Research

28 pages, 9517 KiB

Open AccessArticle

Pacing Dynamics Determines the Arrhythmogenic Mechanism of the CPVT2-Causing CASQ2^G112+5X Mutation in a Guinea Pig Ventricular Myocyte Computational Model

by Roshan Paudel, Mohsin Saleet Jafri and Aman Ullah

Genes 2023, 14(1), 23; https://doi.org/10.3390/genes14010023 - 22 Dec 2022

Cited by 3 | Viewed by 1636

Abstract

Calsequestrin Type 2 (CASQ2) is a high-capacity, low-affinity, Ca²⁺-binding protein expressed in the sarcoplasmic reticulum (SR) of the cardiac myocyte. Mutations in CASQ2 have been linked to the arrhythmia catecholaminergic polymorphic ventricular tachycardia (CPVT2) that occurs with acute emotional stress or [...] Read more.

Calsequestrin Type 2 (CASQ2) is a high-capacity, low-affinity, Ca²⁺-binding protein expressed in the sarcoplasmic reticulum (SR) of the cardiac myocyte. Mutations in CASQ2 have been linked to the arrhythmia catecholaminergic polymorphic ventricular tachycardia (CPVT2) that occurs with acute emotional stress or exercise can result in sudden cardiac death (SCD). CASQ2^G112+5X is a 16 bp (339–354) deletion CASQ2 mutation that prevents the protein expression due to premature stop codon. Understanding the subcellular mechanisms of CPVT2 is experimentally challenging because the occurrence of arrhythmia is rare. To obtain an insight into the characteristics of this rare disease, simulation studies using a local control stochastic computational model of the Guinea pig ventricular myocyte investigated how the mutant CASQ2s may be responsible for the development of an arrhythmogenic episode under the condition of β-adrenergic stimulation or in the slowing of heart rate afterward once β-adrenergic stimulation ceases. Adjustment of the computational model parameters based upon recent experiments explore the functional changes caused by the CASQ2 mutation. In the simulation studies under rapid pacing (6 Hz), electromechanically concordant cellular alternans appeared under β-adrenergic stimulation in the CPVT mutant but not in the wild-type nor in the non-β-stimulated mutant. Similarly, the simulations of accelerating pacing from slow to rapid and back to the slow pacing did not display alternans but did generate early afterdepolarizations (EADs) during the period of second slow pacing subsequent acceleration of rapid pacing. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

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15 pages, 2237 KiB

Open AccessArticle

Racial Disparities in Methylation of NRF1, FTO, and LEPR Gene in Childhood Obesity

by Priyadarshni Patel, Vaithinathan Selvaraju, Jeganathan Ramesh Babu, Xu Wang and Thangiah Geetha

Genes 2022, 13(11), 2030; https://doi.org/10.3390/genes13112030 - 04 Nov 2022

Cited by 2 | Viewed by 1539

Abstract

Childhood obesity has affected the health of millions of children around the world despite vigorous efforts by health experts. The obesity epidemic in the United States has disproportionately afflicted certain racial and ethnic minority groups. African American children are more likely than other [...] Read more.

Childhood obesity has affected the health of millions of children around the world despite vigorous efforts by health experts. The obesity epidemic in the United States has disproportionately afflicted certain racial and ethnic minority groups. African American children are more likely than other children to have obesity-related risk factors such as hyperlipidemia, diabetes, cardiovascular disease, and coronavirus disease (COVID-19). For the reduction in obesity-related health inequalities to be successful, it is essential to identify the variables affecting various groups. A notable advancement in epigenetic biology has been made over the past decade. Epigenetic changes like DNA methylation impact on many genes associated with obesity. Here, we evaluated the DNA methylation levels of the genes NRF1, FTO, and LEPR from the saliva of children using real-time quantitative PCR-based multiplex MethyLight technology. ALU was used as a reference gene, and the Percent of Methylated Reference (PMR) was calculated for each sample. European American children showed a significant increase in PMR of NRF1 and FTO in overweight/obese participants compared to normal weight, but not in African American children. After adjusting for maternal education and annual family income by regression analysis, the PMR of NRF1 and FTO was significantly associated with BMI z-score only in European American children. While for the gene LEPR, African American children had higher methylation in normal weight participants as compared to overweight/obese and no methylation difference in European American children. The PMR of LEPR was significantly negative associated with the obesity measures only in African American children. These findings contribute to a race-specific link between NRF1, FTO, and LEPR gene methylation and childhood obesity. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

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15 pages, 471 KiB

Open AccessArticle

Epigenetic and Proteomic Biomarkers of Elevated Alcohol Use Predict Epigenetic Aging and Cell-Type variation Better Than Self-Report

by Steven R. H. Beach, Mei Ling Ong, Frederick X. Gibbons, Meg Gerrard, Man-Kit Lei, Kelsey Dawes and Robert A. Philibert

Genes 2022, 13(10), 1888; https://doi.org/10.3390/genes13101888 - 18 Oct 2022

Cited by 2 | Viewed by 1625

Abstract

Excessive alcohol consumption (EAC) has a generally accepted effect on morbidity and mortality, outcomes thought to be reflected in measures of epigenetic aging (EA). As the association of self-reported EAC with EA has not been consistent with these expectations, underscoring the need for [...] Read more.

Excessive alcohol consumption (EAC) has a generally accepted effect on morbidity and mortality, outcomes thought to be reflected in measures of epigenetic aging (EA). As the association of self-reported EAC with EA has not been consistent with these expectations, underscoring the need for readily employable non-self-report tools for accurately assessing and monitoring the contribution of EAC to accelerated EA, newly developed alcohol consumption DNA methylation indices, such as the Alcohol T Score (ATS) and Methyl DetectR (MDR), may be helpful. To test that hypothesis, we used these new indices along with the carbohydrate deficient transferrin (CDT), concurrent as well as past self-reports of EAC, and well-established measures of cigarette smoking to examine the relationship of EAC to both accelerated EA and immune cell counts in a cohort of 437 young Black American adults. We found that MDR, CDT, and ATS were intercorrelated, even after controlling for gender and cotinine effects. Correlations between EA and self-reported EAC were low or non-significant, replicating prior research, whereas correlations with non-self-report indices were significant and more substantial. Comparing non-self-report indices showed that the ATS predicted more than four times as much variance in EA, CDT4 cells and B-cells as for both the MDR and CDT, and better predicted indices of accelerated EA. We conclude that each of the non-self-report indices have differing predictive capacities with respect to key alcohol-related health outcomes, and that the ATS may be particularly useful for clinicians seeking to understand and prevent accelerated EA. The results also underscore the likelihood of substantial underestimates of problematic use when self-report is used and a reduction in correlations with EA and variance in cell-types. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

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10 pages, 2377 KiB

Open AccessArticle

A Splice Variant of the MYH7 Gene Is Causative in a Family with Isolated Left Ventricular Noncompaction Cardiomyopathy

by Roman P. Myasnikov, Olga V. Kulikova, Alexey N. Meshkov, Anna A. Bukaeva, Anna V. Kiseleva, Alexandra I. Ershova, Anna V. Petukhova, Mikhail G. Divashuk, Evgenia D. Zotova, Evgeniia A. Sotnikova, Alexandra A. Abisheva, Alisa V. Muraveva, Sergey N. Koretskiy, Sergey V. Popov, Marina V. Utkina, Ekaterina A. Snigir, Sergey I. Mitrofanov, Ksenia D. Konureeva, Elena A. Mershina, Valentin E. Sinitsyn, Sergey M. Yudin and Oxana M. Drapkina Show full author list Hide full author list

Genes 2022, 13(10), 1750; https://doi.org/10.3390/genes13101750 - 28 Sep 2022

Cited by 3 | Viewed by 1929

Abstract

Variants of the MYH7 gene have been associated with a number of primary cardiac conditions, including left ventricular noncompaction cardiomyopathy (LVNC). Most cases of MYH7-related diseases are associated with such variant types as missense substitutions and in-frame indels. Thus, truncating variants in [...] Read more.

Variants of the MYH7 gene have been associated with a number of primary cardiac conditions, including left ventricular noncompaction cardiomyopathy (LVNC). Most cases of MYH7-related diseases are associated with such variant types as missense substitutions and in-frame indels. Thus, truncating variants in MYH7 (MYH7tv) and associated mechanism of haploinsufficiency are usually considered not pathogenic in these disorders. However, recent large-scale studies demonstrated evidence of the significance of MYH7tv for LVNC and gave rise to an assumption that haploinsufficiency may be the causal mechanism for LVNC. In this article, we present a family with isolated LVNC and a heterozygous splice variant of the MYH7 gene, analyze possible consequences of this variant and conclude that not all variants that are predicted truncating really act through haploinsufficiency. This study can highlight the importance of a precise assessment of MYH7 splicing variants and their participation in the development of LVNC. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

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13 pages, 840 KiB

Open AccessArticle

Association of the ACTN3 rs1815739 Polymorphism with Physical Performance and Injury Incidence in Professional Women Football Players

by Juan Del Coso, Gil Rodas, Miguel Ángel Buil, Javier Sánchez-Sánchez, Pedro López, Joaquín González-Ródenas, Pablo Gasulla-Anglés, Álvaro López-Samanes, Sergio Hernández-Sánchez, Ane Iztueta and Víctor Moreno-Pérez

Genes 2022, 13(9), 1635; https://doi.org/10.3390/genes13091635 - 12 Sep 2022

Cited by 7 | Viewed by 2638

Abstract

The p.R577X polymorphism (rs1815739) in the ACTN3 gene causes individuals with the XX genotype to be deficient in functional α-actinin-3. Previous investigations have found that XX athletes are more prone to suffer non-contact muscle injuries, in comparison with RR and RX athletes who [...] Read more.

The p.R577X polymorphism (rs1815739) in the ACTN3 gene causes individuals with the XX genotype to be deficient in functional α-actinin-3. Previous investigations have found that XX athletes are more prone to suffer non-contact muscle injuries, in comparison with RR and RX athletes who produce a functional α-actinin-3 in their fast-twitch fibers. This investigation aimed to determine the influence of the ACTN3 R577X polymorphism on physical performance and injury incidence of players competing in the women’s Spanish first division of football (soccer). Using a cross-sectional experiment, football-specific performance and epidemiology of non-contact football-related injuries were recorded in a group of 191 professional football players. ACTN3 R577X genotype was obtained for each player using genomic DNA samples obtained through buccal swabs. A battery of physical tests, including a countermovement jump, a 20 m sprint test, the sit-and-reach test and ankle dorsiflexion, were performed during the preseason. Injury incidence and characteristics of non-contact injuries were obtained according to the International Olympic Committee (IOC) statement for one season. From the study sample, 28.3% of players had the RR genotype, 52.9% had the RX genotype, and 18.8% had the XX genotype. Differences among genotypes were identified with one-way analysis of variance (numerical variables) or chi-square tests (categorical variables). Jump height (p = 0.087), sprint time (p = 0.210), sit-and-reach distance (p = 0.361), and dorsiflexion in the right (p = 0.550) and left ankle (p = 0.992) were similar in RR, RX, and XX football players. A total of 356 non-contact injuries were recorded in 144 football players while the remaining 47 did not sustain any non-contact injuries during the season. Injury incidence was 10.4 ± 8.6, 8.2 ± 5.7, and 8.9 ± 5.3 injuries per/1000 h of football exposure, without differences among genotypes (p = 0.222). Injury rates during training (from 3.6 ± 3.7 to 4.8 ± 2.1 injuries per/1000 h of training exposure, p = 0.100) and match (from 47.8 ± 9.5 to 54.1 ± 6.3 injuries per/1000 h of match exposure, p = 0.209) were also similar in RR, RX, and XX football players. The ACTN3 genotype did not affect the mode of onset, the time needed to return to play, the type of injury, or the distribution of body locations of the injuries. In summary, women football players with different genotypes of the p.R577X ACTN3 polymorphism had similar values of football-specific performance and injury incidence. From a practical perspective, the ACTN3 genotyping may not be useful to predict performance or injury incidence in professional women football players. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

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11 pages, 2161 KiB

Open AccessArticle

Multinomial Convolutions for Joint Modeling of Regulatory Motifs and Sequence Activity Readouts

by Minjun Park, Salvi Singh, Samin Rahman Khan, Mohammed Abid Abrar, Francisco Grisanti, M. Sohel Rahman and Md. Abul Hassan Samee

Genes 2022, 13(9), 1614; https://doi.org/10.3390/genes13091614 - 08 Sep 2022

Cited by 1 | Viewed by 1406

Abstract

A common goal in the convolutional neural network (CNN) modeling of genomic data is to discover specific sequence motifs. Post hoc analysis methods aid in this task but are dependent on parameters whose optimal values are unclear and applying the discovered motifs to [...] Read more.

A common goal in the convolutional neural network (CNN) modeling of genomic data is to discover specific sequence motifs. Post hoc analysis methods aid in this task but are dependent on parameters whose optimal values are unclear and applying the discovered motifs to new genomic data is not straightforward. As an alternative, we propose to learn convolutions as multinomial distributions, thus streamlining interpretable motif discovery with CNN model fitting. We developed MuSeAM (Multinomial CNNs for Sequence Activity Modeling) by implementing multinomial convolutions in a CNN model. Through benchmarking, we demonstrate the efficacy of MuSeAM in accurately modeling genomic data while fitting multinomial convolutions that recapitulate known transcription factor motifs. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

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20 pages, 6167 KiB

Open AccessArticle

Germline Testing in a Cohort of Patients at High Risk of Hereditary Cancer Predisposition Syndromes: First Two-Year Results from South Italy

by Francesco Paduano, Emma Colao, Fernanda Fabiani, Valentina Rocca, Francesca Dinatolo, Adele Dattola, Lucia D’Antona, Rosario Amato, Francesco Trapasso, Francesco Baudi, Nicola Perrotti and Rodolfo Iuliano

Genes 2022, 13(7), 1286; https://doi.org/10.3390/genes13071286 - 21 Jul 2022

Cited by 6 | Viewed by 2565

Abstract

Germline pathogenic variants (PVs) in oncogenes and tumour suppressor genes are responsible for 5 to 10% of all diagnosed cancers, which are commonly known as hereditary cancer predisposition syndromes (HCPS). A total of 104 individuals at high risk of HCPS were selected by [...] Read more.

Germline pathogenic variants (PVs) in oncogenes and tumour suppressor genes are responsible for 5 to 10% of all diagnosed cancers, which are commonly known as hereditary cancer predisposition syndromes (HCPS). A total of 104 individuals at high risk of HCPS were selected by genetic counselling for genetic testing in the past 2 years. Most of them were subjects having a personal and family history of breast cancer (BC) selected according to current established criteria. Genes analysis involved in HCPS was assessed by next-generation sequencing (NGS) using a custom cancer panel with high- and moderate-risk susceptibility genes. Germline PVs were identified in 17 of 104 individuals (16.3%) analysed, while variants of uncertain significance (VUS) were identified in 21/104 (20.2%) cases. Concerning the germline PVs distribution among the 13 BC individuals with positive findings, 8/13 (61.5%) were in the BRCA1/2 genes, whereas 5/13 (38.4%) were in other high- or moderate-risk genes including PALB2, TP53, ATM and CHEK2. NGS genetic testing showed that 6/13 (46.1%) of the PVs observed in BC patients were detected in triple-negative BC. Interestingly, the likelihood of carrying the PVs in the moderate-to-high-risk genes calculated by the cancer risk model BOADICEA was significantly higher in pathogenic variant carriers than in negative subjects. Collectively, this study shows that multigene panel testing can offer an effective diagnostic approach for patients at high risk of hereditary cancers. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

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8 pages, 610 KiB

Open AccessArticle

MicroRNA Processing Pathway-Based Polygenic Score for Clear Cell Renal Cell Carcinoma in the Volga-Ural Region Populations of Eurasian Continent

by Elizaveta Ivanova, Irina Gilyazova, Valentin Pavlov, Adel Izmailov, Galiya Gimalova, Alexandra Karunas, Inga Prokopenko and Elza Khusnutdinova

Genes 2022, 13(7), 1281; https://doi.org/10.3390/genes13071281 - 20 Jul 2022

Cited by 2 | Viewed by 1436

Abstract

The polygenic scores (PGSs) are developed to help clinicians in distinguishing individuals at high risk of developing disease outcomes from the general population. Clear cell renal cell carcinoma (ccRCC) is a complex disorder that involves numerous biological pathways, one of the most important [...] Read more.

The polygenic scores (PGSs) are developed to help clinicians in distinguishing individuals at high risk of developing disease outcomes from the general population. Clear cell renal cell carcinoma (ccRCC) is a complex disorder that involves numerous biological pathways, one of the most important of which is responsible for the microRNA biogenesis machinery. Here, we defined the biological-pathway-specific PGS in a case-control study of ccRCC in the Volga-Ural region of the Eurasia continent. We evaluated 28 DNA SNP variants, located in microRNA biogenesis genes, in 464 individuals with clinically diagnosed ccRCC and 1042 individuals without the disease. Individual genetic risks were defined using the SNP-variant effects derived from the ccRCC association analysis. The final weighted and unweighted PGS models were based on 21 SNPs, and 7 SNPs were excluded due to high LD. In our dataset, microRNA-machinery-weighted PGS revealed 1.69-fold higher odds (95% CI [1.51–1.91]) for ccRCC risk in individuals with ccRCC compared with controls with a p-value of 2.0 × 10⁻¹⁶. The microRNA biogenesis pathway weighted PGS predicted the risk of ccRCC with an area under the curve (AUC) = 0.642 (95%nCI [0.61–0.67]). Our findings indicate that DNA variants of microRNA machinery genes modulate the risk of ccRCC in Volga-Ural populations. Moreover, larger powerful genome-wide association studies are needed to reveal a wider range of genetic variants affecting microRNA processing. Biological-pathway-based PGSs will advance the development of innovative screening systems for future stratified medicine approaches in ccRCC. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

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16 pages, 4072 KiB

Open AccessArticle

A Chromosome-Length Assembly of the Hawaiian Monk Seal (Neomonachus schauinslandi): A History of “Genetic Purging” and Genomic Stability

by David W. Mohr, Stephen J. Gaughran, Justin Paschall, Ahmed Naguib, Andy Wing Chun Pang, Olga Dudchenko, Erez Lieberman Aiden, Deanna M. Church and Alan F. Scott

Genes 2022, 13(7), 1270; https://doi.org/10.3390/genes13071270 - 18 Jul 2022

Cited by 2 | Viewed by 2372

Abstract

The Hawaiian monk seal (HMS) is the single extant species of tropical earless seals of the genus Neomonachus. The species survived a severe bottleneck in the late 19th century and experienced subsequent population declines until becoming the subject of a NOAA-led species recovery [...] Read more.

The Hawaiian monk seal (HMS) is the single extant species of tropical earless seals of the genus Neomonachus. The species survived a severe bottleneck in the late 19th century and experienced subsequent population declines until becoming the subject of a NOAA-led species recovery effort beginning in 1976 when the population was fewer than 1000 animals. Like other recovering species, the Hawaiian monk seal has been reported to have reduced genetic heterogeneity due to the bottleneck and subsequent inbreeding. Here, we report a chromosomal reference assembly for a male animal produced using a variety of methods. The final assembly consisted of 16 autosomes, an X, and portions of the Y chromosomes. We compared variants in this animal to other HMS and to a frequently sequenced human sample, confirming about 12% of the variation seen in man. To confirm that the reference animal was representative of the HMS, we compared his sequence to that of 10 other individuals and noted similarly low variation in all. Variation in the major histocompatibility (MHC) genes was nearly absent compared to the orthologous human loci. Demographic analysis predicts that Hawaiian monk seals have had a long history of small populations preceding the bottleneck, and their current low levels of heterozygosity may indicate specialization to a stable environment. When we compared our reference assembly to that of other species, we observed significant conservation of chromosomal architecture with other pinnipeds, especially other phocids. This reference should be a useful tool for future evolutionary studies as well as the long-term management of this species. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

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11 pages, 269 KiB

Open AccessArticle

The Genetic Variants in the Renin-Angiotensin System and the Risk of Heart Failure in Polish Patients

by Iwona Gorący, Anna Gorący, Mariusz Kaczmarczyk, Jakub Rosik, Klaudyna Lewandowska and Andrzej Ciechanowicz

Genes 2022, 13(7), 1257; https://doi.org/10.3390/genes13071257 - 15 Jul 2022

Cited by 8 | Viewed by 1339

Abstract

(1) Background: Heart failure (HF) is a complex disease and one of the major causes of morbidity and mortality in the world. The renin-angiotensin system (RAS) may contribute to the pathogenesis of HF. (2) Aim: To investigate the association of RAS key genetic [...] Read more.

(1) Background: Heart failure (HF) is a complex disease and one of the major causes of morbidity and mortality in the world. The renin-angiotensin system (RAS) may contribute to the pathogenesis of HF. (2) Aim: To investigate the association of RAS key genetic variants, rs5051 (A-6G) in the gene encoding angiotensinogen (AGT), rs4646994 (I/D) in the gene for angiotensin I converting enzyme (ACE), and rs5186 (A1166C) in the gene encoding type 1 receptor for angiotensin II (AGTR1), with the HF risk in the cohort of Polish patients. (3) Methods: The study group consisted of 415 patients that were diagnosed with HF, while the control group comprised of 152 healthy individuals. Genomic DNA were extracted from blood and genotyping was carried out using either PCR or PCR-RFLP for ACE or AGT and AGTR1 variants, respectively. (4) Results: No association has been found between the I/D ACE and heart failure. The HF risk was significantly higher for AG AGT heterozygotes (overdominance: AG versus AA + GG) and for carriers of the G AGT allele in codominant and dominant modes of inheritance. However, the risk of HF was significantly lower in the carriers of at least one C AGTR1 allele (AC or CC genotypes) or in AC AGTR1 heterozygotes (overdominant mode). There was a significant relationship for AGT and HF patients in NYHA Class I-II for whom the risk was higher for the carriers of the G allele, and for the AG heterozygotes. There was also a significant interaction between heterozygote advantage of AGT and BMI increasing the risk for HF. (5) Conclusion: Our results suggest that the A(-6)G AGT polymorphism may be associated with HF in the Polish population and the HF risk seems to be modulated by the A1166C AGTR1 polymorphism. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

7 pages, 762 KiB

Open AccessArticle

Genetics and Sport Injuries: New Perspectives for Athletic Excellence in an Italian Court of Rugby Union Players

by Maria Elisabetta Onori, Massimo Pasqualetti, Giacomo Moretti, Giulia Canu, Giulio De Paolis, Silvia Baroni, Angelo Minucci, Christel Galvani and Andrea Urbani

Genes 2022, 13(6), 995; https://doi.org/10.3390/genes13060995 - 01 Jun 2022

Cited by 3 | Viewed by 2215

Abstract

Several genes are involved in sport performance, especially in injuries incidence. The aim of this study was to investigate the association of ACE, ACTN3, COL1A1, and MCT1 genotypes and injuries in rugby players in order to find a genotype/phenotype correlation [...] Read more.

Several genes are involved in sport performance, especially in injuries incidence. The aim of this study was to investigate the association of ACE, ACTN3, COL1A1, and MCT1 genotypes and injuries in rugby players in order to find a genotype/phenotype correlation and provide useful information improving athletic performance. One-hundred male professional and semiprofessional rugby players were selected. Analysis was performed genotyping the genes ACE, ACTN3, COL1A1, and MCT1 as candidate gene of interest involved in athletic performance. A control group of non-athletic Italian male participants was analyzed to compare the results. We found statistical significance of MCT1 rs1049434 AA for total injuries (χ² = 0.115; p = 0.003) and bone injuries (χ² = 0.603; p = 0.007) in the rugby athlete population. No statistical significance was found between injury incidence and ACE, ACTN3, COL1A1 genotypes. The MCT1 AA genotype is associated with the incidence of total and bone injuries in the rugby player population. Although environmental factors such as lifestyle, diet, training, and stress can influence athletic performance, our data demonstrated the importance of genetic study in sport aimed at developing personalized training and achieving the best possible athletic excellence. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

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13 pages, 1253 KiB

Open AccessArticle

The Relationship between ACE, ACTN3 and MCT1 Genetic Polymorphisms and Athletic Performance in Elite Rugby Union Players: A Preliminary Study

by Massimo Pasqualetti, Maria Elisabetta Onori, Giulia Canu, Giacomo Moretti, Angelo Minucci, Silvia Baroni, Alvaro Mordente, Andrea Urbani and Christel Galvani

Genes 2022, 13(6), 969; https://doi.org/10.3390/genes13060969 - 28 May 2022

Cited by 2 | Viewed by 3356

Abstract

Athletic performance is influenced by many factors such as the environment, diet, training and endurance or speed in physical effort and by genetic predisposition. Just a few studies have analyzed the impact of genotypes on physical performance in rugby. The aim of this [...] Read more.

Athletic performance is influenced by many factors such as the environment, diet, training and endurance or speed in physical effort and by genetic predisposition. Just a few studies have analyzed the impact of genotypes on physical performance in rugby. The aim of this study was to verify the modulation of genetic influence on rugby-specific physical performance. Twenty-seven elite rugby union players were involved in the study during the in-season phase. Molecular genotyping was performed for: angiotensin-converting enzyme (ACE rs4646994), alfa-actinin-3 (ACTN3 rs1815739) and monocarboxylate transporter 1 (MCT1 rs1049434) and their variants. Lean mass index (from skinfolds), lower-limb explosive power (countermovement jump), agility (505), speed (20 m), maximal aerobic power (Yo-yo intermittent recovery test level 1) and repeated sprint ability (12 × 20 m) were evaluated. In our rugby union players ACE and ACTN3 variants did not show any influence on athletic performance. MCT1 analysis showed that TT-variant players had the highest peak vertical power (p = 0.037) while the ones with the AA genotype were the fastest in both agility and sprint tests (p = 0.006 and p = 0.012, respectively). Considering the T-dominant model, the AA genotype remains the fastest in both tests (agility: p = 0.013, speed: p = 0.017). Only the MCT1 rs1049434 A allele seems to be advantageous for elite rugby union players, particularly when power and speed are required. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

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17 pages, 7186 KiB

Open AccessArticle

Bioinformatics Analysis Highlight Differentially Expressed CCNB1 and PLK1 Genes as Potential Anti-Breast Cancer Drug Targets and Prognostic Markers

by Leiming Fang, Qi Liu, Hongtu Cui, Yunji Zheng and Chengjun Wu

Genes 2022, 13(4), 654; https://doi.org/10.3390/genes13040654 - 07 Apr 2022

Cited by 10 | Viewed by 4428

Abstract

Breast cancer is one of the most common malignant tumors in women worldwide. Early diagnosis, treatment, and prognosis of breast cancer are global challenges. Identification of valid predictive diagnosis and prognosis biomarkers and drug targets are crucial for breast cancer prevention. This study [...] Read more.

Breast cancer is one of the most common malignant tumors in women worldwide. Early diagnosis, treatment, and prognosis of breast cancer are global challenges. Identification of valid predictive diagnosis and prognosis biomarkers and drug targets are crucial for breast cancer prevention. This study characterizes differentially expressed genes (DEGs) based on the TCGA database by using DESeq2, edgeR, and limma. A total of 2032 DEGs, including 1026 up-regulated genes and 1006 down-regulated genes were screened. Followed with WGCNA, PPI analysis, GEPIA 2, and HPA database verification, thirteen hub genes including CDK1, BUB1, BUB1B, CDC20, CCNB2, CCNB1, KIF2C, NDC80, CDCA8, CENPF, BIRC5, AURKB, PLK1, MAD2L1, and CENPE were obtained, and they may serve as potential therapeutic targets of breast cancer. Especially, overexpression of CCNB1 and PLK1 are strongly associated with the low survival rate of breast cancer patients, demonstrating their potentiality as prognostic markers. Moreover, CCNB1 and PLK1 are highly expressed in all breast cancer stages, suggesting that they could be further studied as potential drug targets. Taken together, our study highlights CCNB1 and PLK1 as potential anti-breast cancer drug targets and prognostic markers. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

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15 pages, 2311 KiB

Open AccessArticle

Identification and Somatic Characterization of the Germline PTEN Promoter Variant rs34149102 in a Family with Gastrointestinal and Breast Tumors

by Vittoria Disciglio, Paola Sanese, Candida Fasano, Claudio Lotesoriere, Anna Maria Valentini, Giovanna Forte, Martina Lepore Signorile, Katia De Marco, Valentina Grossi, Ivan Lolli, Filomena Cariola and Cristiano Simone

Genes 2022, 13(4), 644; https://doi.org/10.3390/genes13040644 - 05 Apr 2022

Viewed by 2108

Abstract

Genetic variants located in non-coding regions can affect processes that regulate protein expression, functionally contributing to human disease. Germline heterozygous mutations in the non-coding region of the PTEN gene have been previously identified in patients with PTEN hamartoma tumor syndrome (PHTS) diagnosed with [...] Read more.

Genetic variants located in non-coding regions can affect processes that regulate protein expression, functionally contributing to human disease. Germline heterozygous mutations in the non-coding region of the PTEN gene have been previously identified in patients with PTEN hamartoma tumor syndrome (PHTS) diagnosed with breast, thyroid, and/or endometrial cancer. In this study, we report a PTEN promoter variant (rs34149102 A allele) that was identified by direct sequencing in an Italian family with a history of gastroesophageal junction (GEJ) adenocarcinoma and breast cancer. In order to investigate the putative functional role of the rs34149102 A allele variant, we evaluated the status of PTEN alterations at the somatic level. We found that PTEN protein expression was absent in the GEJ adenocarcinoma tissue of the index case. Moreover, we detected the occurrence of copy number loss involving the PTEN rs34149102 major C allele in tumor tissue, revealing that the second allele was somatically inactivated. This variant is located within an active regulatory region of the PTEN core promoter, and in silico analysis suggests that it may affect the binding of the nuclear transcription factor MAZ and hence PTEN expression. Overall, these results reveal the functional role of the PTEN promoter rs34149102 A allele variant in the modulation of PTEN protein expression and highlight its contribution to hereditary cancer risk. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

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13 pages, 2257 KiB

Open AccessArticle

Expression of FMRpolyG in Peripheral Blood Mononuclear Cells of Women with Fragile X Mental Retardation 1 Gene Premutation

by Xuan Phuoc Nguyen, Adriana Vilkaite, Birgitta Messmer, Jens E. Dietrich, Katrin Hinderhofer, Knut Schäkel, Thomas Strowitzki and Julia Rehnitz

Genes 2022, 13(3), 451; https://doi.org/10.3390/genes13030451 - 01 Mar 2022

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Abstract

Fragile X-associated primary ovarian insufficiency (FXPOI) is characterized by oligo/amenorrhea and hypergonadotropic hypogonadism and is caused by the expansion of the CGG repeat in the 5′UTR of Fragile X Mental Retardation 1 (FMR1). Approximately 20% of women carrying an FMR1 premutation [...] Read more.

Fragile X-associated primary ovarian insufficiency (FXPOI) is characterized by oligo/amenorrhea and hypergonadotropic hypogonadism and is caused by the expansion of the CGG repeat in the 5′UTR of Fragile X Mental Retardation 1 (FMR1). Approximately 20% of women carrying an FMR1 premutation (PM) allele (55–200 CGG repeat) develop FXPOI. Repeat Associated Non-AUG (RAN)-translation dependent on the variable CGG-repeat length is thought to cause FXPOI, due to the production of a polyglycine-containing FMR1 protein, FMRpolyG. Peripheral blood monocyte cells (PBMCs) and granulosa cells (GCs) were collected to detect FMRpolyG and its cell type-specific expression in FMR1 PM carriers by immunofluorescence staining (IF), Western blotting (WB), and flow cytometric analysis (FACS). For the first time, FMRpolyG aggregates were detected as ubiquitin-positive inclusions in PBMCs from PM carriers, whereas only a weak signal without inclusions was detected in the controls. The expression pattern of FMRpolyG in GCs was comparable to that in the lymphocytes. We detected FMRpolyG as a 15- to 25-kDa protein in the PBMCs from two FMR1 PM carriers, with 124 and 81 CGG repeats. Flow cytometric analysis revealed that FMRpolyG was significantly higher in the T cells from PM carriers than in those from non-PM carriers. The detection of FMRpolyG aggregates in the peripheral blood and granulosa cells of PM carriers suggests that it may have a toxic potential and an immunological role in ovarian damage in the development of FXPOI. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

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16 pages, 2063 KiB

Open AccessArticle

Analysis of Genomic Alternative Splicing Patterns in Rat under Heat Stress Based on RNA-Seq Data

by Shangzhen Huang, Jinhuan Dou, Zhongshu Li, Lirong Hu, Ying Yu and Yachun Wang

Genes 2022, 13(2), 358; https://doi.org/10.3390/genes13020358 - 16 Feb 2022

Cited by 4 | Viewed by 2843

Abstract

Heat stress is one of the most severe challenges faced in livestock production in summer. Alternative splicing as an important post-transcriptional regulation is rarely studied in heat-stressed animals. Here, we performed and analyzed RNA-sequencing assays on the liver of Sprague-Dawley rats in control [...] Read more.

Heat stress is one of the most severe challenges faced in livestock production in summer. Alternative splicing as an important post-transcriptional regulation is rarely studied in heat-stressed animals. Here, we performed and analyzed RNA-sequencing assays on the liver of Sprague-Dawley rats in control (22 °C, n = 5) and heat stress (4 °C for 120 min, H120; n = 5) groups, resulting in the identification of 636 differentially expressed genes. Identification analysis of the alternative splicing events revealed that heat stress-induced alternative splicing events increased by 20.18%. Compared with other types of alternative splicing events, the alternative start increased the most (43.40%) after heat stress. Twenty-eight genes were differentially alternatively spliced (DAS) between the control and H120 groups, among which Acly, Hnrnpd and mir3064 were also differentially expressed. For DAS genes, Srebf1, Shc1, Srsf5 and Ensa were associated with insulin, while Cast, Srebf1, Tmem33, Tor1aip2, Slc39a7 and Sqstm1 were enriched in the composition of the endoplasmic reticulum. In summary, our study conducts a comprehensive profile of alternative splicing in heat-stressed rats, indicating that alternative splicing is one of the molecular mechanisms of heat stress response in mammals and providing reference data for research on heat tolerance in mammalian livestock. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

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14 pages, 1412 KiB

Open AccessArticle

DRD4 Exon 3 Gene Polymorphisms in Patients Diagnosed with Polysubstance Use Disorder and Co-Occurrence of a Depressive Episode

by Krzysztof Chmielowiec, Jolanta Chmielowiec, Jolanta Masiak, Małgorzata Czekaj, Piotr Krawczyk, Ewelina Soroka, Małgorzata Śmiarowska, Wojciech Musiał, Tomasz Pawłowski and Anna Grzywacz

Genes 2021, 12(11), 1834; https://doi.org/10.3390/genes12111834 - 20 Nov 2021

Cited by 2 | Viewed by 2121

Abstract

Background: There has been a noticeable and systematic growth of the use of psychoactive substances over the past few decades. Dual diagnosis is a clinical term referring to the occurrence of psychoactive substance use disorder comorbid with another psychiatric disorder in the same [...] Read more.

Background: There has been a noticeable and systematic growth of the use of psychoactive substances over the past few decades. Dual diagnosis is a clinical term referring to the occurrence of psychoactive substance use disorder comorbid with another psychiatric disorder in the same person. The most common type of dual diagnosis is the co-occurrence of alcohol use disorder and mood disorders in the form of a depressive episode. Co-occurrent substance use disorders are frequently influenced by genetic factors. In selecting our area of research, we focused on dopamine and the DRD4 (Dopamine Receptor D4) gene polymorphism as well as associations with personality features. The aim of the study: The aim of the study was to compare DRD4 exon 3 (DRD4 Ex3) gene polymorphisms in patients diagnosed with polysubstance use disorder and co-occurrence of a depressive episode to DRD4 exon 3 gene polymorphisms in patients diagnosed with polysubstance use disorder and without co-occurrence of a depressive episode and a group of healthy volunteers. The study also aimed at establishing associations between personality features and DRD4 exon 3 gene polymorphisms of male patients diagnosed with polysubstance use disorder with co-occurrence of a depressive episode which may present a specific endophenotype of this group of patients. Methods: The study group comprised 602 male volunteers: patients diagnosed with polysubstance use disorder comorbid with a depressive episode (PUD MDD) (n = 95; mean age = 28.29, standard deviation (SD) = 7.40), patients diagnosed with polysubstance use disorder (PUD) (n = 206; mean age = 28.13, SD = 5.97), and controls (n = 301; mean age = 22.13, SD = 4.57). The patients and control subjects were diagnosed by a psychiatrist using the Mini International Neuropsychiatric Interview (MINI), the NEO Five-Factor Personality Inventory (NEO-FFI), and the State-Trait Anxiety Inventory (STAI) questionnaires. An analysis of the DRD4 exon 3 polymorphism was performed. Results: The patients diagnosed with PUD MDD compared to the control group of healthy volunteers showed significantly higher scores on both the STAI status and features scale and the NEO-FFI Neuroticism and Openness Scale, as well as lower scores on the Extraversion, Agreeableness, and Conscientiousness NEO-FFI scales. In the DRD4 exon 3 gene polymorphism, the s allele was more frequent in the PUD MDD compared to the l allele, which was less frequent. The results of the 2 × 3 factor analysis of variance (ANOVA) in patients and controls and the variant DRD4 exon 3 interaction were found on the Extraversion Scale and the Conscientiousness Scale of the NEO-FFI. Conclusions: The associations show that psychological factors combined with genetic data create a new area of research on addiction, including the problem of dual diagnosis. However, we want to be careful and draw no definite conclusions at this stage of our research. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

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Review

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28 pages, 2041 KiB

Open AccessReview

Molecular Genetic Mechanisms in Age-Related Macular Degeneration

by Aumer Shughoury, Duriye Damla Sevgi and Thomas A. Ciulla

Genes 2022, 13(7), 1233; https://doi.org/10.3390/genes13071233 - 12 Jul 2022

Cited by 11 | Viewed by 3773

Abstract

Age-related macular degeneration (AMD) is among the leading causes of irreversible blindness worldwide. In addition to environmental risk factors, such as tobacco use and diet, genetic background has long been established as a major risk factor for the development of AMD. However, our [...] Read more.

Age-related macular degeneration (AMD) is among the leading causes of irreversible blindness worldwide. In addition to environmental risk factors, such as tobacco use and diet, genetic background has long been established as a major risk factor for the development of AMD. However, our ability to predict disease risk and personalize treatment remains limited by our nascent understanding of the molecular mechanisms underlying AMD pathogenesis. Research into the molecular genetics of AMD over the past two decades has uncovered 52 independent gene variants and 34 independent loci that are implicated in the development of AMD, accounting for over half of the genetic risk. This research has helped delineate at least five major pathways that may be disrupted in the pathogenesis of AMD: the complement system, extracellular matrix remodeling, lipid metabolism, angiogenesis, and oxidative stress response. This review surveys our current understanding of each of these disease mechanisms, in turn, along with their associated pathogenic gene variants. Continued research into the molecular genetics of AMD holds great promise for the development of precision-targeted, personalized therapies that bring us closer to a cure for this debilitating disease. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

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11 pages, 290 KiB

Open AccessReview

Multisystemic Manifestations in Rare Diseases: The Experience of Dyskeratosis Congenita

by Michele Callea, Diego Martinelli, Francisco Cammarata-Scalisi, Chiara Grimaldi, Houweyda Jilani, Piercesare Grimaldi, Colin Eric Willoughby and Antonino Morabito

Genes 2022, 13(3), 496; https://doi.org/10.3390/genes13030496 - 11 Mar 2022

Cited by 7 | Viewed by 2800

Abstract

Dyskeratosis congenital (DC) is the first genetic syndrome described among telomeropathies. Its classical phenotype is characterized by the mucocutaneous triad of reticulated pigmentation of skin lace, nail dystrophy and oral leukoplakia. The clinical presentation, however, is heterogeneous and serious clinical complications include bone [...] Read more.

Dyskeratosis congenital (DC) is the first genetic syndrome described among telomeropathies. Its classical phenotype is characterized by the mucocutaneous triad of reticulated pigmentation of skin lace, nail dystrophy and oral leukoplakia. The clinical presentation, however, is heterogeneous and serious clinical complications include bone marrow failure, hematological and solid tumors. It may also involve immunodeficiencies, dental, pulmonary and liver disorders, and other minor complication. Dyskeratosis congenita shows marked genetic heterogeneity, as at least 14 genes are responsible for the shortening of telomeres characteristic of this disease. This review discusses clinical characteristics, molecular genetics, disease evolution, available therapeutic options and differential diagnosis of dyskeratosis congenita to provide an interdisciplinary and personalized medical assessment that includes family genetic counseling. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

Other

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6 pages, 720 KiB

Open AccessOpinion

Mapping Genetics and Epigenetics to Explore the Pathways beyond the Correlated Ageing Phenotype

by Abdelaziz Ghanemi, Mayumi Yoshioka and Jonny St-Amand

Genes 2022, 13(11), 2169; https://doi.org/10.3390/genes13112169 - 20 Nov 2022

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Abstract

Ageing is defined by the decline in the biological and physiological functions over time, which leads to health problems and increases risks of diseases. The modern societies are characterised by an ageing population, which represents challenges for the healthcare system. Within this context, [...] Read more.

Ageing is defined by the decline in the biological and physiological functions over time, which leads to health problems and increases risks of diseases. The modern societies are characterised by an ageing population, which represents challenges for the healthcare system. Within this context, there is a need to better understand the biological mechanisms beyond ageing in order to optimise geriatric therapies and medical approaches. Herein, we suggest exploring the genetic and epigenetic patterns related to ageing and correlate them with the ageing-related phenotype of the biological entities in order to establish mechanistic links and map the molecular pathways. Such links would have diverse implications in basic research, in clinics, as well as for therapeutic studies. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

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10 pages, 1576 KiB

Open AccessCase Report

A Novel GCK Large Genomic Rearrangement in a Patient with MODY-2 Detected by Clinical Exome Sequencing

by Paola Concolino, Linda Tartaglione, Elisa De Paolis, Cinzia Carrozza, Andrea Urbani, Angelo Minucci, Dario Pitocco and Concetta Santonocito

Genes 2022, 13(11), 2104; https://doi.org/10.3390/genes13112104 - 13 Nov 2022

Cited by 1 | Viewed by 1450

Abstract

Maturity-onset diabetes of the young (MODY) is a rare form of non-autoimmune diabetes with an autosomal dominant inheritance. To date, 14 genes have been reported as genetic basis of MODY. GCK gene, encoding the glucokinase enzyme, was the first MODY gene to be [...] Read more.

Maturity-onset diabetes of the young (MODY) is a rare form of non-autoimmune diabetes with an autosomal dominant inheritance. To date, 14 genes have been reported as genetic basis of MODY. GCK gene, encoding the glucokinase enzyme, was the first MODY gene to be identified. GCK heterozygous inactivating variants cause the GCK-MODY or MODY2 subtype. However, partial or whole gene deletions have been rarely identified, showing it to be a rare cause of GCK-MODY. We reported the molecular evaluation of a Ukrainian patient with clinical diagnosis of MODY2. We performed the Next generation sequencing of the clinical exome using the Clinical Exome Solution^® kit (SOPHiA Genetics), followed by the design of a 14 genes virtual panel related to the suggestive diagnosis of MODY. Bioinformatics analysis was performed using the SOPHiA DDM platform (SOPHiA Genetics). The SALSA MLPA kit for MODY (MRC-Holland) was used for relative quantification of GCK exons. From the molecular evaluation, no pathogenic sequence variants were detected in the investigated genes. Copy Number Variation analysis was able to identify a large deletion involving the last three exons of the GCK gene. This result was confirmed by MLPA. To the best of our knowledge, the identified rearrangement has never been reported in the literature. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

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11 pages, 3189 KiB

Open AccessCase Report

A Case of Severe Left-Ventricular Noncompaction Associated with Splicing Altering Variant in the FHOD3 Gene

by Roman Myasnikov, Anna Bukaeva, Olga Kulikova, Alexey Meshkov, Anna Kiseleva, Alexandra Ershova, Anna Petukhova, Mikhail Divashuk, Evgenia Zotova, Evgeniia Sotnikova, Maria Kharlap, Anastasia Zharikova, Yuri Vyatkin, Vasily Ramensky, Alexandra Abisheva, Alisa Muraveva, Sergey Koretskiy, Maria Kudryavtseva, Sergey Popov, Marina Utkina, Elena Mershina, Valentin Sinitsyn, Evgeniya Kogan, Olga Blagova and Oxana Drapkina Show full author list Hide full author list

Genes 2022, 13(2), 309; https://doi.org/10.3390/genes13020309 - 07 Feb 2022

Cited by 3 | Viewed by 2286

Abstract

Left ventricular noncompaction (LVNC) is a highly heterogeneous primary disorder of the myocardium. Its clinical features and genetic spectrum strongly overlap with other types of primary cardiomyopathies, in particular, hypertrophic cardiomyopathy. Study and the accumulation of genotype–phenotype correlations are the way to improve [...] Read more.

Left ventricular noncompaction (LVNC) is a highly heterogeneous primary disorder of the myocardium. Its clinical features and genetic spectrum strongly overlap with other types of primary cardiomyopathies, in particular, hypertrophic cardiomyopathy. Study and the accumulation of genotype–phenotype correlations are the way to improve the precision of our diagnostics. We present a familial case of LVNC with arrhythmic and thrombotic complications, myocardial fibrosis and heart failure, cosegregating with the splicing variant in the FHOD3 gene. This is the first description of FHOD3-dependent LVNC to our knowledge. We also revise the assumed mechanism of pathogenesis in the case of FHOD3 splicing alterations. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics)

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