Genetic Variation In Genes Research Articles

Connecting the Dots: Exploring the Interplay Between Preeclampsia and Peripartum Cardiomyopathy.

Preeclampsia and peripartum cardiomyopathy (PPCM) are significant obstetric problems that can arise during or after pregnancy. Both are known to be causes of maternal mortality and morbidity. Several recent studies have suggested a link between preeclampsia and the pathophysiology of PPCM. However, the common thread that connects the two has yet to be thoroughly and fully articulated. Here, we investigate the complex dynamics of preeclampsia and PPCM in this review. Our analysis focuses mainly on inflammatory and immunological responses, endothelial dysfunction as a shared pathway, and potential genetic predisposition to both diseases. To begin, we will look at how excessive inflammatory and immunological responses can lead to clinical symptoms of both illnesses, emphasizing the role of proinflammatory cytokines and immune cells in modifying vascular and tissue responses. Second, we consider endothelial dysfunction to be a crucial point at which endothelial damage and activation contribute to pathogenesis through increased vascular permeability, vascular dysfunction, and thrombus formation. Finally, we examine recent information suggesting genetic predispositions to preeclampsia and PPCM, such as genetic variants in genes involved in the management of blood pressure, the inflammatory response, and heart structural integrity. With this synergistic study, we seek to encourage more research and creative therapy solutions by emphasizing the need for an interdisciplinary approach to understanding and managing the connection between preeclampsia and PPCM.

Role of Single-Nucleotide Polymorphisms in Genes Implicated in Capecitabine Pharmacodynamics on the Effectiveness of Adjuvant Therapy in Colorectal Cancer.

Colorectal cancer (CRC) is a highly prevalent form of neoplasm worldwide. Capecitabine, an oral antimetabolite, is widely used for CRC treatment; however, there exists substantial variation in individual therapy response. This may be due to genetic variations in genes involved in capecitabine pharmacodynamics (PD). In this study, we investigated the role of single-nucleotide polymorphisms (SNPs) related to capecitabine's PD on disease-free survival (DFS) in CRC patients under adjuvant treatment. Thirteen SNPs in the TYMS, ENOSF1, MTHFR, ERCC1/2, and XRCC1/3 genes were genotyped in 142 CRC patients using real-time PCR with predesigned TaqMan® probes. A significant association was found between favorable DFS and the ENOSF1 rs2612091-T allele (p = 0.010; HR = 0.34; 95% CI = 0.14-0.83), as well as with the TYMS/ENOSF1 region ACT haplotype (p = 0.012; HR = 0.37; 95% CI = 0.17-0.80). Other factors such as low histological grade (p = 0.009; HR = 0.34; 95% CI = 0.14-0.79) and a family history of cancer (p = 0.040; HR = 0.48; 95% CI = 0.23-0.99) were also linked to improved DFS. Therefore, the SNP ENOSF1 rs2612091 could be considered as a predictive genetic biomarker for survival in CRC patients receiving capecitabine-based adjuvant regimens.

Whole‐exome sequencing of a Portuguese cohort of early‐onset Alzheimer’s disease implicates X‐linked lysosomal gene GLA

AbstractBackgroundCerebrovascular disease is a common comorbidity in patients with Alzheimer’s disease (AD) and other dementias. Accumulating evidence indicates that dysfunction of the cerebral vasculature and AD neuropathology interact in multiple ways. In fact, some studies have associated common variants in COL4A1 and rare variants in HTRA1, NOTCH3, COL4A1, and CST3 with AD pathogenesis.We aimed to identify rare genetic variants in genes associated with monogenic small vessel disease in in a cohort of Portuguese early‐onset AD patients.MethodWe performed whole‐exome sequencing in a cohort of 104 thoroughly studied patients with early‐onset AD, without known pathogenic variants in the genes associated with AD or frontotemporal dementia. In these patients, we searched for rare (MAF<0.001) non‐synonymous variants in genes associated with small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2, CSTA, GLA and TREX1.ResultIn total, we found 12 rare variants in 18 patients. We found 3 male AD patients with a pathogenic GLA variant. We found other rare variants in NOTCH3, COL4A2 and HTRA1. Of the 3 patients carrying a GLA variant, one had a neuropathological study confirming the diagnosis of AD . This individual also revealed Fabry disease pathology in the hippocampal formation (CA1 to CA4 and subiculum).ConclusionWe found several rare variants on the genes of interest in our cohort. We provide evidence supporting the pathogenicity of the GLA variant. We show that 3 carriers of this variant, without other probable genetic cause responsible for the disease, developed early‐onset AD. One of those cases had post‐mortem confirmation of the diagnosis. We further show the localization of Fabry pathology in several areas that are vulnerable in AD. This poses the question of the variant’s possible role in AD pathogenesis.

Role of the Glycine Receptor β Subunit in Synaptic Localization and Pathogenicity in Severe Startle Disease.

Startle disease is due to the disruption of recurrent inhibition in the spinal cord. Most common causes are genetic variants in genes (GLRA1, GLRB) encoding inhibitory glycine receptor (GlyR) subunits. The adult GlyR is a heteropentameric complex composed of α1 and β subunits that localizes at postsynaptic sites and replaces embryonically expressed GlyRα2 homomers. The human GlyR variants of GLRA1 and GLRB, dominant and recessive, have been intensively studied in vitro. However, the role of unaffected GlyRβ, essential for synaptic GlyR localization, in the presence of mutated GlyRα1 in vivo is not fully understood. Here, we used knock-in mice expressing endogenous mEos4b-tagged GlyRβ that were crossed with mouse Glra1 startle disease mutants. We explored the role of GlyRβ under disease conditions in mice carrying a missense mutation (shaky) or resulting from the loss of GlyRα1 (oscillator). Interestingly, synaptic targeting of GlyRβ was largely unaffected in both mouse mutants. While synaptic morphology appears unaltered in shaky animals, synapses were notably smaller in homozygous oscillator animals. Hence, GlyRβ enables transport of functionally impaired GlyRα1 missense variants to synaptic sites in shaky animals, which has an impact on the efficacy of possible compensatory mechanisms. The observed enhanced GlyRα2 expression in oscillator animals points to a compensation by other GlyRα subunits. However, trafficking of GlyRα2β complexes to synaptic sites remains functionally insufficient, and homozygous oscillator mice still die at 3 weeks after birth. Thus, both functional and structural deficits can affect glycinergic neurotransmission in severe startle disease, eliciting different compensatory mechanisms in vivo.

Genetics of human longevity: From variants to genes to pathways.

The current increase in lifespan without an equivalent increase in healthspan poses a grave challenge to the healthcare system and a severe burden on society. However, some individuals seem to be able to live a long and healthy life without the occurrence of major debilitating chronic diseases, and part of this trait seems to be hidden in their genome. In this review, we discuss the findings from studies on the genetic component of human longevity and the main challenges accompanying these studies. We subsequently focus on results from genetic studies in model organisms and comparative genomic approaches to highlight the most important conserved longevity-associated pathways. By combining the results from studies using these different approaches, we conclude that only five main pathways have been consistently linked to longevity, namely (1) insulin/insulin-like growth factor 1 signalling, (2) DNA-damage response and repair, (3) immune function, (4) cholesterol metabolism and (5) telomere maintenance. As our current approaches to study the relevance of these pathways in humans are limited, we suggest that future studies on the genetics of human longevity should focus on the identification and functional characterization of rare genetic variants in genes involved in these pathways.

Food Administration and Not Genetic Variants Causes Pharmacokinetic Variability of Tadalafil and Finasteride.

Tadalafil and finasteride are used in combination for the management of benign prostatic hyperplasia (BPH). Genetic variations in genes involved in the metabolism and transport of tadalafil or finasteride (i.e., pharmacogenes) could affect their pharmacokinetic processes altering their drug exposure, efficacy, and toxicity. The main objective of this study was to investigate the effects of variants in pharmacogenes on the pharmacokinetics of tadalafil and finasteride. An exploratory candidate gene study involving 120 variants in 33 genes was performed with 66 male healthy volunteers from two bioequivalence clinical trials after administration of tadalafil/finasteride 5 mg/5 mg under fed or fasting conditions. Afterwards, a confirmatory study was conducted with 189 male and female volunteers receiving tadalafil 20 mg formulations in seven additional bioequivalence clinical trials. Regarding tadalafil, fed volunteers showed higher area in the time-concentration curve (AUC∞), maximum plasma concentration (Cmax), and time to reach Cmax (tmax) compared to fasting volunteers; male volunteers also showed higher AUC∞ and Cmax compared to female volunteers. Furthermore, fed volunteers presented higher finasteride AUC∞, Cmax and tmax compared to fasting individuals. Variants in ABCC3, CYP1A2, CES1, NUDT15, SLC22A1/A2 and UGT2B10 were nominally associated with pharmacokinetic variation in tadalafil and/or finasteride but did not remain significant after correction for multiple comparisons. Genetic variation did not demonstrate to clinically impact on the pharmacokinetics of finasteride and tadalafil; however, additional studies with larger sample sizes are needed to assess the effect of rare variants, such as CYP3A4*20 or *22, on tadalafil and finasteride pharmacokinetics.

A Non-Coding Fc Gamma Receptor Cis-Regulatory Variant within the 1q23 Gene Cluster Is Associated with Plasmodium falciparum Infection in Children Residing in Burkina Faso

Antibodies play a crucial role in activating protective immunity against malaria by interacting with Fc-gamma receptors (FcγRs). Genetic variations in genes encoding FcγRs can affect immune cell responses to the parasite. In this study, our aim was to investigate whether non-coding variants that regulate FcγR expression could influence the prevalence of Plasmodium falciparum infection. Through bioinformatics approaches, we selected expression quantitative trait loci (eQTL) for FCGR2A, FCGR2B, FCGR2C, FCGR3A, and FCGR3B genes encoding FcγRs (FCGR), in whole blood. We prioritized two regulatory variants, rs2099684 and rs1771575, located in open genomic regions. These variants were identified using RegVar, ImmuNexUT, and transcription factor annotations specific to immune cells. In addition to these, we genotyped the coding variants FCGR2A/rs1801274 and FCGR2B/rs1050501 in 234 individuals from a malaria-endemic area in Burkina Faso. We conducted age and family-based analyses to evaluate associations with the prevalence of malarial infection in both children and adults. The analysis revealed that the regulatory rs1771575-CC genotype was predicted to influence FCGR2B/FCGR2C/FCGR3A transcripts in immune cells and was the sole variant associated with a higher prevalence of malarial infection in children. In conclusion, this study identifies the rs1771575 cis-regulatory variant affecting several FcγRs in myeloid and neutrophil cells and associates it with the inter-individual capacity of children living in Burkina Faso to control malarial infection.

Impact of Sex and Genetic Variation in Relevant Pharmacogenes on the Pharmacokinetics and Safety of Valsartan, Olmesartan and Hydrochlorothiazide.

Drug combination therapy is the most common pharmacological strategy for hypertension management. No pharmacogenetic biomarkers for guiding hypertension pharmacotherapy are available to date. The study population were 64 volunteers from seven bioequivalence trials investigating formulations with valsartan, olmesartan and/or hydrochlorothiazide. Every volunteer was genotyped for 10 genetic variants in different transporters' genes. Additionally, valsartan-treated volunteers were genotyped for 29 genetic variants in genes encoding for different metabolizing enzymes. Variability in pharmacokinetic parameters such as maximum concentration (Cmax) and time to reach it (tmax), the incidence of adverse drug reactions (ADRs) and blood pressure measurements were analyzed as a function of pharmacogenetic and demographic parameters. Individuals with the ABCB1 rs1045642 T/T genotype were associated with a higher valsartan tmax compared to those with T/G and G/G genotypes (p < 0.001, β = 0.821, R2 = 0.459) and with a tendency toward a higher postural dizziness incidence (11.8% vs. 0%, p = 0.070). A higher hydrochlorothiazide dose/weight (DW)-corrected area under the curve (AUC∞/DW) was observed in SLC22A1 rs34059508 G/A volunteers compared to G/G volunteers (p = 0.050, β = 1047.35, R2 = 0.051), and a tendency toward a higher postural dizziness incidence (50% vs. 1.6%, p = 0.063). Sex impacted valsartan and hydrochlorothiazide pharmacokinetics, showing a lower exposure in women, whereas no significant differences were found for olmesartan pharmacokinetics.

Genetic and sporadic forms of tauopathies-TAU as a disease driver for the majority of patients but the minority of tauopathies.

Ageing-associated tauopathies like frontotemporal dementia (FTD), variants thereof (like progressive supranuclear palsy (PSP), pick diseases (PiD), corticobasal degeneration (CBD)), and of course the most prevalent form of dementia, Alzheimer Disease (AD), are widely recognized forms of tauopathies. The list of tauopathies is expanding. We now include: (i) tauopathies where the disease cause or trigger is clearly either physical, such as in Traumatic Brain Injury (TBI) or Chronic Traumatic Encephalopathy (CTE), and (ii) genetic diseases that result in tauopathy but have pathogenic genetic variants in genes not related to TAU. Examples of the latter are myotonic dystrophy Type 1 and Type 2 (DM1, DM2, due to pathogenic genetic variants in the genes DMPK and CNBP, respectively), Niemann-Pick Disease Type C (NPD, due to mutations in NPC1 or NPC2), Kufs Disease (CLN6), Christianson Syndrome (SLC9A6), familial forms of Parkinson Disease (PD), and many others. In terms of affected brain regions and cell types, intracellular distribution of TAU pathology/aggregates, age of disease onset, velocity of disease progression and spreading of TAU pathology, there is, however, little in common in most of these disease entities. Here, I reason that TAU/MAPT is causative for the minority of tauopathies (e.g., MAPT-related FTD/PSP and Vacuolar Tauopathy (VCP)) and a critical mediator for others, like shown by overwhelming evidence for AD. However, TAU may also be a mere bystander or even protective in other settings. Improved understanding of rare tauopathies is necessary to develop specific treatments, but also to improve our understanding of the pathomechanistic role of TAU and to identify diseases that may profit from TAU-based therapies.

Identification and analysis of individuals who deviate from their genetically-predicted phenotype.

Findings from genome-wide association studies have facilitated the generation of genetic predictors for many common human phenotypes. Stratifying individuals misaligned to a genetic predictor based on common variants may be important for follow-up studies that aim to identify alternative causal factors. Using genome-wide imputed genetic data, we aimed to classify 158,951 unrelated individuals from the UK Biobank as either concordant or deviating from two well-measured phenotypes. We first applied our methods to standing height: our primary analysis classified 244 individuals (0.15%) as misaligned to their genetically predicted height. We show that these individuals are enriched for self-reporting being shorter or taller than average at age 10, diagnosed congenital malformations, and rare loss-of-function variants in genes previously catalogued as causal for growth disorders. Secondly, we apply our methods to LDL cholesterol (LDL-C). We classified 156 (0.12%) individuals as misaligned to their genetically predicted LDL-C and show that these individuals were enriched for both clinically actionable cardiovascular risk factors and rare genetic variants in genes previously shown to be involved in metabolic processes. Individuals whose LDL-C was higher than expected based on the genetic predictor were also at higher risk of developing coronary artery disease and type-two diabetes, even after adjustment for measured LDL-C, BMI and age, suggesting upward deviation from genetically predicted LDL-C is indicative of generally poor health. Our results remained broadly consistent when performing sensitivity analysis based on a variety of parametric and non-parametric methods to define individuals deviating from polygenic expectation. Our analyses demonstrate the potential importance of quantitatively identifying individuals for further follow-up based on deviation from genetic predictions.

Utility of pharmacogenetic testing to optimise antidepressant pharmacotherapy in youth: a narrative literature review.

Pharmacogenetics (PGx) is the study and application of how interindividual differences in our genomes can influence drug responses. By evaluating individuals' genetic variability in genes related to drug metabolism, PGx testing has the capabilities to individualise primary care and build a safer drug prescription model than the current "one-size-fits-all" approach. In particular, the use of PGx testing in psychiatry has shown promising evidence in improving drug efficacy as well as reducing toxicity and adverse drug reactions. Despite randomised controlled trials demonstrating an evidence base for its use, there are still numerous barriers impeding its implementation. This review paper will discuss the management of mental health conditions with PGx-guided treatment with a strong focus on youth mental illness. PGx testing in clinical practice, the concerns for its implementation in youth psychiatry, and some of the barriers inhibiting its integration in clinical healthcare will also be discussed. Overall, this paper provides a comprehensive review of the current state of knowledge and application for PGx in psychiatry and summarises the capabilities of genetic information to personalising medicine for the treatment of mental ill-health in youth.

Oxidative stress-related genetic variation and antioxidant vitamin intake in intact and ruptured abdominal aortic aneurysm: a Swedish population-based retrospective cohort study.

The aim of this study is to investigate how genetic variations in genes related to oxidative stress, intake of antioxidant vitamins, and any potential interactions between these factors affect the incidence of intact abdominal aortic aneurysm (AAA) and its rupture (rAAA), accounting for sex differences where possible. The present retrospective cohort study (n = 25 252) uses baseline single-nucleotide polymorphisms (SNPs) and total antioxidant vitamin intake data from the large population-based, Malmö Diet and Cancer Study. Cumulative incidence of intact AAA was 1.6% and of rAAA 0.3% after a median follow-up of 24.3 years. A variant in NOX3 (rs3749930) was associated with higher rAAA risk in males [adjusted hazard ratio (aHR): 2.49; 95% confidence interval (CI): 1.36-4.35] and the overall population (aHR: 1.88; 95% CI: 1.05-3.37). Higher intakes of antioxidant vitamins, riboflavin, and folate were associated with 20% and 19% reduced intact AAA incidence, respectively. Interestingly, the inverse associations between riboflavin and vitamin D intake with intact AAA incidence were stronger in the individuals carrying the NOX3 variant as compared with the wild-type recessive genotype, i.e. by 60% and 66%, respectively (P for interaction < 0.05). Higher riboflavin intake was associated with a 33% male-specific intact AAA risk reduction, while higher intake of vitamin B12 intake was associated with 55% female-specific intact AAA risk increase; both these associations were significantly modified by sex (P for interaction < 0.05). Our findings highlight the role of oxidative stress genetic variations and antioxidant vitamin intake in AAA. Although a low AAA/rAAA sample size limited some analyses, especially in females, our findings highlight the need for future randomized controlled trials and mechanistic studies, to explore the potential benefits of antioxidant vitamins while accounting for genetic and sex differences.

Genetic aspects underlying the normocalcemic and hypercalcemic phenotypes of primary hyperparathyroidism.

Hypercalcemic primary hyperparathyroidism (PHPT) is a common endocrine disorder that has been very well characterized. In contrast, many aspects of normocalcemic primary hyperparathyroidism (NPHPT) such as natural history, organ damage, and management are still matter of debate. In addition, both the pathophysiology and molecular basis of NPHPT are unclear. We investigated whether PHPT and NPHPT patient cohorts share the same pattern of genetic variation in genes known to be involved in calcium and/or bone metabolism. Genotyping for 9 single nucleotide polymorphisms (SNPs) was performed by Real-Time PCR (TaqMan assays) on 27 NPHPT and 31 PHPT patients evaluated in a tertiary referral Center. The data of both groups were compared with 54 in house-controls and 503 subjects from the 1000 Genomes Project. All groups were compared for allele/haplotype frequencies, on a single locus, two loci and multi-locus basis. The NPHPT group differed significantly at SNPs in OPG and ESR1. Also, the NPHPT cohort was peculiar for pairwise associations of genotypes and for the overrepresentation of unusual multilocus genotypes. Our NPHPT patient set harbored a definitely larger quota of genetic diversity than the other samples. Specific genotypes may help in defining subgroups of NPHPT patients which deserve ad hoc clinical and follow-up studies.

Influence of alcohol consumption and alcohol metabolism variants on breast cancer risk among Black women: results from the AMBER consortium

BackgroundModerate to heavy alcohol consumption is associated with an increased risk of breast cancer. The etiologic role of genetic variation in genes involved in ethanol metabolism has not been established, with little information available among women of African ancestry.MethodsOur analysis from the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium included 2889 U.S. Black women who were current drinkers at the time of breast cancer diagnosis (N cases = 715) and had available genetic data for four ethanol metabolism genomic regions (ADH, ALDH, CYP2E1, and ALDH2). We used generalized estimating equations to calculate genetic effects, gene* alcohol consumption (≥ 7drinks/week vs. < 7/week) interactions, and joint main plus interaction effects of up to 23,247 variants in ethanol metabolism genomic regions on odds of breast cancer.ResultsAmong current drinkers, 21% of cases and 14% of controls reported consuming ≥ 7 drinks per week. We identified statistically significant genetic effects for rs79865122-C in CYP2E1 with odds of ER- breast cancer and odds of triple negative breast cancer, as well as a significant joint effect with odds of ER- breast cancer (≥ 7drinks per week OR = 3.92, < 7 drinks per week OR = 0.24, pjoint = 3.74 × 10−6). In addition, there was a statistically significant interaction of rs3858704-A in ALDH2 with consumption of ≥ 7 drinks/week on odds of triple negative breast cancer (≥ 7drinks per week OR = 4.41, < 7 drinks per week OR = 0.57, pint = 8.97 × 10–5).ConclusionsThere is a paucity of information on the impact of genetic variation in alcohol metabolism genes on odds of breast cancer among Black women. Our analysis of variants in four genomic regions harboring ethanol metabolism genes in a large consortium of U.S. Black women identified significant associations between rs79865122-C in CYP2E1 and odds of ER- and triple negative breast cancer. Replication of these findings is warranted.

Genetic disruption of mammalian endoplasmic reticulum-associated protein degradation: Human phenotypes and animal and cellular disease models.

Endoplasmic reticulum-associated protein degradation (ERAD) is a stringent quality control mechanism through which misfolded, unassembled and some native proteins are targeted for degradation to maintain appropriate cellular and organelle homeostasis. Several in vitro and in vivo ERAD-related studies have provided mechanistic insights into ERAD pathway activation and its consequent events; however, a majority of these have investigated the effect of ERAD substrates and their consequent diseases affecting the degradation process. In this review, we present all reported human single-gene disorders caused by genetic variation in genes that encode ERAD components rather than their substrates. Additionally, after extensive literature survey, we present various genetically manipulated higher cellular and mammalian animal models that lack specific components involved in various stages of the ERAD pathway.

Calculation of the pharmacogenomics benefit score for patients with medication-related problems.

Unexpected poor efficacy and intolerable adverse effects are medication-related problems that may result from genetic variation in genes encoding key proteins involved in pharmacokinetics or pharmacodynamics. Pharmacogenomic (PGx) testing can be used in medical practice "pre-emptively" to avoid future patient harm from medications and "reactively" to diagnose medication-related problems following their occurrence. A structured approach to PGx consulting is proposed to calculate the pharmacogenomics benefit score (PGxBS), a patient-centered objective measure of congruency between medication-related problems and patient genotypes. An example case of poor efficacy with multiple medications is presented, together with comments on the potential benefits and limitations of using the PGxBS in medical practice.

Genetic polymorphisms in genes regulating cell death and prognosis of patients with rectal cancer receiving postoperative chemoradiotherapy.

The identification of biomarkers for predicting chemoradiotherapy efficacy is essential to optimize personalized treatment. This study determined the effects of genetic variations in genes involved in apoptosis, pyroptosis, and ferroptosis on the prognosis of patients with locally advanced rectal cancer receiving postoperative chemoradiotherapy (CRT). The Sequenom MassARRAY was used to detect 217 genetic variations in 40 genes from 300 patients with rectal cancer who received postoperative CRT. The associations between genetic variations and overall survival (OS) were evaluated using hazard ratios (HRs) and 95% confidence intervals (CIs) computed using a Cox proportional regression model. Functional experiments were performed to determine the functions of the arachidonate 5-lipoxygenase (ALOX5) gene and the ALOX5 rs702365 variant. We detected 16 genetic polymorphisms in CASP3, CASP7, TRAILR2, GSDME, CASP4, HO-1, ALOX5, GPX4, and NRF2 that were significantly associated with OS in the additive model (P < 0.05). There was a substantial cumulative effect of three genetic polymorphisms (CASP4 rs571407, ALOX5 rs2242332, and HO-1 rs17883419) on OS. Genetic variations in the CASP4 and ALOX5 gene haplotypes were associated with a higher OS. We demonstrated, for the first time, that rs702365 [G] > [C] represses ALOX5 transcription and corollary experiments suggested that ALOX5 may promote colon cancer cell growth by mediating an inflammatory response. Polymorphisms in genes regulating cell death may play essential roles in the prognosis of patients with rectal cancer who are treated with postoperative CRT and may serve as potential genetic biomarkers for individualized treatment.

Thyrotoxic periodic paralysis in a Caucasian man without identifiable genetic predisposition: a case report

BackgroundThyrotoxic periodic paralysis (TPP) is a rare condition characterized by muscle paralysis, thyrotoxicosis, and hypokalemia. It presents with paralysis of both proximal and distal musculature in upper and lower limbs and may affect respiratory musculature and the cardiac conduction system. Early diagnosis is essential, as the condition is potentially reversible by oral or intravenous potassium treatment, leading to rapid resolution without lasting weakness. Overlooking the diagnosis may result in respiratory failure and cardiac arrhythmias including QT prolongation, Torsades de points, and ventricular arrhythmias.Case presentationA 19-year-old Caucasian man was admitted acutely with paralysis in upper and lower limbs and tachycardia. Over several months, he had experienced anxiousness, sweating more than usual, had daily palpitations, shortness of breath on exertion, and loose stools, and had lost 21 kg over the last year. Initial blood gas showed very low potassium of 1.4 mM, and blood tests showed decreased Thyroid-stimulating hormone (TSH) < 0.01 × 10− 3 IU/L, elevated free thyroxine (fT4) of 63.5 pM (reference interval (RI): 12.0–22.0 pM), and elevated total triiodothyronine (T3) of 8.2 nM (RI: 1.0–2.6 nM). He was diagnosed with TPP and treated with liquid oral potassium chloride (30 mmol every 30 minutes) and propylthiouracil (initial dose of 400 mg followed by 200 mg three times daily). TSH-receptor antibodies (TRAB) and thyroid-peroxidase antibodies (TPO-ab) were highly elevated. Thyroid ultrasound showed a normal-sized gland and color Doppler sonography showed increased vascularity throughout the gland, compatible with Graves’ disease. He was discharged on day 4 with a normal potassium level and followed in the outpatient clinic where he received standard care for Graves’ disease. Genetic testing using whole-genome sequencing found no genetic variants in genes previously associated with TPP.ConclusionTPP is very rare in Caucasians but more often affects young men in East Asian populations. The case presents a Caucasian man with TPP where genetic testing of CACNA1S, KCNJ18, SCN4A, KCNJ2, KCNE3, and ABCC8 shows no pathogenic variants in genes previously associated with TPP.

Adiponectin Gene Polymorphisms and Possible Susceptibility to Metabolic Syndrome among the Sudanese Population: A Case-Control Study.

There is a significant difference in genotypic frequencies of the rs266729, rs2241766, and rs1501299 SNPs and allele frequencies (P < 0.05) between the MetS patients and non-MetS group. MetS patients had a significantly higher serum triglycerides (TG), total cholesterol (TC), and low-density lipoprotein-cholesterol (LDL-C) in the GG genotype of rs2241766 (P < 0.05). Additionally; the TT genotype of rs1501299 had higher SBP, serum TG, TC, and LDL-C (P < 0.05). Multivariate logistic regression analysis showed hypertension, hyperglycemia, BMI, WC, serum TG, ADIPOQ rs2241766 (TG allele), and ADIPOQ rs1501299 (GT allele) had independently predicted the incidence of metabolic syndrome in the Sudanese population. The three investigated SNPs of ADIPOQ were in a moderate linkage disequilibrium (LD) connection according to the LD measures (D' = 0.54, 0.62, and 0.69, respectively). The CTT, CGG, and GTG haplotypes, which consist of three alleles of -11377C > G, +45T > G, and +276G > T, were shown to report 1.788-, 1.622,- and 1.641-fold risks toward MetS susceptibility in Sudanese's population, respectively. Along with clinical and biochemical signs, the ADIPOQ gene's genetic variants (rs266729, rs2241766, and rs1501299), CTT, CGG, and GTG haplotypes are connected to the MetS risk among the Sudanese population.

Deep Mutational Scanning and High-throughput Functional Testing to Resolve Variants of Unknown Significance in Sarcoglycanopathies (N4.001)

<h3>Objective:</h3> The goal of this study was to accurately predict the pathogenicity of all possible protein-coding genetic variation in genes causing sarcoglycanopathies. <h3>Background:</h3> Limb-girdle muscular dystrophies R3/R4/R5 are due to recessive mutations in <i>SGCA</i>, <i>SGCB</i> and <i>SGCG</i>. Genetic variation identified within genetic test reports leads to diagnostic uncertainty. Only 14% of missense variants in the sarcoglycan genes have been asserted as either benign or pathogenic; with the vast majority being “variants of unknown significance (VUS).” VUS in LGMD genes leads to an under recognition of these diseases that have treatments within the pre-clinical pipeline. <h3>Design/Methods:</h3> To help resolve VUSs, we performed Deep Mutational Scanning (DMS) to create lentiviral libraries of all possible coding variations in <i>SGCA</i>, <i>SGCB</i> and <i>SGCG</i>. Using these libraries we performed high throughput and orthogonal functional screens in cells followed by sequencing to determine a functional score for each unique variant. <h3>Results:</h3> We tested the effect of all possible coding variants in <i>SGCB</i> to obtain a functional score that predicts the pathogenicity of each genetic variant. The measured scores were perfectly predictive of known pathogenic and benign variants and out-performed all tested bioinformatic prediction algorithms. Validation studies of questionably pathogenic vs benign variants identified in patients support the robustness of our results. Additionally, patient acquired clinical data demonstrated that our DMS functional score was quantitatively correlated with with disease onset and severity. <h3>Conclusions:</h3> In summary, we have generated a valuable resource or “look up table” of functionally defined pathogenic variants in sarcoglycan genes. This type of approach can be utilized for other LGMD genes. In the future these mutational libraries can be used to perform high throughput analysis in the presence and absence of small molecules that may elucidate variant specific therapies. <b>Disclosure:</b> Dr. Haller has nothing to disclose. Dr. Li has nothing to disclose. Dr. Weihl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta. Dr. Weihl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Casma therapeutics. Dr. Weihl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abata. Dr. Weihl has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta. Dr. Weihl has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta. Dr. Weihl has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Acceleron. Dr. Weihl has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Wilson Elser Moskowitz Edelman &amp; Dicker LLP.