Genes

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16 pages, 3441 KiB

Open AccessArticle

Outlining the Clinical Profile of TCIRG1 14 Variants including 5 Novels with Overview of ARO Phenotype and Ethnic Impact in 20 Egyptian Families

by Ghada Y. El-Kamah, Mennat I. Mehrez, Mohamed B. Taher, Hala T. El-Bassyouni, Khaled R. Gaber and Khalda S. Amr

Genes 2023, 14(4), 900; https://doi.org/10.3390/genes14040900 - 12 Apr 2023

Cited by 1 | Viewed by 1443

Abstract

TCIRG1 gene mutations underlie osteopetrosis, a rare genetic disorder impacting osteoclast function with consequent brittle bones prone to fracture, in spite of being characterized by increased bone density. The disorder is known to exhibit marked genetic heterogeneity, has no treatment, and is lethal [...] Read more.

TCIRG1 gene mutations underlie osteopetrosis, a rare genetic disorder impacting osteoclast function with consequent brittle bones prone to fracture, in spite of being characterized by increased bone density. The disorder is known to exhibit marked genetic heterogeneity, has no treatment, and is lethal in most instances. There are reports of ethnic variations affecting bone mineral density and variants’ expression as diverse phenotypes even within individuals descending from the same pedigree. We herein focus on one of osteopetrosis’s three types: the autosomal recessive malignant form (MIM 259700) (ARO) that is almost always associated with severe clinical symptoms. We reviewed the results of about 1800 Egyptian exomes and we did not detect similar variants within our Egyptian dataset and secondary neurological deficit. We studied twenty Egyptian families: sixteen ARO patients, ten carrier parents with at least one ARO affected sib, and two fetuses. They were all subjected to thorough evaluation and TCIRG1 gene sequencing. Our results of twenty-eight individuals descending from twenty Egyptian pedigrees with at least one ARO patient, expand the phenotype as well as genotype spectrum of recessive mutations in the TCIRG1 gene by five novel pathogenic variants. Identifying TCIRG1 gene mutations in Egyptian patients with ARO allowed the provision of proper genetic counseling, carrier detection, and prenatal diagnosis starting with two families included herein. It also could pave the way to modern genomic therapeutic approaches. Full article

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

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13 pages, 779 KiB

Open AccessArticle

Genome-Wide Associations and Confirmatory Meta-Analyses in Diabetic Retinopathy

by Xinting Yu and Shisong Rong

Genes 2023, 14(3), 653; https://doi.org/10.3390/genes14030653 - 05 Mar 2023

Cited by 5 | Viewed by 5480

Abstract

The present study aimed to summarize and validate the genomic association signals for diabetic retinopathy (DR), proliferative DR, and diabetic macular edema/diabetic maculopathy. A systematic search of the genome-wide association study (GWAS) catalog and PubMed/MELINE databases was conducted to curate a comprehensive list [...] Read more.

The present study aimed to summarize and validate the genomic association signals for diabetic retinopathy (DR), proliferative DR, and diabetic macular edema/diabetic maculopathy. A systematic search of the genome-wide association study (GWAS) catalog and PubMed/MELINE databases was conducted to curate a comprehensive list of significant GWAS discoveries. The top signals were then subjected to meta-analysis using established protocols. The results indicate the need for improved consensus among DR GWASs, highlighting the importance of validation efforts. A subsequent meta-analysis confirmed the association of two SNPs, rs4462262 (ZWINT-MRPS35P3) (odds ratio = 1.38, p = 0.001) and rs7903146 (TCF7L2) (odd ratio = 1.30, p < 0.001), with DR in independent populations, strengthening the evidence of their true association. We also compiled a list of candidate SNPs for further validation. This study highlights the importance of consistent validation and replication efforts in the field of DR genetics. The two identified gene loci warrant further functional investigation to understand their role in DR pathogenesis. Full article

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

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12 pages, 4295 KiB

Open AccessArticle

Novel Pathogenic Mutations Identified from Whole-Genome Sequencing in Unsolved Cases of Patients Affected with Inherited Retinal Diseases

by Hafiz Muhammad Jafar Hussain, Meng Wang, Austin Huang, Ryan Schmidt, Xinye Qian, Paul Yang, Molly Marra, Yumei Li, Mark E. Pennesi and Rui Chen

Genes 2023, 14(2), 447; https://doi.org/10.3390/genes14020447 - 09 Feb 2023

Cited by 4 | Viewed by 1865

Abstract

Inherited retinal diseases (IRDs) are a diverse set of visual disorders that collectively represent a major cause of early-onset blindness. With the reduction in sequencing costs in recent years, whole-genome sequencing (WGS) is being used more frequently, particularly when targeted gene panels and [...] Read more.

Inherited retinal diseases (IRDs) are a diverse set of visual disorders that collectively represent a major cause of early-onset blindness. With the reduction in sequencing costs in recent years, whole-genome sequencing (WGS) is being used more frequently, particularly when targeted gene panels and whole-exome sequencing (WES) fail to detect pathogenic mutations in patients. In this study, we performed mutation screens using WGS for a cohort of 311 IRD patients whose mutations were undetermined. A total of nine putative pathogenic mutations in six IRD patients were identified, including six novel mutations. Among them, four were deep intronic mutations that affected mRNA splicing, while the other five affected protein-coding sequences. Our results suggested that the rate of resolution of unsolved cases via targeted gene panels and WES can be further enhanced with WGS; however, the overall improvement may be limited. Full article

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

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19 pages, 2326 KiB

Open AccessArticle

Severe COVID-19 May Impact Hepatic Fibrosis /Hepatic Stellate Cells Activation as Indicated by a Pathway and Population Genetic Study

by Leire Moya, Samaneh Farashi, Prashanth Suravajhala, Panchadsaram Janaththani and Jyotsna Batra

Genes 2023, 14(1), 22; https://doi.org/10.3390/genes14010022 - 22 Dec 2022

Cited by 3 | Viewed by 4216

Abstract

Coronavirus disease 19 (COVID-19) has affected over 112 million people and killed more than 2.5 million worldwide. When the pandemic was declared, Spain and Italy accounted for 29% of the total COVID-19 related deaths in Europe, while most infected patients did not present [...] Read more.

Coronavirus disease 19 (COVID-19) has affected over 112 million people and killed more than 2.5 million worldwide. When the pandemic was declared, Spain and Italy accounted for 29% of the total COVID-19 related deaths in Europe, while most infected patients did not present severe illness. We hypothesised that shared genomic characteristics, distinct from the rest of Europe, could be a contributor factor to a poor prognosis in these two populations. To identify pathways related to COVID-19 severity, we shortlisted 437 candidate genes associated with host viral intake and immune evasion from SARS-like viruses. From these, 21 were associated specifically with clinically aggressive COVID-19. To determine the potential mechanism of viral infections, we performed signalling pathway analysis with either the full list (n = 437) or the subset group (n = 21) of genes. Four pathways were significantly associated with the full gene list (Caveolar-mediated Endocytosis and the MSP-RON Signalling) or with the aggressive gene list (Hepatic Fibrosis/Hepatic Stellate Cell (HSC) Activation and the Communication between Innate and Adaptive Immune Cells). Single nucleotide polymorphisms (SNPs) from the ±1 Mb window of all genes related to these four pathways were retrieved from the dbSNP database. We then performed Principal Component analysis for these SNPs in individuals from the 1000 Genomes of European ancestry. Only the Hepatic Fibrosis/HSC Activation pathway showed population-specific segregation. The Spanish and Italian populations clustered together and away from the rest of the European ancestries, with the first segregating further from the rest. Additional in silico analysis identified potential genetic markers and clinically actionable therapeutic targets in this pathway, that may explain the severe disease. Full article

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

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21 pages, 1014 KiB

Open AccessArticle

Cross-Trait Genetic Analyses Indicate Pleiotropy and Complex Causal Relationships between Headache and Thyroid Function Traits

by Sana Tasnim, Scott G. Wilson, John P. Walsh and Dale R. Nyholt

Genes 2023, 14(1), 16; https://doi.org/10.3390/genes14010016 - 21 Dec 2022

Cited by 2 | Viewed by 1765

Abstract

Epidemiological studies have reported a comorbid relationship between headache and thyroid traits; however, little is known about the shared genetics and causality that contributes to this association. We investigated the genetic overlap and associations between headache and thyroid function traits using genome-wide association [...] Read more.

Epidemiological studies have reported a comorbid relationship between headache and thyroid traits; however, little is known about the shared genetics and causality that contributes to this association. We investigated the genetic overlap and associations between headache and thyroid function traits using genome-wide association study (GWAS) data. We found a significant genetic correlation (r_g) with headache and hypothyroidism (r_g = 0.09, p = 2.00 × 10⁻⁴), free thyroxine (fT4) (r_g = 0.08, p = 5.50 × 10⁻³), and hyperthyroidism (r_g = −0.14, p = 1.80 × 10⁻³), a near significant genetic correlation with secondary hypothyroidism (r_g = 0.20, p = 5.24 × 10⁻²), but not with thyroid stimulating hormone (TSH). Pairwise-GWAS analysis revealed six, 14, four and five shared (pleiotropic) loci with headache and hypothyroidism, hyperthyroidism, secondary hypothyroidism, and fT4, respectively. Cross-trait GWAS meta-analysis identified novel genome-wide significant loci for headache: five with hypothyroidism, three with secondary hypothyroidism, 12 with TSH, and nine with fT4. Of the genes at these loci, six (FAF1, TMX2-CTNND1, AARSD1, PLCD3, ZNF652, and C20orf203; headache-TSH) and six (HMGB1P45, RPL30P1, ZNF462, TMX2-CTNND1, ITPK1, SECISBP2L; headache-fT4) were significant in our gene-based analysis (p_{Fisher’s combined p-value} < 2.09 × 10⁻⁶). Our causal analysis suggested a positive causal relationship between headache and secondary hypothyroidism (p = 3.64 × 10⁻⁴). The results also suggest a positive causal relationship between hypothyroidism and headache (p = 2.45 × 10⁻³) and a negative causal relationship between hyperthyroidism and headache (p = 1.16 × 10⁻¹³). These findings suggest a strong evidence base for a genetic correlation and complex causal relationships between headache and thyroid traits. Full article

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

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7 pages, 272 KiB

Open AccessArticle

Some New Aspects of Genetic Variability in Patients with Cutaneous T-Cell Lymphoma

by Vladimír Vašků, Jan Máchal, Filip Zlámal and Anna Vašků

Genes 2022, 13(12), 2401; https://doi.org/10.3390/genes13122401 - 18 Dec 2022

Cited by 1 | Viewed by 1210

Abstract

Aim: Cutaneous T-cell lymphoma (CTCL) is a group of T-cell malignancies that develop in the skin. Though studied intensively, the etiology and pathogenesis of CTCL remain elusive. This study evaluated the survival of CTCL patients in the 1st Department of Dermatovenereology of St. [...] Read more.

Aim: Cutaneous T-cell lymphoma (CTCL) is a group of T-cell malignancies that develop in the skin. Though studied intensively, the etiology and pathogenesis of CTCL remain elusive. This study evaluated the survival of CTCL patients in the 1st Department of Dermatovenereology of St. Anne’s University Hospital Brno. It included analysis of 19 polymorphic gene variants based on their expected involvement in CTCL severity. Material and methods: 75 patients with CTCL, evaluated and treated at the 1st Department of Dermatovenereology of St. Anne´s University Hospital Brno, Faculty of Medicine, Masaryk University, were recruited for the study over the last 28 years (44 men and 31 women, average age 58 years, range 20–82 years). All patients were genotyped for 19 chosen gene polymorphisms by the conventional PCR method with restriction analysis. A multivariate Cox regression model was calculated to reveal genetic polymorphisms and other risk factors for survival. Results: The model identified MDR Ex21 2677 (rs2032582) as a significant genetic factor influencing the survival of the patients, with the T-allele playing a protective role. A multivariate stepwise Cox regression model confirmed the following as significant independent risk factors for overall survival: increased age at admission, clinical staging of the tumor, and male sex. Conclusion: We showed that the TT genotype at position 2677 of the MDR1 gene exhibited statistically significant longer survival in CTCL patients. As such, the TT genotype of MDR1 confers a significant advantage for the CTCL patients who respond to treatment. Full article

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

16 pages, 1621 KiB

Open AccessArticle

Ontological Analysis of Coronavirus Associated Human Genes at the COVID-19 Disease Portal

by Shur-Jen Wang, Kent C. Brodie, Jeffrey L. De Pons, Wendy M. Demos, Adam C. Gibson, G. Thomas Hayman, Morgan L. Hill, Mary L. Kaldunski, Logan Lamers, Stanley J. F. Laulederkind, Harika S. Nalabolu, Jyothi Thota, Ketaki Thorat, Marek A. Tutaj, Monika Tutaj, Mahima Vedi, Stacy Zacher, Jennifer R. Smith, Melinda R. Dwinell and Anne E. Kwitek

Genes 2022, 13(12), 2304; https://doi.org/10.3390/genes13122304 - 07 Dec 2022

Cited by 1 | Viewed by 1234

Abstract

The COVID-19 pandemic stemmed a parallel upsurge in the scientific literature about SARS-CoV-2 infection and its health burden. The Rat Genome Database (RGD) created a COVID-19 Disease Portal to leverage information from the scientific literature. In the COVID-19 Portal, gene-disease associations are established [...] Read more.

The COVID-19 pandemic stemmed a parallel upsurge in the scientific literature about SARS-CoV-2 infection and its health burden. The Rat Genome Database (RGD) created a COVID-19 Disease Portal to leverage information from the scientific literature. In the COVID-19 Portal, gene-disease associations are established by manual curation of PubMed literature. The portal contains data for nine ontologies related to COVID-19, an embedded enrichment analysis tool, as well as links to a toolkit. Using these information and tools, we performed analyses on the curated COVID-19 disease genes. As expected, Disease Ontology enrichment analysis showed that the COVID-19 gene set is highly enriched with coronavirus infectious disease and related diseases. However, other less related diseases were also highly enriched, such as liver and rheumatic diseases. Using the comparison heatmap tool, we found nearly 60 percent of the COVID-19 genes were associated with nervous system disease and 40 percent were associated with gastrointestinal disease. Our analysis confirms the role of the immune system in COVID-19 pathogenesis as shown by substantial enrichment of immune system related Gene Ontology terms. The information in RGD’s COVID-19 disease portal can generate new hypotheses to potentiate novel therapies and prevention of acute and long-term complications of COVID-19. Full article

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

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17 pages, 1526 KiB

Open AccessArticle

Genome-Wide DNA Methylation Profiling Solves Uncertainty in Classifying NSD1 Variants

by Marco Ferilli, Andrea Ciolfi, Lucia Pedace, Marcello Niceta, Francesca Clementina Radio, Simone Pizzi, Evelina Miele, Camilla Cappelletti, Cecilia Mancini, Tiziana Galluccio, Marco Andreani, Maria Iascone, Luigi Chiriatti, Antonio Novelli, Alessia Micalizzi, Marta Matraxia, Lucia Menale, Flavio Faletra, Paolo Prontera, Alba Pilotta, Maria Francesca Bedeschi, Rossella Capolino, Anwar Baban, Marco Seri, Corrado Mammì, Giuseppe Zampino, Maria Cristina Digilio, Bruno Dallapiccola, Manuela Priolo and Marco Tartaglia Show full author list Hide full author list

Genes 2022, 13(11), 2163; https://doi.org/10.3390/genes13112163 - 19 Nov 2022

Cited by 4 | Viewed by 1867

Abstract

Background: Inactivating NSD1 mutations causing Sotos syndrome have been previously associated with a specific genome-wide DNA methylation (DNAm) pattern. Sotos syndrome is characterized by phenotypic overlap with other overgrowth syndromes, and a definite diagnosis might not be easily reached due to the high [...] Read more.

Background: Inactivating NSD1 mutations causing Sotos syndrome have been previously associated with a specific genome-wide DNA methylation (DNAm) pattern. Sotos syndrome is characterized by phenotypic overlap with other overgrowth syndromes, and a definite diagnosis might not be easily reached due to the high prevalence of variants of unknown significance (VoUS) that are identified in patients with a suggestive phenotype. Objective: we performed microarray DNAm profiling in a set of 11 individuals with a clinical suspicion of Sotos syndrome and carrying an NSD1 VoUS or previously unreported variants to solve uncertainty in defining pathogenicity of the observed variants. The impact of the training cohort size on sensitivity and prediction confidence of the classifier was assessed. Results: The Sotos syndrome-specific DNAm signature was validated in six individuals with a clinical diagnosis of Sotos syndrome and carrying bona fide pathogenic NSD1 variants. Applying this approach to the remaining 11 individuals with NSD1 variants, we succeeded in confirming pathogenicity in eight subjects and excluding the diagnosis of Sotos syndrome in three. The sensitivity and prediction confidence of the classifier based on the different sizes of the training sets did not show substantial differences, though the overall performance was improved by using a data balancing strategy. Conclusions: The present approach solved uncertainty in cases with NDS1 VoUS, further demonstrating the clinical utility of DNAm profiling. Full article

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

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15 pages, 9604 KiB

Open AccessArticle

Genetic and Clinical Spectrum of GNE Myopathy in Russia

by Aysylu Murtazina, Sergey Nikitin, Galina Rudenskaya, Inna Sharkova, Artem Borovikov, Peter Sparber, Olga Shchagina, Alena Chukhrova, Oksana Ryzhkova, Olga Shatokhina, Anna Orlova, Vasilisa Udalova, Ilya Kanivets, Sergey Korostelev, Alexander Polyakov, Elena Dadali and Sergey Kutsev

Genes 2022, 13(11), 1991; https://doi.org/10.3390/genes13111991 - 31 Oct 2022

Cited by 3 | Viewed by 1961

Abstract

GNE myopathy (GNEM) is a rare hereditary disease, but at the same time, it is the most common distal myopathy in several countries due to a founder effect of some pathogenic variants in the GNE gene. We collected the largest cohort of patients [...] Read more.

GNE myopathy (GNEM) is a rare hereditary disease, but at the same time, it is the most common distal myopathy in several countries due to a founder effect of some pathogenic variants in the GNE gene. We collected the largest cohort of patients with GNEM from Russia and analyzed their mutational spectrum and clinical data. In our cohort, 10 novel variants were found, including 2 frameshift variants and 2 large deletions. One novel missense variant c.169_170delGCinsTT (p.(Ala57Phe)) was detected in 4 families in a homozygous state and in 3 unrelated patients in a compound heterozygous state. It was the second most frequent variant in our cohort. All families with this novel frequent variant were non-consanguineous and originated from the 3 neighboring areas in the European part of Russia. The clinical picture of the patients carrying this novel variant was typical, but the severity of clinical manifestation differed significantly. In our study, we reported two atypical cases expanding the phenotypic spectrum of GNEM. One female patient had severe quadriceps atrophy, hand joint contractures, keloid scars, and non-classical pattern on leg muscle magnetic resonance imaging, which was more similar to atypical collagenopathy rather than GNEM. Another patient initially had been observed with spinal muscular atrophy due to asymmetric atrophy of hand muscles and results of electromyography. The peculiar pattern of muscle involvement on magnetic resonance imaging consisted of pronounced changes in the posterior thigh muscle group with relatively spared muscles of the lower legs, apart from the soleus muscles. Different variants in the GNE gene were found in both atypical cases. Thus, our data expand the mutational and clinical spectrum of GNEM. Full article

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

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12 pages, 1062 KiB

Open AccessArticle

CRISPR DNA Base Editing Strategies for Treating Retinitis Pigmentosa Caused by Mutations in Rhodopsin

by Maria Kaukonen, Michelle E. McClements and Robert E. MacLaren

Genes 2022, 13(8), 1327; https://doi.org/10.3390/genes13081327 - 26 Jul 2022

Cited by 6 | Viewed by 2677

Abstract

Retinitis pigmentosa (RP) is the most common group of inherited retinal degenerations and pathogenic variants in the Rhodopsin (RHO) gene are major cause for autosomal dominant RP (adRP). Despite extensive attempts to treat RHO-associated adRP, standardized curative treatment is still [...] Read more.

Retinitis pigmentosa (RP) is the most common group of inherited retinal degenerations and pathogenic variants in the Rhodopsin (RHO) gene are major cause for autosomal dominant RP (adRP). Despite extensive attempts to treat RHO-associated adRP, standardized curative treatment is still lacking. Recently developed base editors offer an exciting opportunity to correct pathogenic single nucleotide variants and are currently able to correct all transition variants and some transversion variants. In this study, we analyzed previously reported pathogenic RHO variants (n = 247) for suitable PAM sites for currently available base editors utilizing the Streptococcus pyogenes Cas9 (SpCas9), Staphylococcus aureus Cas9 (SaCas9) or the KKH variant of SaCas9 (KKH-SaCas9) to assess DNA base editing as a treatment option for RHO-associated adRP. As a result, 55% of all the analyzed variants could, in theory, be corrected with base editors, however, PAM sites were available for only 32% of them and unwanted bystander edits were predicted for the majority of the designed guide RNAs. As a conclusion, base editing offers exciting possibilities to treat RHO-associated adRP in the future, but further research is needed to develop base editing constructs that will provide available PAM sites for more variants and that will not introduce potentially harmful bystander edits. Full article

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

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14 pages, 325 KiB

Open AccessArticle

TGF-β/VEGF-A Genetic Variants Interplay in Genetic Susceptibility to Non-Melanocytic Skin Cancer

by Letizia Scola, Maria Rita Bongiorno, Giusi Irma Forte, Anna Aiello, Giulia Accardi, Chiara Scrimali, Rossella Spina, Domenico Lio and Giuseppina Candore

Genes 2022, 13(7), 1235; https://doi.org/10.3390/genes13071235 - 13 Jul 2022

Cited by 1 | Viewed by 1808

Abstract

Differential genetically determined expression of transforming growth factor-β (TGF-β pathway and of vascular endothelial growth factor-A (VEGF-A) might modulate the molecular “milieu” involved in the etio-pathogenesis of non-melanoma skin cancer (NMSC). We have evaluated the frequency of some functionally relevant SNPs of TGF-β [...] Read more.

Differential genetically determined expression of transforming growth factor-β (TGF-β pathway and of vascular endothelial growth factor-A (VEGF-A) might modulate the molecular “milieu” involved in the etio-pathogenesis of non-melanoma skin cancer (NMSC). We have evaluated the frequency of some functionally relevant SNPs of TGF-β and VEGF-A genes in 70 NMSC patients and 161 healthy controls, typed for TGF-β1 rs1800471, TGF-β2 rs900, TGF-βR1 rs334348 and rs334349, TGF-βR2 rs4522809 and VEGF-A rs3025039 SNPs. TGF-βR2 rs1800629G allele and related genotypes were found to be associated with a possible protective role against NMSC, whereas VEGF-A rs3025039T was associated with an increased risk. To evaluate the effect of genotype combinations on NMSC susceptibility, we determined the frequencies of 31 pseudo-haplotypes due to non-random linkage among alleles of loci not lying on the same chromosome. Two pseudo-haplotypes that imply a minor allele of TGF-βR2 or minor allele of VEGF-A SNPs combined with major alleles of the other SNPs were, respectively, associated with a protective effect, and susceptibility to NMSC. In addition, a pseudo-haplotype involving minor alleles of TGF-β2 rs900, TGF-βR1 rs334348 and rs4522809 SNPs might be a susceptibility marker for NMSC. In conclusion, our data suggest that a complex interplay among the genetic polymorphisms of TGF-β, TGF-β receptors and VEGF-A genes might influence the net effect of genetic background of the patients on NMSC development. This might be relevant in the risk evaluation, diagnosis and treatment of NMSC. Full article

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

9 pages, 1415 KiB

Open AccessArticle

Novel Genetic Diagnoses in Septo-Optic Dysplasia

by Linda M. Reis, Sarah Seese, Mohit Maheshwari, Donald Basel, LuAnn Weik, Julie McCarrier, University of Washington Center for Mendelian Genomics and Elena V. Semina

Genes 2022, 13(7), 1165; https://doi.org/10.3390/genes13071165 - 28 Jun 2022

Cited by 4 | Viewed by 2070

Abstract

Septo-optic dysplasia (SOD) is a developmental phenotype characterized by midline neuroradiological anomalies, optic nerve hypoplasia, and pituitary anomalies, with a high degree of variability and additional systemic anomalies present in some cases. While disruption of several transcription factors has been identified in SOD [...] Read more.

Septo-optic dysplasia (SOD) is a developmental phenotype characterized by midline neuroradiological anomalies, optic nerve hypoplasia, and pituitary anomalies, with a high degree of variability and additional systemic anomalies present in some cases. While disruption of several transcription factors has been identified in SOD cohorts, most cases lack a genetic diagnosis, with multifactorial risk factors being thought to play a role. Exome sequencing in a cohort of families with a clinical diagnosis of SOD identified a genetic diagnosis in 3/6 families, de novo variants in SOX2, SHH, and ARID1A, and explored variants of uncertain significance in the remaining three. The outcome of this study suggests that investigation for a genetic etiology is warranted in individuals with SOD, particularly in the presence of additional syndromic anomalies and when born to older, multigravida mothers. The identification of causative variants in SHH and ARID1A further expands the phenotypic spectra associated with these genes and reveals novel pathways to explore in septo-optic dysplasia. Full article

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

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15 pages, 2156 KiB

Open AccessArticle

Mother and Daughter Carrying of the Same Pathogenic Variant in FGFR2 with Discordant Phenotype

by Filomena Lo Vecchio, Elisabetta Tabolacci, Veronica Nobile, Maria Grazia Pomponi, Roberta Pietrobono, Giovanni Neri, Simona Amenta, Ettore Candida, Cristina Grippaudo, Ettore Lo Cascio, Alessia Vita, Federica Tiberio, Alessandro Arcovito, Wanda Lattanzi, Maurizio Genuardi and Pietro Chiurazzi

Genes 2022, 13(7), 1161; https://doi.org/10.3390/genes13071161 - 27 Jun 2022

Viewed by 2011

Abstract

Craniosynostosis are a heterogeneous group of genetic conditions characterized by the premature fusion of the skull bones. The most common forms of craniosynostosis are Crouzon, Apert and Pfeiffer syndromes. They differ from each other in various additional clinical manifestations, e.g., syndactyly is typical [...] Read more.

Craniosynostosis are a heterogeneous group of genetic conditions characterized by the premature fusion of the skull bones. The most common forms of craniosynostosis are Crouzon, Apert and Pfeiffer syndromes. They differ from each other in various additional clinical manifestations, e.g., syndactyly is typical of Apert and rare in Pfeiffer syndrome. Their inheritance is autosomal dominant with incomplete penetrance and one of the main genes responsible for these syndromes is FGFR2, mapped on chromosome 10, encoding fibroblast growth factor receptor 2. We report an FGFR2 gene variant in a mother and daughter who present with different clinical features of Crouzon syndrome. The daughter is more severely affected than her mother, as also verified by a careful study of the face and oral cavity. The c.1032G>A transition in exon 8, already reported as a synonymous p.Ala344 = variant in Crouzon patients, also activates a new donor splice site leading to the loss of 51 nucleotides and the in-frame removal of 17 amino acids. We observed lower FGFR2 transcriptional and translational levels in the daughter compared to the mother and healthy controls. A preliminary functional assay and a molecular modeling added further details to explain the discordant phenotype of the two patients. Full article

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

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20 pages, 3613 KiB

Open AccessArticle

Internal Introns Promote Backsplicing to Generate Circular RNAs from Spinal Muscular Atrophy Gene

by Diou Luo, Natalia Nikolaevna Singh and Ravindra Narayan Singh

Genes 2022, 13(7), 1145; https://doi.org/10.3390/genes13071145 - 25 Jun 2022

Cited by 3 | Viewed by 2434

Abstract

Human survival motor neuron 1 (SMN1) codes for SMN, an essential housekeeping protein involved in most aspects of RNA metabolism. Deletions or mutations of SMN1 lead to spinal muscular atrophy (SMA), a devastating neurodegenerative disease linked to a high rate of [...] Read more.

Human survival motor neuron 1 (SMN1) codes for SMN, an essential housekeeping protein involved in most aspects of RNA metabolism. Deletions or mutations of SMN1 lead to spinal muscular atrophy (SMA), a devastating neurodegenerative disease linked to a high rate of infant mortality. SMN2, a near identical copy of SMN1 present in humans, cannot compensate for the loss of SMN1 due to predominant skipping of SMN2 exon 7. Restoration of SMN by splicing modulation of SMN2 exon 7 or gene replacement are currently approved therapies of SMA. Human SMN genes produce a vast repertoire of circular RNAs (circRNAs). However, the mechanism of SMN circRNA generation has not yet been examined in detail. For example, it remains unknown if forward splicing impacts backsplicing that generates circRNAs containing multiple exons. Here, we employed SMN as a model system to examine the impact of intronic sequences on the generation of circRNAs. We performed our experiments in HeLa cells transiently transfected with minigenes expressing three abundantly represented circRNAs containing two or more SMN exons. We observed an enhanced rate of circRNA generation when introns joining exons to be incorporated into circRNAs were present as compared to the intronless context. These results underscore the stimulatory effect of forward splicing in the generation of circRNAs containing multiple exons. These findings are consistent with the reported low abundance of SMN circRNAs comprised of single exons. We confirmed our findings using inducible HEK 293 cells stably expressing the SMN circRNAs. Our results support the role of the exon junction complex in the generation of the exon-only-containing circRNAs. We showed that SMN circRNAs were preferentially localized in the cytoplasm. These findings provide new insights regarding our understanding of circRNA generation and open avenues to uncover novel functions of the SMN genes. Full article

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

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19 pages, 933 KiB

Open AccessArticle

Genotype-Phenotype Correlations in Neurofibromatosis Type 1: Identification of Novel and Recurrent NF1 Gene Variants and Correlations with Neurocognitive Phenotype

by Filomena Napolitano, Milena Dell’Aquila, Chiara Terracciano, Giuseppina Franzese, Maria Teresa Gentile, Giulio Piluso, Claudia Santoro, Davide Colavito, Anna Patanè, Paolo De Blasiis, Simone Sampaolo, Simona Paladino and Mariarosa Anna Beatrice Melone

Genes 2022, 13(7), 1130; https://doi.org/10.3390/genes13071130 - 23 Jun 2022

Cited by 11 | Viewed by 4991

Abstract

Neurofibromatosis type 1 (NF1) is one of the most common genetic tumor predisposition syndrome, caused by mutations in the NF1. To date, few genotype-phenotype correlations have been discerned in NF1, due to a highly variable clinical presentation. We aimed to study the [...] Read more.

Neurofibromatosis type 1 (NF1) is one of the most common genetic tumor predisposition syndrome, caused by mutations in the NF1. To date, few genotype-phenotype correlations have been discerned in NF1, due to a highly variable clinical presentation. We aimed to study the molecular spectrum of NF1 and genotype-phenotype correlations in a monocentric study cohort of 85 NF1 patients (20 relatives, 65 sporadic cases). Clinical data were collected at the time of the mutation analysis and reviewed for accuracy in this investigation. An internal phenotypic categorization was applied. The 94% of the patients enrolled showed a severe phenotype with at least one systemic complication and a wide range of associated malignancies. Spine deformities were the most common complications in this cohort. We also reported 66 different NF1 mutations, of which 7 are novel mutations. Correlation analysis identified a slight significant inverse correlation between age at diagnosis and delayed acquisition of psychomotor skills with residual multi-domain cognitive impairment. Odds ratio with 95% confidence interval showed a higher prevalence of learning disabilities in patients carrying frameshift mutations. Overall, our results aim to offer an interesting contribution to studies on the genotype–phenotype of NF1 and in genetic management and counselling. Full article

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

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22 pages, 4240 KiB

Open AccessArticle

A Formative Study of the Implementation of Whole Genome Sequencing in Northern Ireland

by Katie Kerr, Caoimhe McKenna, Shirley Heggarty, Caitlin Bailie, Julie McMullan, Ashleen Crowe, Jill Kilner, Michael Donnelly, Saralynne Boyle, Gillian Rea, Cheryl Flanagan, Shane McKee and Amy Jayne McKnight

Genes 2022, 13(7), 1104; https://doi.org/10.3390/genes13071104 - 21 Jun 2022

Cited by 1 | Viewed by 2858

Abstract

Background: The UK 100,000 Genomes Project was a transformational research project which facilitated whole genome sequencing (WGS) diagnostics for rare diseases. We evaluated experiences of introducing WGS in Northern Ireland, providing recommendations for future projects. Methods: This formative evaluation included (1) an appraisal [...] Read more.

Background: The UK 100,000 Genomes Project was a transformational research project which facilitated whole genome sequencing (WGS) diagnostics for rare diseases. We evaluated experiences of introducing WGS in Northern Ireland, providing recommendations for future projects. Methods: This formative evaluation included (1) an appraisal of the logistics of implementing and delivering WGS, (2) a survey of participant self-reported views and experiences, (3) semi-structured interviews with healthcare staff as key informants who were involved in the delivery of WGS and (4) a workshop discussion about interprofessional collaboration with respect to molecular diagnostics. Results: We engaged with >400 participants, with detailed reflections obtained from 74 participants including patients, caregivers, key National Health Service (NHS) informants, and researchers (patient survey n = 42; semi-structured interviews n = 19; attendees of the discussion workshop n = 13). Overarching themes included the need to improve rare disease awareness, education, and support services, as well as interprofessional collaboration being central to an effective, mainstreamed molecular diagnostic service. Conclusions: Recommendations for streamlining precision medicine for patients with rare diseases include administrative improvements (e.g., streamlining of the consent process), educational improvements (e.g., rare disease training provided from undergraduate to postgraduate education alongside genomics training for non-genetic specialists) and analytical improvements (e.g., multidisciplinary collaboration and improved computational infrastructure). Full article

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

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11 pages, 2868 KiB

Open AccessArticle

Robust Prediction of Prognosis and Immunotherapy Response for Bladder Cancer through Machine Learning Algorithm

by Shanshan Hu, Shengying Gu, Shuowen Wang, Chendong Qi, Chenyang Shi, Fengdan Qian and Guorong Fan

Genes 2022, 13(6), 1073; https://doi.org/10.3390/genes13061073 - 16 Jun 2022

Cited by 1 | Viewed by 2190

Abstract

The important roles of machine learning and ferroptosis in bladder cancer (BCa) are still poorly understood. In this study, a comprehensive analysis of 19 ferroptosis-related genes (FRGs) was performed in 1322 patients with BCa from four independent patient cohorts and a pan-cancer cohort [...] Read more.

The important roles of machine learning and ferroptosis in bladder cancer (BCa) are still poorly understood. In this study, a comprehensive analysis of 19 ferroptosis-related genes (FRGs) was performed in 1322 patients with BCa from four independent patient cohorts and a pan-cancer cohort of 9824 patients. Twelve FRGs were selected through machine learning algorithm to construct the prognosis model. Significantly differential survival outcomes (hazard ratio (HR) = 2.09, 95% confidence interval (CI): 1.55–2.82, p < 0.0001) were observed between patients with high and low ferroptosis scores in the TCGA cohort, which was also verified in the E-MTAB-4321 cohort (HR = 4.71, 95% CI: 1.58–14.03, p < 0.0001), the GSE31684 cohort (HR = 1.76, 95% CI: 1.08–2.87, p = 0.02), and the pan-cancer cohort (HR = 1.15, 95% CI: 1.07–1.24, p < 0.0001). Tumor immunity-related pathways, including the IL-17 signaling pathway and JAK-STAT signaling pathway, were found to be associated with the ferroptosis score in BCa through a functional enrichment analysis. Further verification in the IMvigor210 cohort revealed the BCa patients with high ferroptosis scores tended to have worse survival outcome after receiving tumor immunotherapy. Significantly different ferroptosis scores could also be found between BCa patients with different reactions to treatment with immune checkpoint inhibitors. Full article

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

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12 pages, 2118 KiB

Open AccessArticle

High Resolution Analysis of DMPK Hypermethylation and Repeat Interruptions in Myotonic Dystrophy Type 1

by Astrid Rasmussen, Mathis Hildonen, John Vissing, Morten Duno, Zeynep Tümer and Ulf Birkedal

Genes 2022, 13(6), 970; https://doi.org/10.3390/genes13060970 - 28 May 2022

Cited by 9 | Viewed by 2537

Abstract

Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular disorder caused by the expansion of a CTG repeat in the 3′-UTR of DMPK, which is transcribed to a toxic gain-of-function RNA that affects splicing of a range of genes. The expanded repeat [...] Read more.

Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular disorder caused by the expansion of a CTG repeat in the 3′-UTR of DMPK, which is transcribed to a toxic gain-of-function RNA that affects splicing of a range of genes. The expanded repeat is unstable in both germline and somatic cells. The variable age at disease onset and severity of symptoms have been linked to the inherited CTG repeat length, non-CTG interruptions, and methylation levels flanking the repeat. In general, the genetic biomarkers are investigated separately with specific methods, making it tedious to obtain an overall characterisation of the repeat for a given individual. In the present study, we employed Oxford nanopore sequencing in a pilot study to simultaneously determine the repeat lengths, investigate the presence and nature of repeat interruptions, and quantify methylation levels in the regions flanking the CTG-repeats in four patients with DM1. We determined the repeat lengths, and in three patients, we observed interruptions which were not detected using repeat-primed PCR. Interruptions may thus be more common than previously anticipated and should be investigated in larger cohorts. Allele-specific analyses enabled characterisation of aberrant methylation levels specific to the expanded allele, which greatly increased the sensitivity and resolved cases where the methylation levels were ambiguous. Full article

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

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24 pages, 332 KiB

Open AccessArticle

The Skin We Live in: Pigmentation Traits and Tanning Behaviour in British Young Adults, an Observational and Genetically-Informed Study

by Carolina Bonilla and Cilia Mejia-Lancheros

Genes 2022, 13(5), 896; https://doi.org/10.3390/genes13050896 - 17 May 2022

Cited by 1 | Viewed by 2048

Abstract

Skin cancer incidence has been increasing worldwide, representing a particularly high burden for populations of European ancestry. Outdoor and indoor tanning using ultraviolet (UV) radiation devices are major risk factors for skin cancer. While tanning behaviours can be modified by targeted interventions to [...] Read more.

Skin cancer incidence has been increasing worldwide, representing a particularly high burden for populations of European ancestry. Outdoor and indoor tanning using ultraviolet (UV) radiation devices are major risk factors for skin cancer. While tanning behaviours can be modified by targeted interventions to reduce skin cancer rates, there is insufficient evidence on the motivations for tanning preferences and their relationship with pigmentation phenotypes. The present observational and genetically-informed study investigates motives for tanning and the role that pigmentation phenotypes play on outdoor and indoor tanning behaviour in British young adults. This study included 3722 participants from the Avon Longitudinal Study of Parents and Children in South West England, with data on pigmentation features, tanning ability and preferences, and SNP genotypes. Liking to tan and outdoor tanning were strongly influenced by pigmentary traits and tanning ability. However, the association of these phenotypes with UV indoor tanning was weaker. Our results provide evidence to support the implementation of skin cancer preventative interventions that consider individual biological characteristics and motives for undergoing outdoor and indoor tanning. Full article

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

11 pages, 625 KiB

Open AccessArticle

Polymorphism rs3742330 in microRNA Biogenesis Gene DICER1 Is Associated with Pseudoexfoliation Glaucoma in Saudi Cohort

by Altaf A. Kondkar, Taif A. Azad, Tahira Sultan, Rakesh Radhakrishnan, Essam A. Osman, Faisal A. Almobarak, Glenn P. Lobo and Saleh A. Al-Obeidan

Genes 2022, 13(3), 489; https://doi.org/10.3390/genes13030489 - 10 Mar 2022

Cited by 3 | Viewed by 2044

Abstract

We investigated the association between DICER1 (rs3742330) and DROSHA (rs10719) polymorphisms and pseudoexfoliation glaucoma (PXG) and related clinical phenotypes in a Saudi cohort. In a retrospective case-control study, TaqMan real-time, PCR-based genotyping was performed in 340 participants with 246 controls and 94 PXG [...] Read more.

We investigated the association between DICER1 (rs3742330) and DROSHA (rs10719) polymorphisms and pseudoexfoliation glaucoma (PXG) and related clinical phenotypes in a Saudi cohort. In a retrospective case-control study, TaqMan real-time, PCR-based genotyping was performed in 340 participants with 246 controls and 94 PXG cases. The minor (G) allele frequency of rs3742330 in PXG (0.03) was significantly different from that in the controls (0.08) and protective against PXG (odds ratio (OR) = 0.38, 95% confidence interval (CI) = 0.16–0.92), p = 0.017). Similarly, the rs3742330 genotypes showed a significant protective association with PXG in dominant (p = 0.019, OR = 0.38, 95% CI = 0.15–0.92), over-dominant (p = 0.024, OR = 0.39, 95% CI = 0.16–0.95), and log-additive models (p = 0.017, OR = 0.38, 95% CI = 0.16–0.92). However, none remained significant after an adjustment for age, sex, and multiple testing. Rs10719 in DROSHA did not show any significant allelic or genotype association with PXG. However, a protective effect of the GA haplotype in DICER1 and DROSHA and PXG (p = 0.034) was observed. Both polymorphisms showed no significant effect on intraocular pressure and the cup–disk ratio. In conclusion, we report a significant genetic association between variant rs3742330 in DICER1, a gene involved in miRNA biogenesis, and PXG. Further investigation in a larger group of patients of different ethnicities and functional studies are warranted to replicate and validate its potential role in PXG. Full article

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

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Review

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11 pages, 579 KiB

Open AccessReview

The PPARGC1A Is the Gene Responsible for Thrifty Metabolism Related Metabolic Diseases: A Scoping Review

by Riandini Aisyah, Ahmad Hamim Sadewa, Suryono Yudha Patria and Abdul Wahab

Genes 2022, 13(10), 1894; https://doi.org/10.3390/genes13101894 - 18 Oct 2022

Cited by 1 | Viewed by 2252

Abstract

The “thrifty genotype” hypothesis has thus far described the relationship between specific genes and the population’s resilience to food scarcity circumstances, but its link to the widespread prevalence of genetic diseases and metabolic syndrome has not been adequately mapped. The purpose of the [...] Read more.

The “thrifty genotype” hypothesis has thus far described the relationship between specific genes and the population’s resilience to food scarcity circumstances, but its link to the widespread prevalence of genetic diseases and metabolic syndrome has not been adequately mapped. The purpose of the study was to discover genes responsible for thrifty metabolism. A systematic search with keywords was performed for relevant titles. This study used the article’s database published by Pubmed, Proquest, and EBSCO from January, 2009 to September, 2022. Out of 418 papers screened for eligibility, the final evaluation determined that five studies should be included in the analysis. Results indicated that PPARGC1A Gly482Ser led to high BMI in the Tongans population but was unrelated to the onset of type 2 diabetes mellitus, but this was not the case in the Maori population. Significantly differing frequencies of PPAR C1431T and Pro12Ala gene polymorphisms were observed in the Iranian population. GWAS identification of additional genes in Asian and European populations did not produce consistent findings. As a summary, PPARGC1A Gly482Ser addresses as the gene responsible for thrifty metabolism in the Pacific population although some studies show inconsistent results. Full article

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

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18 pages, 803 KiB

Open AccessFeature PaperReview

From Genotype to Phenotype—A Review of Kabuki Syndrome

by Kelly K. Barry, Michaelangelo Tsaparlis, Deborah Hoffman, Deborah Hartman, Margaret P. Adam, Christina Hung and Olaf A. Bodamer

Genes 2022, 13(10), 1761; https://doi.org/10.3390/genes13101761 - 29 Sep 2022

Cited by 16 | Viewed by 7573

Abstract

Kabuki syndrome (KS) is a rare neuro-developmental disorder caused by variants in genes of histone modification, including KMT2D and KDM6A. This review assesses our current understanding of KS, which was originally named Niikawa–Kuroki syndrome, and aims to guide surveillance and medical care [...] Read more.

Kabuki syndrome (KS) is a rare neuro-developmental disorder caused by variants in genes of histone modification, including KMT2D and KDM6A. This review assesses our current understanding of KS, which was originally named Niikawa–Kuroki syndrome, and aims to guide surveillance and medical care of affected individuals as well as identify gaps in knowledge and unmet patient needs. Ovid MEDLINE and EMBASE databases were searched from 1981 to 2021 to identify reports related to genotype and systems-based phenotype characterization of KS. A total of 2418 articles were retrieved, and 152 were included in this review, representing a total of 1369 individuals with KS. Genotype, phenotype, and the developmental and behavioral profile of KS are reviewed. There is a continuous clinical phenotype spectrum associated with KS with notable variability between affected individuals and an emerging genotype–phenotype correlation. The observed clinical variability may be attributable to differences in genotypes and/or unknown genetic and epigenetic factors. Clinical management is symptom oriented, fragmented, and lacks established clinical care standards. Additional research should focus on enhancing understanding of the burden of illness, the impact on quality of life, the adult phenotype, life expectancy and development of standard-of-care guidelines. Full article

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

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25 pages, 1139 KiB

Open AccessReview

The Multi-Omic Landscape of Primary Breast Tumors and Their Metastases: Expanding the Efficacy of Actionable Therapeutic Targets

by Guang Yang, Tao Lu, Daniel J. Weisenberger and Gangning Liang

Genes 2022, 13(9), 1555; https://doi.org/10.3390/genes13091555 - 29 Aug 2022

Cited by 2 | Viewed by 2463

Abstract

Breast cancer (BC) mortality is almost exclusively due to metastasis, which is the least understood aspect of cancer biology and represents a significant clinical challenge. Although we have witnessed tremendous advancements in the treatment for metastatic breast cancer (mBC), treatment resistance inevitably occurs [...] Read more.

Breast cancer (BC) mortality is almost exclusively due to metastasis, which is the least understood aspect of cancer biology and represents a significant clinical challenge. Although we have witnessed tremendous advancements in the treatment for metastatic breast cancer (mBC), treatment resistance inevitably occurs in most patients. Recently, efforts in characterizing mBC revealed distinctive genomic, epigenomic and transcriptomic (multi-omic) landscapes to that of the primary tumor. Understanding of the molecular underpinnings of mBC is key to understanding resistance to therapy and the development of novel treatment options. This review summarizes the differential molecular landscapes of BC and mBC, provides insights into the genomic heterogeneity of mBC and highlights the therapeutically relevant, multi-omic features that may serve as novel therapeutic targets for mBC patients. Full article

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

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14 pages, 628 KiB

Open AccessReview

Relationship between Nutrition, Lifestyle, and Neurodegenerative Disease: Lessons from ADH1B, CYP1A2 and MTHFR

by Shila Barati, Carlo Fabrizio, Claudia Strafella, Raffaella Cascella, Valerio Caputo, Domenica Megalizzi, Cristina Peconi, Julia Mela, Luca Colantoni, Carlo Caltagirone, Andrea Termine and Emiliano Giardina

Genes 2022, 13(8), 1498; https://doi.org/10.3390/genes13081498 - 22 Aug 2022

Cited by 3 | Viewed by 3737

Abstract

In the present review, the main features involved in the susceptibility and progression of neurodegenerative disorders (NDDs) have been discussed, with the purpose of highlighting their potential application for promoting the management and treatment of patients with NDDs. In particular, the impact of [...] Read more.

In the present review, the main features involved in the susceptibility and progression of neurodegenerative disorders (NDDs) have been discussed, with the purpose of highlighting their potential application for promoting the management and treatment of patients with NDDs. In particular, the impact of genetic and epigenetic factors, nutrients, and lifestyle will be presented, with particular emphasis on Alzheimer’s disease (AD) and Parkinson’s disease (PD). Metabolism, dietary habits, physical exercise and microbiota are part of a complex network that is crucial for brain function and preservation. This complex equilibrium can be disrupted by genetic, epigenetic, and environmental factors causing perturbations in central nervous system homeostasis, contributing thereby to neuroinflammation and neurodegeneration. Diet and physical activity can directly act on epigenetic modifications, which, in turn, alter the expression of specific genes involved in NDDs onset and progression. On this subject, the introduction of nutrigenomics shed light on the main molecular players involved in the modulation of health and disease status. In particular, the review presents data concerning the impact of ADH1B, CYP1A2, and MTHFR on the susceptibility and progression of NDDs (especially AD and PD) and how they may be exploited for developing precision medicine strategies for the disease treatment and management. Full article

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

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14 pages, 2292 KiB

Open AccessReview

Hypothesis: Why Different Types of SDH Gene Variants Cause Divergent Tumor Phenotypes

by Jean-Pierre Bayley and Peter Devilee

Genes 2022, 13(6), 1025; https://doi.org/10.3390/genes13061025 - 07 Jun 2022

Cited by 3 | Viewed by 2559

Abstract

Despite two decades of paraganglioma-pheochromocytoma research, the fundamental question of how the different succinate dehydrogenase (SDH)-related tumor phenotypes are initiated has remained unanswered. Here, we discuss two possible scenarios by which missense (hypomorphic alleles) or truncating (null alleles) SDH gene variants determine clinical [...] Read more.

Despite two decades of paraganglioma-pheochromocytoma research, the fundamental question of how the different succinate dehydrogenase (SDH)-related tumor phenotypes are initiated has remained unanswered. Here, we discuss two possible scenarios by which missense (hypomorphic alleles) or truncating (null alleles) SDH gene variants determine clinical phenotype. Dysfunctional SDH is a major source of reactive oxygen species (ROS) but ROS are inhibited by rising succinate levels. In scenario 1, we propose that SDH missense variants disrupt electron flow, causing elevated ROS levels that are toxic in sympathetic PPGL precursor cells but well controlled in oxygen-sensing parasympathetic paraganglion cells. We also suggest that SDHAF2 variants, solely associated with HNPGL, may cause the reversal of succinate dehydrogenase to fumarate reductase, producing very high ROS levels. In scenario 2, we propose a modified succinate threshold model of tumor initiation. Truncating SDH variants cause high succinate accumulation and likely initiate tumorigenesis via disruption of 2-oxoglutarate-dependent enzymes in both PPGL and HNPGL precursor tissues. We propose that missense variants (including SDHAF2) cause lower succinate accumulation and thus initiate tumorigenesis only in very metabolically active tissues such as parasympathetic paraganglia, which naturally show very high levels of succinate. Full article

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

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18 pages, 1297 KiB

Open AccessEditor’s ChoiceReview

Multisystem Proteinopathy Due to VCP Mutations: A Review of Clinical Heterogeneity and Genetic Diagnosis

by Gerald Pfeffer, Grace Lee, Carly S. Pontifex, Roberto D. Fanganiello, Allison Peck, Conrad C. Weihl and Virginia Kimonis

Genes 2022, 13(6), 963; https://doi.org/10.3390/genes13060963 - 27 May 2022

Cited by 23 | Viewed by 4216

Abstract

In this work, we review clinical features and genetic diagnosis of diseases caused by mutations in the gene encoding valosin-containing protein (VCP/p97), the functionally diverse AAA-ATPase. VCP is crucial to a multitude of cellular functions including protein quality control, stress granule formation and [...] Read more.

In this work, we review clinical features and genetic diagnosis of diseases caused by mutations in the gene encoding valosin-containing protein (VCP/p97), the functionally diverse AAA-ATPase. VCP is crucial to a multitude of cellular functions including protein quality control, stress granule formation and clearance, and genomic integrity functions, among others. Pathogenic mutations in VCP cause multisystem proteinopathy (VCP-MSP), an autosomal dominant, adult-onset disorder causing dysfunction in several tissue types. It can result in complex neurodegenerative conditions including inclusion body myopathy, frontotemporal dementia, amyotrophic lateral sclerosis, or combinations of these. There is also an association with other neurodegenerative phenotypes such as Alzheimer-type dementia and Parkinsonism. Non-neurological presentations include Paget disease of bone and may also include cardiac dysfunction. We provide a detailed discussion of genotype-phenotype correlations, recommendations for genetic diagnosis, and genetic counselling implications of VCP-MSP. Full article

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

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33 pages, 657 KiB

Open AccessReview

by Md Rafiqul Islam and Dale R. Nyholt

Genes 2022, 13(5), 730; https://doi.org/10.3390/genes13050730 - 22 Apr 2022

Cited by 5 | Viewed by 5564

Abstract

Migraine and glucose-related (glycaemic) traits (fasting glucose, fasting insulin, and type 2 diabetes) are common and complex comorbid disorders that cause major economic and social burdens on patients and their families. Studies on the relationship between migraine and glucose-related traits have yielded inconsistent [...] Read more.

Migraine and glucose-related (glycaemic) traits (fasting glucose, fasting insulin, and type 2 diabetes) are common and complex comorbid disorders that cause major economic and social burdens on patients and their families. Studies on the relationship between migraine and glucose-related traits have yielded inconsistent results. The purpose of this review is to synthesise and discuss the information from the available literature on the relationship between fasting glucose, fasting insulin, and type 2 diabetes (T2D) with migraine. Publications on migraine and fasting glucose, migraine and fasting insulin, and migraine and T2D were identified from a PubMed and Google Scholar database search and reviewed for this article. Multiple publications have suggested that the comorbidity of migraine and glucose-related traits may have a similar complex pathogenic mechanism, including impaired glucose homeostasis, insulin resistance, reduced cerebrovascular reactivity, abnormal brain metabolism, shared genetic factors, neurotransmitters, and sex hormones. Furthermore, several studies have found a bi-directional link between migraine with insulin resistance and T2D. There is strong evidence for a biological association between migraine headache and glucose-related traits, and burgeoning evidence for shared genetic influences. Therefore, genetic research into these comorbid traits has the potential to identify new biomarkers and therapeutic targets and provide biological insight into their relationships. We encourage healthcare professionals to consider the co-occurrence of migraine with glucose-related traits in the evaluation and treatment of their patients. Full article

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

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27 pages, 478 KiB

Open AccessReview

Electrophysiological and Behavioral Evidence for Hyper- and Hyposensitivity in Rare Genetic Syndromes Associated with Autism

by Anastasia Neklyudova, Kirill Smirnov, Anna Rebreikina, Olga Martynova and Olga Sysoeva

Genes 2022, 13(4), 671; https://doi.org/10.3390/genes13040671 - 11 Apr 2022

Cited by 10 | Viewed by 4529

Abstract

Our study reviewed abnormalities in spontaneous, as well as event-related, brain activity in syndromes with a known genetic underpinning that are associated with autistic symptomatology. Based on behavioral and neurophysiological evidence, we tentatively subdivided the syndromes on primarily hyper-sensitive (Fragile X, Angelman) and [...] Read more.

Our study reviewed abnormalities in spontaneous, as well as event-related, brain activity in syndromes with a known genetic underpinning that are associated with autistic symptomatology. Based on behavioral and neurophysiological evidence, we tentatively subdivided the syndromes on primarily hyper-sensitive (Fragile X, Angelman) and hypo-sensitive (Phelan–McDermid, Rett, Tuberous Sclerosis, Neurofibromatosis 1), pointing to the way of segregation of heterogeneous idiopathic ASD, that includes both hyper-sensitive and hypo-sensitive individuals. This segmentation links abnormalities in different genes, such as FMR1, UBE3A, GABRB3, GABRA5, GABRG3, SHANK3, MECP2, TSC1, TSC2, and NF1, that are causative to the above-mentioned syndromes and associated with synaptic transmission and cell growth, as well as with translational and transcriptional regulation and with sensory sensitivity. Excitation/inhibition imbalance related to GABAergic signaling, and the interplay of tonic and phasic inhibition in different brain regions might underlie this relationship. However, more research is needed. As most genetic syndromes are very rare, future investigations in this field will benefit from multi-site collaboration with a common protocol for electrophysiological and event-related potential (EEG/ERP) research that should include an investigation into all modalities and stages of sensory processing, as well as potential biomarkers of GABAergic signaling (such as 40-Hz ASSR). Full article

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

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13 pages, 304 KiB

Open AccessReview

Aspirin Colorectal Cancer Prevention in Lynch Syndrome: Recommendations in the Era of Precision Medicine

by Davide Serrano, Paola Patrignani, Vittoria Stigliano, Daniela Turchetti, Stefania Sciallero, Franco Roviello, Alessandro D’Arpino, Ignazio Grattagliano, Salvo Testa, Cristina Oliani, Lucio Bertario and Bernardo Bonanni

Genes 2022, 13(3), 460; https://doi.org/10.3390/genes13030460 - 03 Mar 2022

Cited by 7 | Viewed by 3361

Abstract

Cancer prevention in the era of precision medicine has to consider integrated therapeutic approaches. Therapeutic cancer prevention should be offered to selected cohorts with increased cancer risk. Undoubtedly, carriers of hereditary cancer syndromes have a well-defined high cancer risk. Lynch Syndrome is one [...] Read more.

Cancer prevention in the era of precision medicine has to consider integrated therapeutic approaches. Therapeutic cancer prevention should be offered to selected cohorts with increased cancer risk. Undoubtedly, carriers of hereditary cancer syndromes have a well-defined high cancer risk. Lynch Syndrome is one of the most frequent hereditary syndromes; it is mainly associated with colorectal cancer (CRC). Nonsteroidal anti-inflammatory drugs and, in particular, aspirin use, has been associated with reduced CRC risk in several studies, initially with contradictory results; however, longer follow-up confirmed a reduced CRC incidence and mortality. The CAPP2 study recruited 861 Lynch syndrome participants randomly assigned to 600 mg of aspirin versus placebo. Like sporadic CRCs, a significant CRC risk reduction was seen after an extended follow-up, with a median treatment time that was relatively short (2 years). The ongoing CAPP3 will address whether lower doses are equally effective. Based on pharmacology and clinical data on sporadic CRCs, the preventive effect should also be obtained with low-dose aspirin. The leading international guidelines suggest discussing with Lynch syndrome carriers the possibility of using low-dose aspirin for CRC prevention. We aim systematically promote this intervention with all Lynch syndrome carriers. Full article

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

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Other

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10 pages, 14946 KiB

Open AccessBrief Report

Involvement of Mitochondrial Dysfunction in FOXG1 Syndrome

by Victoria A. Bjerregaard, Amanda M. Levy, Mille S. Batz, Ravina Salehi, Mathis Hildonen, Trine B. Hammer, Rikke S. Møller, Claus Desler and Zeynep Tümer

Genes 2023, 14(2), 246; https://doi.org/10.3390/genes14020246 - 17 Jan 2023

Viewed by 1756

Abstract

FOXG1 (Forkhead box g1) syndrome is a neurodevelopmental disorder caused by a defective transcription factor, FOXG1, important for normal brain development and function. As FOXG1 syndrome and mitochondrial disorders have shared symptoms and FOXG1 regulates mitochondrial function, we investigated whether defective FOXG1 leads [...] Read more.

FOXG1 (Forkhead box g1) syndrome is a neurodevelopmental disorder caused by a defective transcription factor, FOXG1, important for normal brain development and function. As FOXG1 syndrome and mitochondrial disorders have shared symptoms and FOXG1 regulates mitochondrial function, we investigated whether defective FOXG1 leads to mitochondrial dysfunction in five individuals with FOXG1 variants compared to controls (n = 6). We observed a significant decrease in mitochondrial content and adenosine triphosphate (ATP) levels and morphological changes in mitochondrial network in the fibroblasts of affected individuals, indicating involvement of mitochondrial dysfunction in FOXG1 syndrome pathogenesis. Further investigations are warranted to elucidate how FOXG1 deficiency impairs mitochondrial homeostasis. Full article

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

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9 pages, 1241 KiB

Open AccessBrief Report

Distinct Roles of Histone Lysine Demethylases and Methyltransferases in Developmental Eye Disease

by Linda M. Reis, Huban Atilla, Peter Kannu, Adele Schneider, Samuel Thompson, Tanya Bardakjian and Elena V. Semina

Genes 2023, 14(1), 216; https://doi.org/10.3390/genes14010216 - 14 Jan 2023

Cited by 1 | Viewed by 1985

Abstract

Histone lysine methyltransferase and demethylase enzymes play a central role in chromatin organization and gene expression through the dynamic regulation of histone lysine methylation. Consistent with this, genes encoding for histone lysine methyltransferases (KMTs) and demethylases (KDMs) are involved in complex human syndromes, [...] Read more.

Histone lysine methyltransferase and demethylase enzymes play a central role in chromatin organization and gene expression through the dynamic regulation of histone lysine methylation. Consistent with this, genes encoding for histone lysine methyltransferases (KMTs) and demethylases (KDMs) are involved in complex human syndromes, termed congenital regulopathies. In this report, we present several lines of evidence for the involvement of these genes in developmental ocular phenotypes, suggesting that individuals with structural eye defects, especially when accompanied by craniofacial, neurodevelopmental and growth abnormalities, should be examined for possible variants in these genes. We identified nine heterozygous damaging genetic variants in KMT2D (5) and four other histone lysine methyltransferases/demethylases (KMT2C, SETD1A/KMT2F, KDM6A and KDM5C) in unrelated families affected with developmental eye disease, such as Peters anomaly, sclerocornea, Axenfeld-Rieger spectrum, microphthalmia and coloboma. Two families were clinically diagnosed with Axenfeld-Rieger syndrome and two were diagnosed with Peters plus-like syndrome; others received no specific diagnosis prior to genetic testing. All nine alleles were novel and five of them occurred de novo; five variants resulted in premature truncation, three were missense changes and one was an in-frame deletion/insertion; and seven variants were categorized as pathogenic or likely pathogenic and two were variants of uncertain significance. This study expands the phenotypic spectra associated with KMT and KDM factors and highlights the importance of genetic testing for correct clinical diagnosis. Full article

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

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