Special Issue "Genetics and Genomics of Inherited Metabolic Diseases"

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

Deadline for manuscript submissions: closed (15 October 2021).

Special Issue Editors

Dr. Ewa Piotrowska
E-Mail Website
Guest Editor
Department of Molecular Biology, University of Gdansk, Gdansk, Poland
Interests: lysosomal storage disorders; human genetics; epigenetics
Dr. Magdalena Podlacha
E-Mail Website
Guest Editor
Department of Molecular Biology, University of Gdansk, Gdansk, Poland
Interests: metabolic diseases; neuromolecular physiology; behavioral genetics

Special Issue Information

Dear Colleagues,

Inherited metabolic diseases comprise a vast and complex array of separately rare genetic disorders. However, since the first inborn error of metabolism was described by Sir Archibald Garrod in 1902, over 1400 conditions have been included into this category (IEMbase), remarkably heightening the combined risk for any of them.

Rapid advances in the field of genomics and related disciplines have facilitated progress in our understanding of the pathophysiology of most metabolic disorders, and led to the development of various therapeutic approaches including cell therapy, enzyme replacement therapy, substrate reduction therapy, gene therapy, and others. Nevertheless, while improved screening and diagnosis methods enable presymptomatic treatment, they do not indicate what therapies would be most beneficial to the individual patient. Further research is therefore needed addressing disease pathophysiology, combination therapies, and optimal therapeutic timing.

This Special Issue of Genes aims to attract original research articles, reviews, and short communications on understanding recent advances in the genetics and genomics of inherited metabolic diseases. We look forward to submissions that describe basic, translational, epidemiological, and clinical research providing insight into current genetic and genomic findings as well as critical perspectives on upcoming challenges in this area.

Dr. Ewa Piotrowska
Dr. Magdalena Podlacha
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • metabolic diseases
  • inborn errors of metabolism
  • molecular mechanisms
  • metabolic pathways
  • treatment
  • novel therapies
  • genetic variations
  • genetics
  • epigenetics
  • genomics

Published Papers (6 papers)

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Research

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Article
Clinical, Biochemical, and Genetic Heterogeneity in Glutaric Aciduria Type II Patients
Genes 2021, 12(9), 1334; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091334 - 27 Aug 2021
Viewed by 577
Abstract
The variants of electron transfer flavoprotein (ETFA, ETFB) and ETF dehydrogenase (ETFDH) are the leading cause of glutaric aciduria type II (GA-II). In this study, we identified 13 patients harboring six variants of two genes associated with GA-II. [...] Read more.
The variants of electron transfer flavoprotein (ETFA, ETFB) and ETF dehydrogenase (ETFDH) are the leading cause of glutaric aciduria type II (GA-II). In this study, we identified 13 patients harboring six variants of two genes associated with GA-II. Out of the six variants, four were missense, and two were frameshift mutations. A missense variant (ETFDH:p.Gln269His) was observed in a homozygous state in nine patients. Among nine patients, three had experienced metabolic crises with recurrent vomiting, abdominal pain, and nausea. In one patient with persistent metabolic acidosis, hypoglycemia, and a high anion gap, the ETFDH:p.Gly472Arg, and ETFB:p.Pro94Thrfs*8 variants were identified in a homozygous, and heterozygous state, respectively. A missense variant ETFDH:p.Ser442Leu was detected in a homozygous state in one patient with metabolic acidosis, hypoglycemia, hyperammonemia and liver dysfunction. The ETFDH:p.Arg41Leu, and ETFB:p.Ile346Phefs*19 variants were observed in a homozygous state in one patient each. Both these variants have not been reported so far. In silico approaches were used to evaluate the pathogenicity and structural changes linked with these six variants. Overall, the results indicate the importance of a newborn screening program and genetic investigations for patients with GA-II. Moreover, careful interpretation and correlation of variants of uncertain significance with clinical and biochemical findings are needed to confirm the pathogenicity of such variants. Full article
(This article belongs to the Special Issue Genetics and Genomics of Inherited Metabolic Diseases)
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Article
Phenylketonuria Diagnosis by Massive Parallel Sequencing and Genotype-Phenotype Association in Brazilian Patients
Genes 2021, 12(1), 20; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12010020 - 25 Dec 2020
Cited by 1 | Viewed by 1125
Abstract
Phenylketonuria (PKU) is a common inborn error of amino acid metabolism in which the enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine, is functionally impaired due to pathogenic variants in the PAH gene. Thirty-four Brazilian patients with a biochemical diagnosis of PKU, from [...] Read more.
Phenylketonuria (PKU) is a common inborn error of amino acid metabolism in which the enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine, is functionally impaired due to pathogenic variants in the PAH gene. Thirty-four Brazilian patients with a biochemical diagnosis of PKU, from 33 unrelated families, were analyzed through next-generation sequencing in the Ion Torrent PGM™ platform. Phenotype–genotype correlations were made based on the BioPKU database. Three patients required additional Sanger sequencing analyses. Twenty-six different pathogenic variants were identified. The most frequent variants were c.1315+1G>A (n = 8/66), c.473G>A (n = 6/66), and c.1162G>A (n = 6/66). One novel variant, c.524C>G (p.Pro175Arg), was found in one allele and was predicted as likely pathogenic by the American College of Medical Genetics and Genomics (ACMG) criteria. The molecular modeling of p.Pro175Arg indicated that this substitution can affect monomers binding in the PAH tetramer, which could lead to a change in the stability and activity of this enzyme. Next-generation sequencing was a fast and effective method for diagnosing PKU and is useful for patient phenotype prediction and genetic counseling. Full article
(This article belongs to the Special Issue Genetics and Genomics of Inherited Metabolic Diseases)
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Review

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Review
Successful Genetic Screening and Creating Awareness of Familial Hypercholesterolemia and Other Heritable Dyslipidemias in the Netherlands
Genes 2021, 12(8), 1168; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081168 - 29 Jul 2021
Viewed by 723
Abstract
The genetic screening program for familial hypercholesterolemia (FH) in the Netherlands, which was embraced by the Dutch Ministry of Health from 1994 to 2014, has led to twenty years of identification of at least 1500 FH cases per year. Although funding by the [...] Read more.
The genetic screening program for familial hypercholesterolemia (FH) in the Netherlands, which was embraced by the Dutch Ministry of Health from 1994 to 2014, has led to twenty years of identification of at least 1500 FH cases per year. Although funding by the government was terminated in 2014, the approach had proven its effectiveness and had built the foundation for the development of more sophisticated diagnostic tools, clinical collaborations, and new molecular-based treatments for FH patients. As such, the community was driven to continue the program, insurance companies were convinced to collaborate, and multiple approaches were launched to find new index cases with FH. Additionally, the screening was extended, now also including other heritable dyslipidemias. For this purpose, a diagnostic next-generation sequencing (NGS) panel was developed, which not only comprised the culprit LDLR, APOB, and PCSK9 genes, but also 24 other genes that are causally associated with genetic dyslipidemias. Moreover, the NGS technique enabled further optimization by including pharmacogenomic genes in the panel. Using such a panel, more patients that are prone to cardiovascular diseases are being identified nowadays and receive more personalized treatment. Moreover, the NGS output teaches us more and more about the dyslipidemic landscape that is less straightforward than we originally thought. Still, continuous progress is being made that underlines the strength of genetics in dyslipidemia, such as discovery of alternative genomic pathogenic mechanisms of disease development and polygenic contribution. Full article
(This article belongs to the Special Issue Genetics and Genomics of Inherited Metabolic Diseases)
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Review
The Molecular Basis of Calcium and Phosphorus Inherited Metabolic Disorders
Genes 2021, 12(5), 734; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12050734 - 13 May 2021
Viewed by 630
Abstract
Calcium (Ca) and Phosphorus (P) hold a leading part in many skeletal and extra-skeletal biological processes. Their tight normal range in serum mirrors their critical role in human well-being. The signalling “voyage” starts at Calcium Sensing Receptor (CaSR) localized on the surface of [...] Read more.
Calcium (Ca) and Phosphorus (P) hold a leading part in many skeletal and extra-skeletal biological processes. Their tight normal range in serum mirrors their critical role in human well-being. The signalling “voyage” starts at Calcium Sensing Receptor (CaSR) localized on the surface of the parathyroid glands, which captures the “oscillations” of extracellular ionized Ca and transfers the signal downstream. Parathyroid hormone (PTH), Vitamin D, Fibroblast Growth Factor (FGF23) and other receptors or ion-transporters, work synergistically and establish a highly regulated signalling circuit between the bone, kidneys, and intestine to ensure the maintenance of Ca and P homeostasis. Any deviation from this well-orchestrated scheme may result in mild or severe pathologies expressed by biochemical and/or clinical features. Inherited disorders of Ca and P metabolism are rare. However, delayed diagnosis or misdiagnosis may cost patient’s quality of life or even life expectancy. Unravelling the thread of the molecular pathways involving Ca and P signaling, we can better understand the link between genetic alterations and biochemical and/or clinical phenotypes and help in diagnosis and early therapeutic intervention. Full article
(This article belongs to the Special Issue Genetics and Genomics of Inherited Metabolic Diseases)
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Review
Fucosidosis—Clinical Manifestation, Long-Term Outcomes, and Genetic Profile—Review and Case Series
Genes 2020, 11(11), 1383; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11111383 - 22 Nov 2020
Cited by 2 | Viewed by 848
Abstract
Fucosidosis is a neurodegenerative disorder which progresses inexorably. Clinical features include coarse facial features, growth retardation, recurrent upper respiratory infections, dysostosis multiplex, and angiokeratoma corporis diffusum. Fucosidosis is caused by mutations in the FUCA1 gene resulting in α-L-fucosidase deficiency. Only 36 pathogenic variants [...] Read more.
Fucosidosis is a neurodegenerative disorder which progresses inexorably. Clinical features include coarse facial features, growth retardation, recurrent upper respiratory infections, dysostosis multiplex, and angiokeratoma corporis diffusum. Fucosidosis is caused by mutations in the FUCA1 gene resulting in α-L-fucosidase deficiency. Only 36 pathogenic variants in the FUCA1 gene are related to fucosidosis. Most of them are missense/nonsense substitutions; six missense and 11 nonsense mutations. Among deletions there were eight small and five gross changes. So far, only three splice site variants have been described—one small deletion, one complete deletion and one stop-loss mutation. The disease has a significant clinical variability, the cause of which is not well understood. The genotype–phenotype correlation has not been well defined. This review describes the genetic profile and clinical manifestations of fucosidosis in pediatric and adult cases. Full article
(This article belongs to the Special Issue Genetics and Genomics of Inherited Metabolic Diseases)
Review
Biomarkers of Fabry Nephropathy: Review and Future Perspective
Genes 2020, 11(9), 1091; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11091091 - 18 Sep 2020
Cited by 2 | Viewed by 1306
Abstract
Progressive nephropathy is one of the main features of Fabry disease, which largely contributes to the overall morbidity and mortality burden of the disease. Due to the lack of specific biomarkers, the heterogeneity of the disease, and unspecific symptoms, diagnosis is often delayed. [...] Read more.
Progressive nephropathy is one of the main features of Fabry disease, which largely contributes to the overall morbidity and mortality burden of the disease. Due to the lack of specific biomarkers, the heterogeneity of the disease, and unspecific symptoms, diagnosis is often delayed. Clinical presentation in individual patients varies widely, even in patients from the same family carrying the same pathogenic GLA variant. Therefore, it is reasonable to anticipate that additional genomic, transcriptomic, proteomic, and metabolomics factors influence the manifestation and progression of the disease. The aim of this article is to provide an overview of nephropathy in Fabry patients and the biomarkers currently used in the diagnosis and follow-up. Current biomarkers are associated with late signs of kidney damage. Therefore, there is a need to identify biomarkers associated with early stages of kidney damage that would enable early diagnosis, which is crucial for effective treatment and prevention of severe irreversible complications. Recent advances in sequencing and -omics technologies have led to several studies investigating new biomarkers. We will provide an overview of the novel biomarkers, critically evaluate their clinical utility, and propose future perspectives, which we believe might be in their integration. Full article
(This article belongs to the Special Issue Genetics and Genomics of Inherited Metabolic Diseases)
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