and society overall in the conscious and responsible adoption of this innovative technology, taking into account its potential benefits and the ethical and practical challenges that it presents. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2023)

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14 pages, 800 KiB

Open AccessReview

The Regulatory Role of MicroRNAs in Obesity and Obesity-Derived Ailments

by Javier A. Benavides-Aguilar, Andrea Torres-Copado, José Isidoro-Sánchez, Surajit Pathak, Asim K. Duttaroy, Antara Banerjee and Sujay Paul

Genes 2023, 14(11), 2070; https://doi.org/10.3390/genes14112070 - 13 Nov 2023

Cited by 8 | Viewed by 2827

Abstract

Obesity is a condition that is characterized by the presence of excessive adipose tissue in the body. Obesity has become one of the main health concerns worldwide since it can lead to other chronic ailments, such as type 2 diabetes or fatty liver [...] Read more.

Obesity is a condition that is characterized by the presence of excessive adipose tissue in the body. Obesity has become one of the main health concerns worldwide since it can lead to other chronic ailments, such as type 2 diabetes or fatty liver disease, and it could be an aggravating factor in infections. MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression and can play an important role in controlling crucial biological processes involved in the onset of obesity, such as lipogenesis, adipogenesis, lipid metabolism, or the regulation of cytokines and chemokines. Moreover, chemical compounds present in food or food packaging can alter miRNA expression and regulate the aforementioned biological mechanisms related to diabetes onset and progression. Furthermore, therapies, such as bariatric surgery and aerobic exercise training, can also influence the expression profile of miRNAs in obesity. Therefore, the present review provides insight into the current research on the role of miRNAs in obesity and obesity-derived ailments, intending to develop novel therapies to effectively manage these disorders. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2023)

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23 pages, 434 KiB

Open AccessReview

The Human Microbiome and Its Role in Musculoskeletal Disorders

by Khaled Aboushaala, Arnold Y. L. Wong, Juan Nicolas Barajas, Perry Lim, Lena Al-Harthi, Ana Chee, Christopher B. Forsyth, Chun-do Oh, Sheila J. Toro, Frances M. K. Williams, Howard S. An and Dino Samartzis

Genes 2023, 14(10), 1937; https://doi.org/10.3390/genes14101937 - 14 Oct 2023

Cited by 6 | Viewed by 3056

Abstract

Musculoskeletal diseases (MSDs) are characterized as injuries and illnesses that affect the musculoskeletal system. MSDs affect every population worldwide and are associated with substantial global burden. Variations in the makeup of the gut microbiota may be related to chronic MSDs. There is growing [...] Read more.

Musculoskeletal diseases (MSDs) are characterized as injuries and illnesses that affect the musculoskeletal system. MSDs affect every population worldwide and are associated with substantial global burden. Variations in the makeup of the gut microbiota may be related to chronic MSDs. There is growing interest in exploring potential connections between chronic MSDs and variations in the composition of gut microbiota. The human microbiota is a complex community consisting of viruses, archaea, bacteria, and eukaryotes, both inside and outside of the human body. These microorganisms play crucial roles in influencing human physiology, impacting metabolic and immunological systems in health and disease. Different body areas host specific types of microorganisms, with facultative anaerobes dominating the gastrointestinal tract (able to thrive with or without oxygen), while strict aerobes prevail in the nasal cavity, respiratory tract, and skin surfaces (requiring oxygen for development). Together with the immune system, these bacteria have coevolved throughout time, forming complex biological relationships. Changes in the microbial ecology of the gut may have a big impact on health and can help illnesses develop. These changes are frequently impacted by lifestyle choices and underlying medical disorders. The potential for safety, expenses, and efficacy of microbiota-based medicines, even with occasional delivery, has attracted interest. They are, therefore, a desirable candidate for treating MSDs that are chronic and that may have variable progression patterns. As such, the following is a narrative review to address the role of the human microbiome as it relates to MSDs. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2023)

Other

Jump to: Research, Review

8 pages, 452 KiB

Open AccessBrief Report

Erythrokeratodermia Variabilis-like Phenotype in Patients Carrying ABCA12 Mutations

by Alrun Hotz, Regina Fölster-Holst, Vinzenz Oji, Emmanuelle Bourrat, Jorge Frank, Slaheddine Marrakchi, Mariem Ennouri, Lotta Wankner, Katalin Komlosi, Svenja Alter and Judith Fischer

Genes 2024, 15(3), 288; https://doi.org/10.3390/genes15030288 - 24 Feb 2024

Cited by 2 | Viewed by 1481

Abstract

Erythrokeratodermia variabilis (EKV) is a rare genodermatosis characterized by well-demarcated erythematous patches and hyperkeratotic plaques. EKV is most often transmitted in an autosomal dominant manner. Until recently, only mutations in connexins such as GJB3 (connexin 31), GJB4 (connexin 30.3), and occasionally GJA1 (connexin [...] Read more.

Erythrokeratodermia variabilis (EKV) is a rare genodermatosis characterized by well-demarcated erythematous patches and hyperkeratotic plaques. EKV is most often transmitted in an autosomal dominant manner. Until recently, only mutations in connexins such as GJB3 (connexin 31), GJB4 (connexin 30.3), and occasionally GJA1 (connexin 43) were known to cause EKV. In recent years, mutations in other genes have been described as rare causes of EKV, including the genes KDSR, KRT83, and TRPM4. Features of the EKV phenotype can also appear with other genodermatoses: for example, in Netherton syndrome, which hampers correct diagnosis. However, in autosomal recessive congenital ichthyosis (ARCI), an EKV phenotype has rarely been described. Here, we report on seven patients who clinically show a clear EKV phenotype, but in whom molecular genetic analysis revealed biallelic mutations in ABCA12, which is why the patients are classified in the ARCI group. Our study indicates that ARCI should be considered as a differential diagnosis in EKV. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2023)

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13 pages, 457 KiB

Open AccessStudy Protocol

Autism Spectrum Disorder with Epilepsy: A Research Protocol for a Clinical and Genetic Study

by Roberto Canitano and Yuri Bozzi

Genes 2024, 15(1), 61; https://doi.org/10.3390/genes15010061 - 31 Dec 2023

Cited by 1 | Viewed by 2439

Abstract

Autism spectrum disorder (ASD) is a common neurodevelopmental condition affecting ~1% of people worldwide. Core ASD features present with impaired social communication abilities, repetitive and stereotyped behaviors, and atypical sensory responses and are often associated with a series of comorbidities. Among these, epilepsy [...] Read more.

Autism spectrum disorder (ASD) is a common neurodevelopmental condition affecting ~1% of people worldwide. Core ASD features present with impaired social communication abilities, repetitive and stereotyped behaviors, and atypical sensory responses and are often associated with a series of comorbidities. Among these, epilepsy is frequently observed. The co-occurrence of ASD and epilepsy is currently thought to result from common abnormal neurodevelopmental pathways, including an imbalanced excitation/inhibition ratio. However, the pathological mechanisms involved in ASD-epilepsy co-morbidity are still largely unknown. Here, we propose a research protocol aiming to investigate electrophysiological and genetic features in subjects with ASD and epilepsy. This study will include a detailed electroencephalographic (EEG) and blood transcriptomic characterization of subjects with ASD with and without epilepsy. The combined approach of EEG and transcriptomic studies in the same subjects will contribute to a novel stratification paradigm of the heterogeneous ASD population based on quantitative gene expression and neurophysiological biomarkers. In addition, our protocol has the potential to indicate new therapeutic options, thus amending the current condition of absence of data and guidelines for the treatment of ASD with epilepsy. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2023)

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10 pages, 716 KiB

Open AccessBrief Report

Alternative Genetic Diagnoses in Axenfeld–Rieger Syndrome Spectrum

by Linda M. Reis, David J. Amor, Raad A. Haddad, Catherine B. Nowak, Kim M. Keppler-Noreuil, Smith Ann Chisholm and Elena V. Semina

Genes 2023, 14(10), 1948; https://doi.org/10.3390/genes14101948 - 17 Oct 2023

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Abstract

Axenfeld–Rieger anomaly (ARA) is a specific ocular disorder that is frequently associated with other systemic abnormalities. PITX2 and FOXC1 variants explain the majority of individuals with Axenfeld–Rieger syndrome (ARS) but leave ~30% unsolved. Here, we present pathogenic/likely pathogenic variants in nine families with [...] Read more.

Axenfeld–Rieger anomaly (ARA) is a specific ocular disorder that is frequently associated with other systemic abnormalities. PITX2 and FOXC1 variants explain the majority of individuals with Axenfeld–Rieger syndrome (ARS) but leave ~30% unsolved. Here, we present pathogenic/likely pathogenic variants in nine families with ARA/ARS or similar phenotypes affecting five different genes/regions. USP9X and JAG1 explained three families each. USP9X was recently linked with syndromic cognitive impairment that includes hearing loss, dental defects, ventriculomegaly, Dandy–Walker malformation, skeletal anomalies (hip dysplasia), and other features showing a significant overlap with FOXC1-ARS. Anterior segment anomalies are not currently associated with USP9X, yet our cases demonstrate ARA, congenital glaucoma, corneal neovascularization, and cataracts. The identification of JAG1 variants, linked with Alagille syndrome, in three separate families with a clinical diagnosis of ARA/ARS highlights the overlapping features and high variability of these two phenotypes. Finally, intragenic variants in CDK13, BCOR, and an X chromosome deletion encompassing HCCS and AMELX (linked with ocular and dental anomalies, correspondingly) were identified in three additional cases with ARS. Accurate diagnosis has important implications for clinical management. We suggest that broad testing such as exome sequencing be applied as a second-tier test for individuals with ARS with normal results for PITX2/FOXC1 sequencing and copy number analysis, with attention to the described genes/regions. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2023)

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