Genetic Variants Research Articles

Clinical phenotype, genetic characteristics, and creation of immortalized cell lines for patients from a pedigree affected with Hunter syndrome

To explore the clinical phenotype and genetic variant in a Chinese pedigree affected with Hunter syndrome and create immortalized cell lines for the affected pedigree members. A pedigree of six members who had visited Xi'an Children's Hospital in July 2022 was selected as the study subject. Clinical data was collected. Whole exome sequencing was carried out for the pedigree members. Candidate variant was verified by Sanger sequencing. In addition, peripheral B lymphocytes were transfected with Epstein-Barr virus to create immortalized cell lines, which were then subjected to enzyme activity analysis. The patient, a five-year-and-seven-month-old boy, had exhibited stiff limbs and enlarged joints. He had developed hernia, scaphocephaly, and barrel chest from 3 months of age. His uncle also had stiff limbs, poor hearing, blindness, and right oblique inguinal hernia. Above features had resembled those of Hunter syndrome. Genetic testing revealed that both the child and his uncle had harbored an IDS (NM_000202.8): c.823G>A (p.D275N) variant, which was unreported previously. Bioinformatic analysis indicated that the D275 to be a highly conserved site, and the D275N variant may affect the stability of the protein's spatial conformation, thereby decrease the catalytic activity of the enzyme. The successfully constructed immortalized lymphoblastoid cell lines for the child and his parents showed increased volume, irregular shape, burr structure and cluster growth. And the value of IDS activity of the patient's immortalized lymphoblastoid cells was below the limit of detection. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic (PS3+PM2_Supporting+PM5+PP1+PP3). Above finding has enriched the phenotypic and mutational spectra of Hunter syndrome, and provided a basis for the genetic counseling for this pedigree. The creation of immortalized cell lines has offered a model for further investigation of the impact of variant on the function of IDS and development of targeted drugs.

ГЕНЕТИЧЕСКАЯ ХАРАКТЕРИСТИКА Х-СЦЕПЛЕННОГО СИНДРОМА АЛЬПОРТА У ДЕТЕЙ: ДАННЫЕ ОДНОЦЕНТРОВОГО КОГОРТНОГО ИССЛЕДОВАНИЯ

X-linked Alport syndrome (XLAS) is a monogenic disease characterized by the progressive nephropathy development, sensorineural hearing loss and the lens and retina pathology. The clinical manifestations of the syndrome and the renal prognosis of patients are determined by the nature of the gene COL4A5 mutation. The range of COL4A5 genetic variants is different among populations. Information about the XLAS genetic structure in Russian pediatric cohort is insufficient. The purpose of this research was to determine the features of the spectrum of the gene COL4A5 genetic variants in children with XLAS. Materials and methods used: a single-center retrospective cohort study included children aged 2 to 17 y/o with genetically confirmed XLAS. Descriptions of variants in gene COL4A5 were performed using genome build GRCh37/hg19 in accordance with the reference sequence GRCh37/hg19 (Reference Sequence, HGVS) and the American College of Medical Genetics and Genomics (ACMG), AMP Clinical Practice Guidelines. Results: analysis of data from 174 probands from unrelated families showed that 108 (62%) children had missense variants in gene COL4A5 (62% v. 38%, missense v. non-missense variants, respectively, p=0.028), 24 (13.8%) had mutations leading to impaired RNA splicing, 17 (9.8%) had frameshift mutations, 14 (8%) had gene deletions and 10 (5.7%) had nonsense mutations. Missense variants were predominantly localized in the collagen domain compared to the non-collagen domain (n=102, 94.4%, p<0.001), in exons 18 to 41 (n=94; 94.8%) and were represented by glycine substitutions (n=90, 83.3%). Two common variants were identified in the cohort: NM_033380.3(COL4A5):c.1871G>A (p.Gly624Asp) in 28 (26%) and NM_033380.3(COL4A5):c.3319G>A (p.Gly1107Arg) in 4 (3.7%). Conclusion: the structure of COL4A5 genetic variants in the studied cohort was comparable with the current Worldwide data, such as two thirds of the examined had missense variants and ca. one-fifth had genetic variants leading to the protein synthesis absence. Two common missense variants in gene COL4A5 were identified, including the common variant NM_033380.3(COL4A5):c.1871G>A (p.Gly624Asp) that is of frequent occurrence in the European population.

СПЕКТР КЛИНИЧЕСКИХ ПРОЯВЛЕНИЙ Х-СЦЕПЛЕННОГО СИНДРОМА АЛЬПОРТА У ДЕВОЧЕК: ОДНОЦЕНТРОЕ КОГОРТНОЕ ИССЛЕДОВАНИЕ

X-linked Alport syndrome (XLAS) is an inherited disorder caused by genetic variants in gene COL4A5. The frequency and the severity of clinical manifestations as well as the risk of glomerulopathy progression are variable in XLAS in females, and the disease course features have not been sufficiently studied as yet. Since patient management tactics is determined by the disease course nature, studying the spectrum of XLAS clinical manifestations and prognosis in girls remains relevant. The purpose of this research was to determine the spectrum and the features of clinical manifestations of XLAS in girls. Materials and methods used: a single-center cohort prospective study was carried out by the Authors that included 74 girls aged 2 to 17 y/o with genetically proven XLAS diagnosis. Authors have analyzed the patients’ medical records identifying sensorineural hearing loss (SNHL), arterial hypertension (AH; blood pressure (BP) over 95% than at the patient’s age/height), albuminuria (Alb; norm<30 mg/mmol of creatinine), proteinuria (Pr; norm<100 mg/sq m/day) - with its degree, decrease in estimated glomerular filtration rate (eGFR, ml/min/1.73 sq m; norm≥90 ml/min/1.73 sq m) and angiotensin-converting enzyme inhibitors (ACEIs) therapy data. Results: all patients had hematuria with episodical macrohematuria in 27% of cases, proteinuria in 40%, eGFR decrease in 15%, SNHL in 8% and peripheral retinopathy in 7%. Girls with missense v. those with non-missense variants of COL4A5 more often had macrohematuria (0.15 v. 0.05; p=0.015) and albuminuria (1 v. 0.5; p<0.001) whilst no statistically significant difference was showed in proteinuria frequency and age of onset (0.48 v. 0.5 and 6.5 [3; 11] v. 5 [5; 8] y/o), eGFR decrease (0.15 v. 0.15; 12.4±2.6 v. 13.2 ±2.8 y/o), SNHL (0.07 v. 0.1; 13±2.8 v. 14.4±3.1 y/o) and retinopathy (0.04 v. 0.15; 14.3±3.5 v. 12.6±2.9 y/o). ACEIs therapy did not show any statistically significant effect on the cumulative proportion of patients with both proteinuria and eGFR decrease (log-rank test=1.25, p=0.213 and log-rank test=0.66, p=0.512, respectively). Conclusion: the results obtained demonstrate the need for a dynamic follow-up of girls with XLAS with the purpose of earliest possible detection of proteinuria and timely prescribing with nephroprotective therapy as well as hearing loss diagnosing and timely audiological correction.

GENEVIC: GENetic data exploration and visualization via intelli- gent interactive console.

The vast generation of genetic data poses a significant challenge in efficiently uncovering valuable knowledge. Introducing GENEVIC, an AI-driven chat framework that tackles this challenge by bridging the gap between genetic data generation and biomedical knowledge discovery. Leveraging generative AI, notably ChatGPT, it serves as a biologist's 'copilot'. It automates the analysis, retrieval, and visualization of customized domain-specific genetic information, and integrates functionalities to generate protein interaction networks, enrich gene sets, and search scientific literature from PubMed, Google Scholar, and arXiv, making it a comprehensive tool for biomedical research. In its pilot phase, GENEVIC is assessed using a curated database that ranks genetic variants associated with Alzheimer's disease, schizophrenia, and cognition, based on their effect weights from the Polygenic Score (PGS) Catalog, thus enabling researchers to prioritize genetic variants in complex diseases. GENEVIC's operation is user-friendly, accessible without any specialized training, secured by Azure OpenAI's HIPAA-compliant infrastructure, and evaluated for its efficacy through real-time query testing. As a prototype, GENEVIC is set to advance genetic research, enabling informed biomedical decisions. GENEVIC is publicly accessible at https://genevic- anath2024.streamlit.app. The underlying code is open-source and available via GitHub at https://github.com/bsml320/GENEVIC.git (also at https://github.com/anath2110/GENEVIC.git). Available at Bioinformatics online and at https://github.com/bsml320/GENEVIC_Supplementary.git (also at https://github.com/anath2110/GENEVIC_Supplementary.git).

Two genetic variants in the HIBCH and FTCDNL1 genes are associated with susceptibility to developmental dysplasia of the hips among the Han Chinese population of Southwest China

BackgroundDevelopmental dysplasia of the hip (DDH) is a common cause of childhood disability, and the incidence of DDH shows significant familial aggregation. As the genetic factors of DDH remain unknown, the correlation between five candidate single nucleotide polymorphisms (SNPs) and DDH was evaluated in the Han Chinese population of Southwest China.MethodsA case‒control association study was conducted in 276 patients with DDH and 318 healthy controls. SNP genotyping in the case and control groups was performed by SNPshot and multiple PCR. SNPs were genotyped in the case and control groups by multiplex PCR. The relationship between DDH and candidate SNPs was evaluated using the χ2 test.ResultsThe genotype distributions of rs291412 in HIBCH and rs769956 in FTCDNL1 were different between the case and control groups (P < 0.05). After genetic model analysis, logistic regression analysis revealed that the C allele of rs291412 had a protective effect on DDH (OR = 0.605, P = 0.010) and that the G allele of rs769956 was a risk factor (OR = 2.939, P = 0.010).s.ConclusionThese SNPs could be associated with susceptibility to DDH but larger population-based studies should confirm the current results.

Draft genome of akame (Lates japonicus) reveals possible genetic mechanisms for long-term persistence and adaptive evolution with low genetic diversity.

It is known that some endangered species have persisted for thousands of years despite their very small effective population sizes and low levels of genetic polymorphisms. To understand the genetic mechanisms of long-term persistence in threatened species, we determined the whole genome sequences of akame (Lates japonicus), which has survived for a long time with extremely low genetic variations. Genome-wide heterozygosity in akame was estimated to be 3.3-3.4 × 10-4/bp, one of the smallest values in teleost fishes. Analysis of demographic history revealed that the effective population size in akame was around 1,000 from 30,000 years ago to the recent past. The relatively high ratio of nonsynonymous to synonymous heterozygosity in akame indicated an increased genetic load. However, a detailed analysis of genetic diversity in the akame genome revealed that multiple genomic regions, including genes involved in immunity, synaptic development, and olfactory sensory systems, have retained relatively high nucleotide polymorphisms. This implies that the akame genome has preserved the functional genetic variations by balancing selection, to avoid a reduction in viability and loss of adaptive potential. Analysis of synonymous and nonsynonymous nucleotide substitution rates has detected signs of positive selection in many akame genes, suggesting adaptive evolution to temperate waters after the speciation of akame and its close relative, barramundi (L. calcarifer). Our results indicate that the functional genetic diversity likely contributed to the long-term persistence of this species by avoiding the harmful effects of the population size reduction.

Drug Response of Iranian Alzheimer's Patients to Rivastigmine Concerning Their Genotype for VDR rs11568820 and MTHFR C677T Variants: A Pharmacogenetic and Association Study.

Alzheimer's disease is a neurodegenerative disorder with polygenic etiology. Genetic risk variants for Alzheimer's disease differ among populations. Thus, discovering them in each population is clinically important. A total of 118 patients and 97 controls for VDR rs11568820 and 88 patients and 100 healthy controls for MTHFR C677T polymorphism were genotyped to evaluate the association of these polymorphisms with late-onset Alzheimer's disease in the Iranian population, along with their impacts on the response to Rivastigmine treatment. The VDR C allele was significantly associated with Alzheimer's disease and provided protection against it (P = 0.003, RR = 1.14, 95% CI 1.04-1.24), while the T allele increased susceptibility (P = 0.003, RR = 1.93, 95% CI 1.23-3.02). These results were also considerable upon excluding the effect of APOE ε4 allele. The Prevalence-corrected Positive Predictive Value was 1.71% for the VDR CC genotype and 4% for the VDR CT genotype, indicating lower and almost twofold higher chances of developing Alzheimer's disease, respectively. No significant correlation was observed between MTHFR C677T and Alzheimer's disease. Based on our pharmacogenetic study, MTHFR T allele carriers lacking APOE ε4 allele showed a better response to Rivastigmine treatment after a 2-year follow-up. Moreover, patients with VDR CC genotype displayed milder Alzheimer's disease, particularly when coincided with the APOE ε4 allele. The VDR rs11568820 polymorphism affects both Alzheimer's disease risk and the response to Rivastigmine in Iranian patients. Also, MTHFR C677T polymorphism may play a role in the response to Rivastigmine, through a pathway that needs to be elucidated in future studies.

Pharmacogenetics of Calcineurin inhibitors in kidney transplant recipients: the African gap. A narrative review.

Calcineurin inhibitors (CNIs) are the mainstay of immunosuppression in kidney transplantation. Interpatient variability in the disposition of calcineurin inhibitors is a well-researched phenomenon and has a well-established genetic contribution. There is great diversity in the makeup of African genomes, but very little is known about the pharmacogenetics of CNIs and transplant outcomes. This review focuses on genetic variants of calcineurin inhibitors' metabolizing enzymes (CYP3A4, CYP3A5), related molecules (POR, PPARA) and membrane transporters involved in the metabolism of calcineurin inhibitors. Given the genetic diversity across the African continent, it is imperative to generate pharmacogenetic data, especially in the era of personalized medicine and emphasizes the need for studies specific to African populations. The study of allelic variants in populations where they have greater frequencies will help answer questions regarding their impact. We aim to fill the knowledge gaps by reviewing existing research and highlighting areas where African research can contribute.

The kpc-1 3'UTR facilitates dendritic transport and translation efficiency of mRNAs for dendrite arborization of a mechanosensory neuron important for male courtship.

A recently reported Schizophrenia-associated genetic variant in the 3'UTR of the human furin gene, a homolog of C. elegans kpc-1, highlights an important role of the furin 3'UTR in neuronal development. We isolate three kpc-1 mutants that display abnormal dendrite arborization in PVD neurons and defective male mating behaviors. We show that the kpc-1 3'UTR participates in dendrite branching and self-avoidance. The kpc-1 3'UTR facilitates mRNA localization to branching points and contact points between sibling dendrites and promotes translation efficiency. A predicted secondary structural motif in the kpc-1 3'UTR is required for dendrite self-avoidance. Animals with over-expression of DMA-1, a PVD dendrite receptor, exhibit similar dendrite branching and self-avoidance defects that are suppressed with kpc-1 over-expression. Our results support a model in which KPC-1 proteins are synthesized at branching points and contact points to locally down-regulate DMA-1 receptors to promote dendrite branching and self-avoidance of a mechanosensory neuron important for male courtship.

The past 25 years in paediatric rheumatology: insights from monogenic diseases.

The past 25 years have seen major novel developments in the field of paediatric rheumatology. The concept of autoinflammation was introduced to this field, and medicine more broadly, with studies of familial Mediterranean fever, the most common autoinflammatory disease globally. New data on the positive evolutionary selection of familial Mediterranean fever-associated genetic variants might be pertinent to mild gain-of-function variants reported in other disease-associated genes. Genetic studies have unveiled the complexity of human heritability to inflammation and flourishing data from rare monogenic disorders have contributed to a better understanding of general disease mechanisms in paediatric rheumatic conditions. Beyond genomics, the application of other 'omics' technologies, including transcriptomics, proteomics and metabolomics, has generated an enormous dataset that can be applied to the development of new therapies and in the practice of precision medicine. Novel biomarkers for monitoring disease activity and progression have also emerged. A surge in the development of targeted biologic therapies has led to durable remission and improved prognosis for many diseases that in the past caused major complications. Last but not least, the COVID-19 pandemic has affected paediatric rheumatology practice and has sparked new investigations into the link between viral infections and unregulated inflammatory responses in children.

Highlights of Gene and Cell Therapy for Epidermolysis Bullosa and Ichthyosis.

Advancements in the molecular genetics of epidermolysis bullosa (EB) and ichthyosis, two rare inherited skin conditions, have enabled the identification of genetic variants that cause these diseases. Alongside technological advancements in genetic medicine, the identification of variants causal of these rare skin conditions has led to preclinical research and the clinical development of various in vivo and ex vivo gene and cell therapies for their treatment. Gene and cell therapies are considered to be the most advanced forms of personalized medicine, demonstrating safety and efficacy in numerous rare diseases. Although the orphan drug development boom has resulted in regulatory approval of multiple gene and cell therapies for various rare conditions, the application of these modalities to rare inherited skin conditions remains limited. Nonetheless, there are successful examples of both in vivo gene therapy- and ex vivo cell therapy-based approaches developed to treat EB and ichthyosis. This review highlights preclinical research and the clinical development of gene and cell therapies for multiple subtypes of these two devastating congenital skin conditions, including a gene therapy recently approved by the U.S. Food and Drug Administration for the treatment of recessive dystrophic EB.

T1R2/T1R3 polymorphism affects sweet and fat perception: Correlation between SNP and BMI in the context of obesity development.

Genetic variations in taste receptors are associated with gustatory perceptionand obesity, which in turn affects dietary preferences. Given the increasing tendency of people with obesity choosing sweet, high-fat meals, the current study assessed the cross-regulation of two polymorphisms of the sweet taste receptor (T1R2/T1R3), rs35874116 and rs307355, on fat sensitivity in Indian adults. We investigated the association between taste sensitivity and BMI in the T1R2, T1R3, and CD36 polymorphic and non-polymorphic groups. The general labelled magnitude scale (gLMS) was used to assess the taste sensitivity of 249 participants in addition to anthropometric data. TaqMan Probe-based RT-PCR was employedto determine the polymorphisms. Additionally, the colorimetric method utilizing 3, 5-dinitro salicylic acid was used to evaluate the participants' salivary amylase activity. The mean detection thresholds for linoleic acid (LA) and sucrose were greater in individuals with obesity (i.e., 0.97±0.08mM and 0.22±0.02M, respectively) than in healthy adults (p < 0.0001), indicating lower sensitivity. Moreover, it was found that a greater proportion of persons with obesity fall into the polymorphic groups (i.e., 52% with genotype CD36 AA, 44% with genotype T1R2 CC, and 40% with genotype T1R3 TT). All three single nucleotide polymorphisms support the Hardy-Weinberg equilibrium (p = 0.78). The Pearson correlation analysis between LA and the sucrose detection threshold revealed a significant (p < 0.0001) positive relationship with an rvalue of 0.5299. Moreover, salivary amylase activity was significantly (p < 0.05) higher in the polymorphic sub-groups. The results of our study imply that genetic variations in T1R2/T1R3 receptors affect perception of both sweetness and fat, which may have an effect on obesity.

Exploring the contribution of genetic variants to high sunitinib exposure in patients with cancer.

Sunitinib exhibits considerable interindividual variability in exposure. While the target total plasma concentration of sunitinib and its active metabolite is 50-87.5ng/mL for the intermittent dosing schedule, ~10-21% of patients experience higher exposures (>87.5ng/mL), correlated with an increased risk for toxicity. Previous research identified single nucleotide variants (SNVs) in genes from the sunitinib pharmacokinetic pathway to be associated with efficacy and toxicity. However, significant interindividual variability in exposure remains unexplained. Our aim was to identify genetic variants associated with supratherapeutic exposure of sunitinib. This was a genome-wide association study. Cases were identified during routine therapeutic drug monitoring and consisted of patients with dose-normalized sunitinib plasma concentrations >87.5 ng/mL (intermittent dosing) or >75 ng/mL (continuous dosing). Controls were sampled from the historical cohort EuroTARGET who tolerated the standard dose of 50 mg in an intermittent schedule. SNVs were tested for an association with sunitinib exposure. A P-value ≤5 × 10-8 was considered significant and a P-value between 5 × 10-8 and 5 × 10-6 was considered suggestive. Sixty-nine cases and 345 controls were included for association analysis. One SNV (rs6923761), located on the gene glucagon-like peptide 1 receptor, was significantly associated with increased sunitinib exposure (P = 7.86 × 10-19). Twelve SNVs were suggestive for an association with sunitinib exposure (P≤ 5 × 10-6). While rs6923671 is associated with high sunitinib exposure, the underlying mechanism is not yet clarified and warrants further investigation. We could not confirm the earlier found associations between SNVs in candidate genes involved in the pharmacokinetic pathway of sunitinib and its efficacy and toxicity.

Evaluation of the Behavioral Effect of Psychostimulants in Children with Autism Spectrum Disorder: A Cross-Sectional Study.

Autism spectrum disorder (ASD) is often accompanied by comorbid conditions such as attention deficit hyperactivity disorder and epilepsy. In this context, patients are often treated with psychostimulants in an attempt to control behavioral symptoms. This study aims to understand the behavioral effects of psychostimulants in children with ASD and investigate if interictal epileptiform discharges on electroencephalogram (EEG) can act as a modifying factor in this behavior. Sixty-eight patients with ASD who were being accompanied in the Department of Child and Adolescent Psychiatry of the Centro Hospitalar Universitário de São João and had previously done an EEG assessment answered a questionnaire regarding their behavioral response to psychostimulants. In total, 47.4% of patients reported improved agitation, 56.1% enhanced concentration, and 8.8% improved sleep. Conversely, 28.1% experienced worsened agitation, 15.8% worsened concentration, and 17.5% worsened sleep. The remaining reported no alterations. The age of diagnosis correlated significantly with improved agitation, with a higher diagnosis age being associated with a higher probability of improvement. Extended-release methylphenidate and genetic variations were significantly associated with worsening of agitation. Regarding speech, 86% exhibited no changes, while 14% showed alterations, mostly, 87.5%, characterized as negative. For other behavioral alterations, 45.6% reported negative changes, 3.5% reported positive changes, and 50.9% reported no additional alterations. Female gender was significantly associated with other negative behavioral changes. A significant correlation was found between treatment duration and the probability of improvement in agitation, concentration, and other behavioral changes.

Analysis of the Mitochondrial COI Gene and Genetic Diversity of Endangered Goose Breeds

The mitochondrial cytochrome c oxidase subunit I (COI) genes of six endangered goose breeds (Xupu, Yangjiang, Yan, Wuzong, Baizi, and Lingxian) were sequenced and compared to assess the genetic diversity of endangered goose breeds. By constructing phylogenetic trees and evolutionary maps of genetic relationships, the affinities and degrees of genetic variations among the six different breeds were revealed. A total of 92 polymorphic sites were detected in the 741 bp sequence of the mtDNA COI gene after shear correction, and the GC content of the processed sequence (51.11%) was higher than that of the AT content (48.89%). The polymorphic loci within the populations of five of the six breeds (Xupu, Yangjiang, Yan, Baizi, and Lingxian) were more than 10, the haplotype diversity &gt; 0.5, and the nucleotide diversity (Pi) &gt; 0.005, with the Baizi geese being the exception. A total of 35 haplotypes were detected based on nucleotide variation among sequences, and the goose breed haplotypes showed a central star-shaped dispersion; the FST values were −0.03781 to 0.02645, The greatest genetic differentiation (FST = 0.02645) was observed in Yan and Wuzong breeds. The most frequent genetic exchange (Nm &gt; 15.00) was between the Wuzong and Yangjiang geese. An analysis of molecular variance showed that the population genetic variation mainly came from within the population; the base mismatch differential distribution analysis of the goose breeds and the Tajima’s D and Fu’s Fs neutral detection of the historical occurrence dynamics of their populations were negative (p &gt; 0.10). The distribution curve of the base mismatches showed a multimodal peak, which indicated that the population tended to be stabilised. These results provide important genetic information for the conservation and management of endangered goose breeds and a scientific basis for the development of effective conservation strategies.

RBPs: an RNA editor’s choice

RNA-binding proteins (RBPs) play a key role in gene expression and post-transcriptional RNA regulation. As integral components of ribonucleoprotein complexes, RBPs are susceptible to genomic and RNA Editing derived amino acid substitutions, impacting functional interactions. This article explores the prevalent RNA Editing of RBPs, unravelling the complex interplay between RBPs and RNA Editing events. Emphasis is placed on their influence on single amino acid variants (SAAVs) and implications for disease development. The role of Proteogenomics in identifying SAAVs is briefly discussed, offering insights into the RBP landscape. RNA Editing within RBPs emerges as a promising target for precision medicine, reshaping our understanding of genetic and epigenetic variations in health and disease.

Exploring the causality of appendectomy and ischaemic heart disease: a Mendelian randomization study and meta-analysis

BackgroundThe risk of ischaemic heart disease (IHD) is increased in appendectomy patients, but it is not clear whether there is a causal relationship. We aimed to systematically estimate the causal relationship between appendectomy and IHD and its subtypes, acute myocardial infarction (AMI) and angina pectoris (AP), using Mendelian randomization (MR) study methods and meta-analysis.MethodsAs the discovery cohort analysis, we extracted independent genetic variants strongly associated with appendectomy from the FinnGen study (28,601 cases) as instrumental variables (IVs). Genome-wide association study (GWAS) from UK Biobank were selected for outcome data. A first two-sample MR analysis was then conducted. As the replication cohort, IVs associated with appendectomy were extracted in the UK Biobank (50,105 cases). GWAS from the FinnGen study were selected for outcome data. A second MR analysis was then performed. Finally, meta-analyses were applied to assess the combined causal effects of the MR results.ResultsIn the discovery cohort, there was a significant positive causal relationship between appendectomy and IHD and its subtypes AMI and AP. The replication cohort only found a positive causal relationship between appendectomy and AMI. Meta-analysis showed a positive causal relationship between appendectomy and IHD (OR: 1.128, 95% CI: 1.067–1.193, P = 2.459e-05), AMI (OR: 1.195, 95% CI: 1.095–1.305, P = 6.898e-05), and AP (OR: 1.087, 95% CI: 1.016–1.164, P = 1.598e-02).ConclusionsThis comprehensive MR analysis suggests that genetically predicted appendectomy may be a risk factor for the development of IHD and its subtypes AMI and AP. We need to continue to pay attention to these links.

The known and unknown about attention deficit hyperactivity disorder (ADHD) genetics: a special emphasis on Arab population

Attention deficit hyperactivity disorder (ADHD) is a clinically and genetically heterogeneous neurodevelopmental syndrome characterized by behavioral appearances such as impulsivity, inattention, and hyperactivity. The prevalence of ADHD is high in childhood when compared to adults. ADHD has been significantly advanced by genetic research over the past 25 years. However, it is logically conceivable that both genetic and/or non-genetic factors, such as postnatal environmental and social influences, are associated with ADHD phenotype in Arab populations. While genetic influences are strongly linked with the etiology of ADHD, it remains obscure how consanguinity which is an underlying factor for many genetic diseases, contributes to ADHD subtypes. Arabian Gulf Nations have one the highest rates of consanguineous marriages, and consanguinity plays an important contributing factor in many genetic diseases that exist in higher percentages in Arabian Gulf Nations. Therefore, the current review aims to shed light on the genetic variants associated with ADHD subtypes in Arabian Gulf nations and Saudi Arabia in particular. It also focuses on the symptoms and the diagnosis of ADHD before turning to the neuropsychological pathways and subgroups of ADHD. The impact of a consanguinity-based understanding of the ADHD subtype will help to understand the genetic variability of the Arabian Gulf population in comparison with the other parts of the world and will provide novel information to develop new avenues for future research in ADHD.

DNA-binding factor footprints and enhancer RNAs identify functional non-coding genetic variants

BackgroundGenome-wide association studies (GWAS) have revealed a multitude of candidate genetic variants affecting the risk of developing complex traits and diseases. However, the highlighted regions are typically in the non-coding genome, and uncovering the functional causative single nucleotide variants (SNVs) is challenging. Prioritization of variants is commonly based on genomic annotation with markers of active regulatory elements, but current approaches still poorly predict functional variants. To address this, we systematically analyze six markers of active regulatory elements for their ability to identify functional variants.ResultsWe benchmark against molecular quantitative trait loci (molQTL) from assays of regulatory element activity that identify allelic effects on DNA-binding factor occupancy, reporter assay expression, and chromatin accessibility. We identify the combination of DNase footprints and divergent enhancer RNA (eRNA) as markers for functional variants. This signature provides high precision, but with a trade-off of low recall, thus substantially reducing candidate variant sets to prioritize variants for functional validation. We present this as a framework called FINDER—Functional SNV IdeNtification using DNase footprints and eRNA.ConclusionsWe demonstrate the utility to prioritize variants using leukocyte count trait and analyze variants in linkage disequilibrium with a lead variant to predict a functional variant in asthma. Our findings have implications for prioritizing variants from GWAS, in development of predictive scoring algorithms, and for functionally informed fine mapping approaches.

In Silico Deciphering of the Potential Impact of Variants of Uncertain Significance in Hereditary Colorectal Cancer Syndromes

Colorectal cancer (CRC) ranks third in terms of cancer incidence worldwide and is responsible for 8% of all deaths globally. Approximately 10% of CRC cases are caused by inherited pathogenic mutations in driver genes involved in pathways that are crucial for CRC tumorigenesis and progression. These hereditary mutations significantly increase the risk of initial benign polyps or adenomas developing into cancer. In recent years, the rapid and accurate sequencing of CRC-specific multigene panels by next-generation sequencing (NGS) technologies has enabled the identification of several recurrent pathogenic variants with established functional consequences. In parallel, rare genetic variants that are not characterized and are, therefore, called variants of uncertain significance (VUSs) have also been detected. The classification of VUSs is a challenging task because each amino acid has specific biochemical properties and uniquely contributes to the structural stability and functional activity of proteins. In this scenario, the ability to computationally predict the effect of a VUS is crucial. In particular, in silico prediction methods can provide useful insights to assess the potential impact of a VUS and support additional clinical evaluation. This approach can further benefit from recent advances in artificial intelligence-based technologies. In this review, we describe the main in silico prediction tools that can be used to evaluate the structural and functional impact of VUSs and provide examples of their application in the analysis of gene variants involved in hereditary CRC syndromes.