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Genetic, Genomic and Metabolomic Investigation of Rare Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (30 April 2024) | Viewed by 6102

Special Issue Editors

Department of Medical Genetics, Medical School, University of Pécs, 7624 Pécs, Hungary
Interests: molecular genetics and genomics; next generation sequencing; rare diseases; genetic testing; neurocutaneous syndromes; copy number variations
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Guest Editor
Department of Medical Genetics, Medical School, University of Pécs, Pecs, Hungary
Interests: autism spectrum disorders; genomic disorders; epilepsy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Rare diseases, defined as life-threatening, chronically debilitating conditions, represent a substantial public health burden as they affect ca. 2–6 % of the population. Currently, there are around 5000–8000 different rare diseases, and these numbers are continuing to increase. Despite intensive research, the genetic etiology and pathomechanisms of the majority of rare diseases are still unclear, and most of them do not yet have an approved therapy. Their diagnostics and care pathways are also challenging due to their rarity, heterogeneous manifestations, multisystem involvement and the often-observed incomplete penetrance. In addition, patients with undiagnosed genetic diseases often face a diagnostic odyssey that lasts for an average of eight years; moreover, a certain number of patients receive a misdiagnosis.

However, due to new sophisticated technologies, such as high-throughput sequencing and mass spectrometry, an increasing number of genomic and metabolomic data for various rare disorders have recently become available. These data could help us to understand biological mechanisms, identify new genes, determine causative mutations, discover biomarkers and ultimately develop novel therapeutics and diagnostics methods.

The aim of this Special Issue is to collect original and review articles that provide cutting-edge knowledge related to genetic, genomic and metabolomic investigations in rare disorders.

Dr. Judit Bene
Dr. Kinga Hadzsiev
Guest Editors

Manuscript Submission Information

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Keywords

  • rare diseases
  • genotype–phenotype analyses
  • NGS
  • mass spectrometry
  • biomarker discovery
  • molecular targeted therapy

Published Papers (4 papers)

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10 pages, 1318 KiB  
Article
Genetic Landscape of Factor VII Deficiency: Insights from a Comprehensive Analysis of Pathogenic Variants and Their Impact on Coagulation Activity
by Barbara Preisler, Behnaz Pezeshkpoor, Anja Merzenich, Sandra Ohlenforst, Heiko Rühl, Vytautas Ivaškevičius, Ute Scholz, Hagen Bönigk, Wolfgang Eberl, Barbara Zieger, Anna Pavlova and Johannes Oldenburg
Int. J. Mol. Sci. 2024, 25(4), 2384; https://doi.org/10.3390/ijms25042384 - 17 Feb 2024
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Abstract
Congenital factor VII (FVII) deficiency is a rare genetic bleeding disorder characterized by deficient or reduced activity of coagulation FVII. It is caused by genetic variants in the F7 gene. We aimed to evaluate the rate of detection of pathogenic variants in the [...] Read more.
Congenital factor VII (FVII) deficiency is a rare genetic bleeding disorder characterized by deficient or reduced activity of coagulation FVII. It is caused by genetic variants in the F7 gene. We aimed to evaluate the rate of detection of pathogenic variants in the F7 gene in a large group of patients with FVII deficiency and investigate the correlations between the F7 genotype and FVII activity (FVII:C). Moreover, the influence of the common genetic variant rs6046: c.1238G>A; p.(Arg413Gln), designated as the M2 allele, on FVII:C was investigated. Genetic analysis of the F7 gene was performed on 704 index patients (IPs) using either direct Sanger- or next-generation sequencing. Genetic variants were detected in 390 IPs, yielding a variant detection rate (VDR) of 55%. Notably, the VDR exhibited a linear decline with increasing FVII:C levels. We identified 124 genetic variants, of which 48 were not previously reported. Overall, the frequency of the M2 allele was considerably higher in patients with mild deficiency (FVII:C > 20 IU/dl). Furthermore, IPs lacking an identified pathogenic variant exhibited a significantly higher prevalence of the M2 allele (69%) compared to IPs with a disease-causing variant (47%). These results strongly support the association of the M2 allele with decreased FVII:C levels. This study shows the utility of FVII:C as a predictive marker for identifying pathogenic variants in patients with FVII deficiency. The M2 allele contributes to the reduction of FVII:C levels, particularly in cases of mild deficiency. Full article
(This article belongs to the Special Issue Genetic, Genomic and Metabolomic Investigation of Rare Diseases)
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17 pages, 3206 KiB  
Article
Quantitative Lipid Profiling Reveals Major Differences between Liver Organoids with Normal Pi*M and Deficient Pi*Z Variants of Alpha-1-antitrypsin
by Sara Pérez-Luz, Jaanam Lalchandani, Nerea Matamala, Maria Jose Barrero, Sara Gil-Martín, Sheila Ramos-Del Saz, Sarai Varona, Sara Monzón, Isabel Cuesta, Iago Justo, Alberto Marcacuzco, Loreto Hierro, Cristina Garfia, Gema Gomez-Mariano, Sabina Janciauskiene and Beatriz Martínez-Delgado
Int. J. Mol. Sci. 2023, 24(15), 12472; https://doi.org/10.3390/ijms241512472 - 5 Aug 2023
Cited by 2 | Viewed by 1681
Abstract
Different mutations in the SERPINA1 gene result in alpha-1 antitrypsin (AAT) deficiency and in an increased risk for the development of liver diseases. More than 90% of severe deficiency patients are homozygous for Z (Glu342Lys) mutation. This mutation causes Z-AAT polymerization and intrahepatic [...] Read more.
Different mutations in the SERPINA1 gene result in alpha-1 antitrypsin (AAT) deficiency and in an increased risk for the development of liver diseases. More than 90% of severe deficiency patients are homozygous for Z (Glu342Lys) mutation. This mutation causes Z-AAT polymerization and intrahepatic accumulation which can result in hepatic alterations leading to steatosis, fibrosis, cirrhosis, and/or hepatocarcinoma. We aimed to investigate lipid status in hepatocytes carrying Z and normal M alleles of the SERPINA1 gene. Hepatic organoids were developed to investigate lipid alterations. Lipid accumulation in HepG2 cells overexpressing Z-AAT, as well as in patient-derived hepatic organoids from Pi*MZ and Pi*ZZ individuals, was evaluated by Oil-Red staining in comparison to HepG2 cells expressing M-AAT and liver organoids from Pi*MM controls. Furthermore, mass spectrometry-based lipidomics analysis and transcriptomic profiling were assessed in Pi*MZ and Pi*ZZ organoids. HepG2 cells expressing Z-AAT and liver organoids from Pi*MZ and Pi*ZZ patients showed intracellular accumulation of AAT and high numbers of lipid droplets. These latter paralleled with augmented intrahepatic lipids, and in particular altered proportion of triglycerides, cholesterol esters, and cardiolipins. According to transcriptomic analysis, Pi*ZZ organoids possess many alterations in genes and cellular processes of lipid metabolism with a specific impact on the endoplasmic reticulum, mitochondria, and peroxisome dysfunction. Our data reveal a relationship between intrahepatic accumulation of Z-AAT and alterations in lipid homeostasis, which implies that liver organoids provide an excellent model to study liver diseases related to the mutation of the SERPINA1 gene. Full article
(This article belongs to the Special Issue Genetic, Genomic and Metabolomic Investigation of Rare Diseases)
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14 pages, 3533 KiB  
Article
Genetic Etiology of Nonsyndromic Hearing Loss in Hungarian Patients
by Margit Pál, Dóra Nagy, Alexandra Neller, Katalin Farkas, Dóra Leprán-Török, Nikoletta Nagy, Dalma Füstös, Roland Nagy, Adrienne Németh, Judit Szilvássy, László Rovó, József Géza Kiss and Márta Széll
Int. J. Mol. Sci. 2023, 24(8), 7401; https://doi.org/10.3390/ijms24087401 - 17 Apr 2023
Cited by 1 | Viewed by 1489
Abstract
Hearing loss is the most prevalent sensory disorder worldwide. The majority of congenital nonsyndromic hearing loss (NSHL) cases are caused by hereditary factors. Previously, the majority of NSHL studies focused on the GJB2 gene; however, with the availability of next-generation sequencing (NGS) methods, [...] Read more.
Hearing loss is the most prevalent sensory disorder worldwide. The majority of congenital nonsyndromic hearing loss (NSHL) cases are caused by hereditary factors. Previously, the majority of NSHL studies focused on the GJB2 gene; however, with the availability of next-generation sequencing (NGS) methods, the number of novel variants associated with NSHL has increased. The purpose of this study was to design effective genetic screening for a Hungarian population based on a pilot study with 139 NSHL patients. A stepwise, comprehensive genetic approach was developed, including bidirectional capillary sequencing, multiplex ligation-dependent probe amplification (MLPA), and an NGS panel of 108 hearing loss genes. With our results, a genetic diagnosis was possible for 92 patients. Sanger sequencing and MLPA identified the genetic background of 50% of these diagnosed cases, and the NGS panel identified another 16%. The vast majority (92%) of the diagnosed cases showed autosomal recessive inheritance and 76% were attributed to GJB2. The implementation of this stepwise analysis markedly increased our diagnostic yield and proved to be cost-effective as well. Full article
(This article belongs to the Special Issue Genetic, Genomic and Metabolomic Investigation of Rare Diseases)
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7 pages, 612 KiB  
Case Report
Double Heterozygosity for Rare Deleterious Variants in the BRCA1 and BRCA2 Genes in a Hungarian Patient with Breast Cancer
by László Madar, Viktória Majoros, Zsuzsanna Szűcs, Orsolya Nagy, Tamás Babicz, Henriett Butz, Attila Patócs, István Balogh and Katalin Koczok
Int. J. Mol. Sci. 2023, 24(20), 15334; https://doi.org/10.3390/ijms242015334 - 18 Oct 2023
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Abstract
Hereditary breast cancer is most commonly attributed to germline BRCA1 and BRCA2 gene variants. The vast majority of BRCA1 and BRCA2 mutation carriers are single heterozygotes, and double heterozygosity (DH) is a very rare finding. Here, we describe the case of a BRCA1 [...] Read more.
Hereditary breast cancer is most commonly attributed to germline BRCA1 and BRCA2 gene variants. The vast majority of BRCA1 and BRCA2 mutation carriers are single heterozygotes, and double heterozygosity (DH) is a very rare finding. Here, we describe the case of a BRCA1/BRCA2 double heterozygous female proband diagnosed with breast cancer. Genetic testing for hereditary breast and ovarian cancer revealed two pathogenic variants in the BRCA1 (c.5095C>T, p.(Arg1699Trp)) and in BRCA2 genes (c.658_659delGT, p.(Val220Ilefs*4)) in heterozygous form. None of the variants were founder Jewish mutations; to our knowledge, these rare deleterious variants have not been previously described in DH patients in the literature. The patient had triple-negative unilateral breast cancer at the age of 36 and 44 years. Based on family studies, the BRCA1 variant was maternally inherited. Full article
(This article belongs to the Special Issue Genetic, Genomic and Metabolomic Investigation of Rare Diseases)
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