Editorial

4 pages, 372 KiB

Open AccessEditorial

Advance in Genomics of Rare Genetic Diseases

by Elena Sommariva, Milena Bellin and Chiara Di Resta

Biomolecules 2023, 13(10), 1441; https://doi.org/10.3390/biom13101441 - 25 Sep 2023

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Recent technical breakthroughs in genotyping and bioinformatics techniques have greatly facilitated the translation of genomics into clinical care [...] Full article

(This article belongs to the Special Issue Advance in Genomics of Rare Genetic Diseases)

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Research

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15 pages, 1515 KiB

Open AccessFeature PaperArticle

From Genetics to Clinical Implications: A Study of 675 Dutch Osteogenesis Imperfecta Patients

by Silvia Storoni, Sara J. E. Verdonk, Lidiia Zhytnik, Gerard Pals, Sanne Treurniet, Mariet W. Elting, Ralph J. B. Sakkers, Joost G. van den Aardweg, Elisabeth M. W. Eekhoff and Dimitra Micha

Biomolecules 2023, 13(2), 281; https://doi.org/10.3390/biom13020281 - 02 Feb 2023

Cited by 5 | Viewed by 1706

Abstract

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder that causes bone fragility due to pathogenic variants in genes responsible for the synthesis of type I collagen. Efforts to classify the high clinical variability in OI led to the Sillence classification. However, this [...] Read more.

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder that causes bone fragility due to pathogenic variants in genes responsible for the synthesis of type I collagen. Efforts to classify the high clinical variability in OI led to the Sillence classification. However, this classification only partially takes into account extraskeletal manifestations and the high genetic variability. Little is known about the relation between genetic variants and phenotype as of yet. The aim of the study was to create a clinically relevant genetic stratification of a cohort of 675 Dutch OI patients based on their pathogenic variant types and to provide an overview of their respective medical care demands. The clinical records of 675 OI patients were extracted from the Amsterdam UMC Genome Database and matched with the records from Statistics Netherlands (CBS). The patients were categorized based on their harbored pathogenic variant. The information on hospital admissions, outpatient clinic visits, medication, and diagnosis-treatment combinations (DTCs) was compared between the variant groups. OI patients in the Netherlands appear to have a higher number of DTCs, outpatient clinic visits, and hospital admissions when compared to the general Dutch population. Furthermore, medication usage seems higher in the OI cohort in comparison to the general population. The patients with a COL1A1 or COL1A2 dominant negative missense non-glycine substitution appear to have a lower health care need compared to the other groups, and even lower than patients with COL1A1 or COL1A2 haploinsufficiency. It would be useful to include the variant type in addition to the Sillence classification when categorizing a patient’s phenotype. Full article

(This article belongs to the Special Issue Advance in Genomics of Rare Genetic Diseases)

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14 pages, 835 KiB

Open AccessArticle

Ultra-Rare Variants Identify Biological Pathways and Candidate Genes in the Pathobiology of Non-Syndromic Cleft Palate Only

by Emanuela Iovino, Luca Scapoli, Annalisa Palmieri, Rossella Sgarzani, Nayereh Nouri, Agnese Pellati, Francesco Carinci, Marco Seri, Tommaso Pippucci and Marcella Martinelli

Biomolecules 2023, 13(2), 236; https://doi.org/10.3390/biom13020236 - 26 Jan 2023

Cited by 1 | Viewed by 1822

Abstract

In recent decades, many efforts have been made to elucidate the genetic causes of non-syndromic cleft palate (nsCPO), a complex congenital disease caused by the interaction of several genetic and environmental factors. Since genome-wide association studies have evidenced a minor contribution of common [...] Read more.

In recent decades, many efforts have been made to elucidate the genetic causes of non-syndromic cleft palate (nsCPO), a complex congenital disease caused by the interaction of several genetic and environmental factors. Since genome-wide association studies have evidenced a minor contribution of common polymorphisms in nsCPO inheritance, we used whole exome sequencing data to explore the role of ultra-rare variants in this study. In a cohort of 35 nsCPO cases and 38 controls, we performed a gene set enrichment analysis (GSEA) and a hypergeometric test for assessing significant overlap between genes implicated in nsCPO pathobiology and genes enriched in ultra-rare variants in our cohort. GSEA highlighted an enrichment of ultra-rare variants in genes principally belonging to cytoskeletal protein binding pathway (Probability Density Function corrected p-value = 1.57 × 10⁻⁴); protein-containing complex binding pathway (p-value = 1.06 × 10⁻²); cell adhesion molecule binding pathway (p-value = 1.24 × 10⁻²); ECM-receptor interaction pathway (p-value = 1.69 × 10⁻²); and in the Integrin signaling pathway (p-value = 1.28 × 10⁻²). Two genes implicated in nsCPO pathobiology, namely COL2A1 and GLI3, ranked among the genes (n = 34) with nominal enrichment in the ultra-rare variant collapsing analysis (Fisher’s exact test p-value < 0.05). These genes were also part of an independent list of genes highly relevant to nsCPO biology (n = 25). Significant overlap between the two sets of genes (hypergeometric test p-value = 5.86 × 10⁻³) indicated that enriched genes are likely to be implicated in physiological palate development and/or the pathological processes of oral clefting. In conclusion, ultra-rare variants collectively impinge on biological pathways crucial to nsCPO pathobiology and point to candidate genes that may contribute to the individual risk of disease. Sequencing can be an effective approach to identify candidate genes and pathways for nsCPO. Full article

(This article belongs to the Special Issue Advance in Genomics of Rare Genetic Diseases)

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13 pages, 747 KiB

Open AccessArticle

Next Generation Sequencing of Genotype Variants and Genetic Association between Heat Shock Proteins HSPA1B Single Nucleotide Polymorphism at the g.31829044 Locus and Heat Tolerance: A Pilot Quasi-Experimental Study

by Faith O. Alele, John R. Otto, Bunmi S. Malau-Aduli and Aduli E. O. Malau-Aduli

Biomolecules 2022, 12(10), 1465; https://doi.org/10.3390/biom12101465 - 12 Oct 2022

Cited by 1 | Viewed by 1460

Abstract

Heat tolerance and exertional heat stroke (EHS) are rare health conditions that have been described and characterised but have never been genetically solved. Knowledge of the role of single nucleotide polymorphisms (SNPs) in heat shock proteins (HSPs) genes and their associations with heat [...] Read more.

Heat tolerance and exertional heat stroke (EHS) are rare health conditions that have been described and characterised but have never been genetically solved. Knowledge of the role of single nucleotide polymorphisms (SNPs) in heat shock proteins (HSPs) genes and their associations with heat tolerance and EHS is limited. This pilot study aimed to identify SNP in HSPA1B, HSP90AA2 and DNAJA1 genes and their associations with heat tolerance and EHS history in a quasi-experimental design. Participants comprised Australian Defence Force members (ADF) who had a history of EHS and the general population. Genomic DNA samples were extracted from the venous blood samples of 48 participants, sequenced and analysed for SNP. Forty-four per cent (44%) of the participants were heat intolerant, and 29% had a history of EHS. Among participants with a history of EHS, there was an association between heat tolerance and HSPA1B SNP at the g.31829044 locus. However, there were no associations between HSPA1B and HSP90AA2 SNP and heat tolerance. All participants had the same distribution for the DNAJA1 SNP. In conclusion, the findings indicate an association between the HSPA1B genetic variant at the g.31829044 locus and heat tolerance among ADF participants with a history of EHS. Further research with a larger number of military participants will shed more light on the associations between HSP genes and heat tolerance. Full article

(This article belongs to the Special Issue Advance in Genomics of Rare Genetic Diseases)

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19 pages, 1558 KiB

Open AccessEditor’s ChoiceArticle

Next-Generation Sequencing Gene Panels in Inheritable Cardiomyopathies and Channelopathies: Prevalence of Pathogenic Variants and Variants of Unknown Significance in Uncommon Genes

by Cristina Mazzaccara, Raffaella Lombardi, Bruno Mirra, Ferdinando Barretta, Maria Valeria Esposito, Fabiana Uomo, Martina Caiazza, Emanuele Monda, Maria Angela Losi, Giuseppe Limongelli, Valeria D’Argenio and Giulia Frisso

Biomolecules 2022, 12(10), 1417; https://doi.org/10.3390/biom12101417 - 03 Oct 2022

Cited by 12 | Viewed by 1783

Abstract

The diffusion of next-generation sequencing (NGS)-based approaches allows for the identification of pathogenic mutations of cardiomyopathies and channelopathies in more than 200 different genes. Since genes considered uncommon for a clinical phenotype are also now included in molecular testing, the detection rate of [...] Read more.

The diffusion of next-generation sequencing (NGS)-based approaches allows for the identification of pathogenic mutations of cardiomyopathies and channelopathies in more than 200 different genes. Since genes considered uncommon for a clinical phenotype are also now included in molecular testing, the detection rate of disease-causing variants has increased. Here, we report the prevalence of genetic variants detected by using a NGS custom panel in a cohort of 133 patients with inherited cardiomyopathies (n = 77) or channelopathies (n = 56). We identified 82 variants, of which 50 (61%) were identified in genes without a strong or definitive evidence of disease association according to the NIH-funded Clinical Genome Resource (ClinGen; “uncommon genes”). Among these, 35 (70%) were variants of unknown significance (VUSs), 13 (26%) were pathogenic (P) or likely pathogenic (LP) mutations, and 2 (4%) benign (B) or likely benign (LB) variants according to American College of Medical Genetics (ACMG) classifications. These data reinforce the need for the screening of uncommon genes in order to increase the diagnostic sensitivity of the genetic testing of inherited cardiomyopathies and channelopathies by allowing for the identification of mutations in genes that are not usually explored due to a currently poor association with the clinical phenotype. Full article

(This article belongs to the Special Issue Advance in Genomics of Rare Genetic Diseases)

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14 pages, 2350 KiB

Open AccessArticle

Heterogeneous Clinical Phenotypes of dHMN Caused by Mutation in HSPB1 Gene: A Case Series

by Xiya Shen, Jiawei Zhang, Feixia Zhan, Wotu Tian, Qingqing Jiang, Xinghua Luan, Xiaojie Zhang and Li Cao

Biomolecules 2022, 12(10), 1382; https://doi.org/10.3390/biom12101382 - 27 Sep 2022

Cited by 1 | Viewed by 1639

Abstract

Mutations in HSPB1 are known to cause Charcot-Marie-Tooth disease type 2F (CMT2F) and distal hereditary motor neuropathy (dHMN). In this study, we presented three patients with mutation in HSPB1 who were diagnosed with dHMN. Proband 1 was a 14-year-old male with progressive bilateral [...] Read more.

Mutations in HSPB1 are known to cause Charcot-Marie-Tooth disease type 2F (CMT2F) and distal hereditary motor neuropathy (dHMN). In this study, we presented three patients with mutation in HSPB1 who were diagnosed with dHMN. Proband 1 was a 14-year-old male with progressive bilateral lower limb weakness and walking difficulty for four years. Proband 2 was a 65-year-old male with chronic lower limb weakness and restless legs syndrome from the age of 51. Proband 3 was a 50-year-old female with progressive weakness, lower limbs atrophy from the age of 44. The nerve conduction studies (NCS) suggested axonal degeneration of the peripheral motor nerves and needle electromyography (EMG) revealed chronic neurogenic changes in probands. Open sural nerve biopsy for proband 2 and the mother of proband 1 showed mild to moderate loss of myelinated nerve fibers with some nerve fiber regeneration. A novel p.V97L in HSPB1 was identified in proband 3, the other two variants (p.P182A and p.R127W) in HSPB1 have been reported previously. The functional studies showed that expressing mutant p.V97L HSPB1 in SH-SY5Y cells displayed a decreased cell activity and increased apoptosis under stress condition. Our study expands the clinical phenotypic spectrum and etiological spectrum of HSPB1 mutation. Full article

(This article belongs to the Special Issue Advance in Genomics of Rare Genetic Diseases)

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16 pages, 981 KiB

Open AccessFeature PaperArticle

Spectrum of Rare and Common Genetic Variants in Arrhythmogenic Cardiomyopathy Patients

by Melania Lippi, Mattia Chiesa, Ciro Ascione, Matteo Pedrazzini, Saima Mushtaq, Davide Rovina, Daniela Riggio, Anna Maria Di Blasio, Maria Luisa Biondi, Giulio Pompilio, Gualtiero I. Colombo, Michela Casella, Valeria Novelli and Elena Sommariva

Biomolecules 2022, 12(8), 1043; https://doi.org/10.3390/biom12081043 - 28 Jul 2022

Cited by 2 | Viewed by 1820

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a rare inherited disorder, whose genetic cause is elusive in about 50–70% of cases. ACM presents a variable disease course which could be influenced by genetics. We performed next-generation sequencing on a panel of 174 genes associated with inherited [...] Read more.

Arrhythmogenic cardiomyopathy (ACM) is a rare inherited disorder, whose genetic cause is elusive in about 50–70% of cases. ACM presents a variable disease course which could be influenced by genetics. We performed next-generation sequencing on a panel of 174 genes associated with inherited cardiovascular diseases on 82 ACM probands (i) to describe and classify the pathogenicity of rare variants according to the American College of Medical Genetics and Genomics both for ACM-associated genes and for genes linked to other cardiovascular genetic conditions; (ii) to assess, for the first time, the impact of common variants on the ACM clinical disease severity by genotype-phenotype correlation and survival analysis. We identified 15 (likely) pathogenic variants and 66 variants of uncertain significance in ACM-genes and 4 high-impact variants in genes never associated with ACM (ABCC9, APOB, DPP6, MIB1), which deserve future consideration. In addition, we found 69 significant genotype-phenotype associations between common variants and clinical parameters. Arrhythmia-associated polymorphisms resulted in an increased risk of arrhythmic events during patients’ follow-up. The description of the genetic framework of our population and the observed genotype-phenotype correlation constitutes the starting point to address the current lack of knowledge in the genetics of ACM. Full article

(This article belongs to the Special Issue Advance in Genomics of Rare Genetic Diseases)

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17 pages, 1711 KiB

Open AccessEditor’s ChoiceArticle

Genetic and Metabolic Determinants of Atrial Fibrillation in a General Population Sample: The CHRIS Study

by David B. Emmert, Vladimir Vukovic, Nikola Dordevic, Christian X. Weichenberger, Chiara Losi, Yuri D’Elia, Claudia Volpato, Vinicius V. Hernandes, Martin Gögele, Luisa Foco, Giulia Pontali, Deborah Mascalzoni, Francisco S. Domingues, Rupert Paulmichl, Peter P. Pramstaller, Cristian Pattaro, Alessandra Rossini, Johannes Rainer, Christian Fuchsberger and Marzia De Bortoli

Biomolecules 2021, 11(11), 1663; https://doi.org/10.3390/biom11111663 - 09 Nov 2021

Cited by 4 | Viewed by 2556

Abstract

Atrial fibrillation (AF) is a supraventricular arrhythmia deriving from uncoordinated electrical activation with considerable associated morbidity and mortality. To expand the limited understanding of AF biological mechanisms, we performed two screenings, investigating the genetic and metabolic determinants of AF in the Cooperative Health [...] Read more.

Atrial fibrillation (AF) is a supraventricular arrhythmia deriving from uncoordinated electrical activation with considerable associated morbidity and mortality. To expand the limited understanding of AF biological mechanisms, we performed two screenings, investigating the genetic and metabolic determinants of AF in the Cooperative Health Research in South Tyrol study. We found 110 AF cases out of 10,509 general population individuals. A genome-wide association scan (GWAS) identified two novel loci (p-value < 5 × 10⁻⁸) around SNPs rs745582874, next to gene PBX1, and rs768476991, within gene PCCA, with genotype calling confirmed by Sanger sequencing. Risk alleles at both SNPs were enriched in a family detected through familial aggregation analysis of the phenotype, and both rare alleles co-segregated with AF. The metabolic screening of 175 metabolites, in a subset of individuals, revealed a 41% lower concentration of lysophosphatidylcholine lysoPC a C20:3 in AF cases compared to controls (p-adj = 0.005). The genetic findings, combined with previous evidence, indicate that the two identified GWAS loci may be considered novel genetic rare determinants for AF. Considering additionally the association of lysoPC a C20:3 with AF by metabolic screening, our results demonstrate the valuable contribution of the combined genomic and metabolomic approach in studying AF in large-scale population studies. Full article

(This article belongs to the Special Issue Advance in Genomics of Rare Genetic Diseases)

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Review

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12 pages, 924 KiB

Open AccessEditor’s ChoiceReview

Genomics of Wolfram Syndrome 1 (WFS1)

by Sulev Kõks

Biomolecules 2023, 13(9), 1346; https://doi.org/10.3390/biom13091346 - 04 Sep 2023

Cited by 3 | Viewed by 1550

Abstract

Wolfram Syndrome (WFS) is a rare, autosomal, recessive neurogenetic disorder that affects many organ systems. It is characterised by diabetes insipidus, diabetes mellites, optic atrophy, and deafness and, therefore, is also known as DIDMOAD. Nearly 15,000–30,000 people are affected by WFS worldwide, and, [...] Read more.

Wolfram Syndrome (WFS) is a rare, autosomal, recessive neurogenetic disorder that affects many organ systems. It is characterised by diabetes insipidus, diabetes mellites, optic atrophy, and deafness and, therefore, is also known as DIDMOAD. Nearly 15,000–30,000 people are affected by WFS worldwide, and, on average, patients suffering from WFS die at 30 years of age, usually from central respiratory failure caused by massive brain atrophy. The more prevalent of the two kinds of WFS is WFS1, which is a monogenic disease and caused by the loss of the WFS1 gene, whereas WFS2, which is more uncommon, is caused by mutations in the CISD2 gene. Currently, there is no treatment for WFS1 to increase the life expectancy of patients, and the treatments available do not significantly improve their quality of life. Understanding the genetics and the molecular mechanisms of WFS1 is essential to finding a cure. The inability of conventional medications to treat WFS1 points to the need for innovative strategies that must address the fundamental cause: the deletion of the WFS1 gene that leads to the profound ER stress and disturbances in proteostasis. An important approach here is to understand the mechanism of the cell degeneration after the deletion of the WFS1 gene and to describe the differences in these mechanisms for the different tissues. The studies so far have indicated that remarkable clinical heterogeneity is caused by the variable vulnerability caused by WFS1 mutations, and these differences cannot be attributed solely to the positions of mutations in the WFS1 gene. The present review gives a broader overview of the results from genomic studies on the WFS1 mouse model. Full article

(This article belongs to the Special Issue Advance in Genomics of Rare Genetic Diseases)

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24 pages, 4390 KiB

Open AccessEditor’s ChoiceReview

Myocardial Inflammation as a Manifestation of Genetic Cardiomyopathies: From Bedside to the Bench

by Giovanni Peretto, Elena Sommariva, Chiara Di Resta, Martina Rabino, Andrea Villatore, Davide Lazzeroni, Simone Sala, Giulio Pompilio and Leslie T. Cooper

Biomolecules 2023, 13(4), 646; https://doi.org/10.3390/biom13040646 - 04 Apr 2023

Cited by 11 | Viewed by 2822

Abstract

Over recent years, preclinical and clinical evidence has implicated myocardial inflammation (M-Infl) in the pathophysiology and phenotypes of traditionally genetic cardiomyopathies. M-Infl resembling myocarditis on imaging and histology occurs frequently as a clinical manifestation of classically genetic cardiac diseases, including dilated and arrhythmogenic [...] Read more.

Over recent years, preclinical and clinical evidence has implicated myocardial inflammation (M-Infl) in the pathophysiology and phenotypes of traditionally genetic cardiomyopathies. M-Infl resembling myocarditis on imaging and histology occurs frequently as a clinical manifestation of classically genetic cardiac diseases, including dilated and arrhythmogenic cardiomyopathy. The emerging role of M-Infl in disease pathophysiology is leading to the identification of druggable targets for molecular treatment of the inflammatory process and a new paradigm in the field of cardiomyopathies. Cardiomyopathies constitute a leading cause of heart failure and arrhythmic sudden death in the young population. The aim of this review is to present, from bedside to bench, the current state of the art about the genetic basis of M-Infl in nonischemic cardiomyopathies of the dilated and arrhythmogenic spectrum in order to prompt future research towards the identification of novel mechanisms and treatment targets, with the ultimate goal of lowering disease morbidity and mortality. Full article

(This article belongs to the Special Issue Advance in Genomics of Rare Genetic Diseases)

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13 pages, 915 KiB

Open AccessReview

Circular RNA—Is the Circle Perfect?

by Lavinia Caba, Laura Florea, Cristina Gug, Daniela Cristina Dimitriu and Eusebiu Vlad Gorduza

Biomolecules 2021, 11(12), 1755; https://doi.org/10.3390/biom11121755 - 24 Nov 2021

Cited by 24 | Viewed by 3409

Abstract

Circular RNA (circRNA) is a distinct class of non-coding RNA produced, in principle, using a back-splicing mechanism, conserved during evolution, with increased stability and a tissue-dependent expression. Circular RNA represents a functional molecule with roles in the regulation of transcription and splicing, microRNA [...] Read more.

Circular RNA (circRNA) is a distinct class of non-coding RNA produced, in principle, using a back-splicing mechanism, conserved during evolution, with increased stability and a tissue-dependent expression. Circular RNA represents a functional molecule with roles in the regulation of transcription and splicing, microRNA sponge, and the modulation of protein–protein interaction. CircRNAs are involved in essential processes of life such as apoptosis, cell cycle, and proliferation. Due to the regulatory role (upregulation/downregulation) in pathogenic mechanisms of some diseases (including cancer), its potential roles as a biomarker or therapeutic target in these diseases were studied. This review focuses on the importance of circular RNA in cancer. Full article

(This article belongs to the Special Issue Advance in Genomics of Rare Genetic Diseases)

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18 pages, 958 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Rare Does Not Mean Worthless: How Rare Diseases Have Shaped Neurodevelopment Research in the NGS Era

by Mattia Zaghi, Federica Banfi, Edoardo Bellini and Alessandro Sessa

Biomolecules 2021, 11(11), 1713; https://doi.org/10.3390/biom11111713 - 17 Nov 2021

Cited by 3 | Viewed by 2558

Abstract

The advent of next-generation sequencing (NGS) is heavily changing both the diagnosis of human conditions and basic biological research. It is now possible to dig deep inside the genome of hundreds of thousands or even millions of people and find both common and [...] Read more.

The advent of next-generation sequencing (NGS) is heavily changing both the diagnosis of human conditions and basic biological research. It is now possible to dig deep inside the genome of hundreds of thousands or even millions of people and find both common and rare genomic variants and to perform detailed phenotypic characterizations of both physiological organs and experimental models. Recent years have seen the introduction of multiple techniques using NGS to profile transcription, DNA and chromatin modifications, protein binding, etc., that are now allowing us to profile cells in bulk or even at a single-cell level. Although rare and ultra-rare diseases only affect a few people, each of these diseases represent scholarly cases from which a great deal can be learned about the pathological and physiological function of genes, pathways, and mechanisms. Therefore, for rare diseases, state-of-the-art investigations using NGS have double valence: their genomic cause (new variants) and the characterize the underlining the mechanisms associated with them (discovery of gene function) can be found. In a non-exhaustive manner, this review will outline the main usage of NGS-based techniques for the diagnosis and characterization of neurodevelopmental disorders (NDDs), under whose umbrella many rare and ultra-rare diseases fall. Full article

(This article belongs to the Special Issue Advance in Genomics of Rare Genetic Diseases)

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