Search Results (359)

Autism spectrum disorder (ASD) is a heritable neurodevelopmental condition with a complex genetic architecture. Dissecting the interplay between inherited variants and high-impact de novo variants is critical for understanding its etiology. We conducted a family-based study involving 42 families with ASD (139 individuals). Using a targeted next-generation sequencing (NGS) panel of 236 genes, we identified and characterized rare inherited and de novo variants in affected probands, parents, and unaffected siblings. Our analysis revealed a complex genetic landscape marked by diverse inheritance patterns. De novo variants were predominantly observed in individuals with atypical autism, while biparental (homozygous) inheritance was more common in Asperger syndrome. Maternally inherited variants showed significant enrichment in intronic regions, pointing to a potential regulatory role. We also detected variants in several high-confidence ASD risk genes, including SHANK3, MYT1L, MCPH1, NIPBL, and TSC2, converging on pathways central to synaptic function and neurogenesis. Across the cohort, five variants of uncertain significance (VUS) were identified, comprising two inherited variants in ABCC8 and additional variants in CUL23, TSC2, and MCPH1. Our findings underscore the profound genetic heterogeneity of ASD and suggest that distinct genetic mechanisms and inheritance patterns may contribute to different clinical presentations within the spectrum. This highlights the power of family-based genomic analyses in elucidating the complex interplay of inherited and de novo variants that underlies ASD. Full article

Background/Objectives: Orofacial clefts (OFCs) are among the most common birth defects globally, sometimes exacerbated by adverse drug reactions (ADRs) from corticosteroids and antiepileptics. Comprehending the pharmacogenomic and pharmacogenetic elements that lead to ADRs is essential for enhancing precision medicine and clinical outcomes. This study examines rare genetic variants in drug-metabolizing and drug-transporting genes among Ghanaian and Nigerian families with a history of OFCs, intending to assess their pathogenicity and functional implications. Methods: We recruited 104 Ghanaian families and 26 Nigerian families, generating whole-genome sequencing (WGS) data from 390 individuals (130 case-parent trios). DNA isolated from saliva and buccal swab samples underwent WGS, and subsequent WGS data were analyzed through extensive bioinformatics analyses. Variants were called and annotated using the GATK workflow. The HOPE in silico modeling tool evaluated the structural impact of genetic variants on encoded proteins, while molecular docking using PyRx examined alterations in ligand binding affinity. Results: Our study revealed pathogenic variants in vital genes associated with drug metabolism and transport, specifically CYP1A2, CYP2C18, CYP27A1, CYP2B6, SLC6A2, and ABCC3. Structural modeling research demonstrated substantial size, charge, conformation, and hydrophobicity variations between wildtype and mutant proteins. Variants positioned near conserved regions or within functional domains were anticipated to be deleterious, potentially compromising protein function and ligand interactions. Molecular docking studies verified changes in binding affinities between wildtype and mutant proteins for common ligands. The identified variations were linked to the metabolism of frequently used pharmaceuticals in Africa, such as caffeine, ketoconazole, efavirenz, carbamazepine, and artemether. Conclusions: These findings highlight the need for pharmacogenetic screening to inform personalized medicine, diminish ADRs, and enhance the clinical care of OFCs in Sub-Saharan Africa. Full article

The color of flowers constitutes one of the most significant ornamental characteristics in roses. Red pigmentation in rose flowers is generally controlled by the biosynthetic pathway of anthocyanins. In this study, the red petals from the rose cultivar ‘Silk Road’ (SR) and the white petals from its color mutant ‘Arctic Road’ (AR) were investigated. Transcriptomic and metabolomic analyses were utilized to identify the crucial genes and metabolites associated with the biosynthesis of flavonoids. A total of 479 flavonoid- related metabolites and 39,201 genes were detected in the rose petals. Comparative analyses revealed significant differences in 277 metabolites and 2556 genes between the blooming flowers of AR and SR. The contents of 11 anthocyanins, 11 proanthocyanidins, as well as the expression levels of CHS, ANS, 3GT, COMT, and CCoAOMT differ significantly between the two cultivars, which may contribute to the formation of white petals in AR. Additionally, 5 GSTs, 4 ABCCs, and 8 MATEs were found to be downregulated in AR, potentially resulting in reduced sequestration of anthocyanins in petal vacuoles. Through comprehensive data analyses, the correlations between genes and metabolites associated with anthocyanin variation in rose petals were identified. The MYB gene (Chr1g0360311) may serve as a key regulator in anthocyanin biosynthesis. This study offers new perspectives on the specific genes and metabolites regulating petal pigmentation, as well as the molecular mechanisms underlying flavonoid synthesis in roses. The candidate key genes associated with anthocyanin biosynthesis and sequestration could serve as important genetic resources for developing ornamental plant varieties with specific pigmentation traits. Full article

Since the first paper published by Susan Cole in 1990 detailing multidrug resistance mediated by ABCC1/MRP1, research into the C-subfamily of ATP-binding cassette transporters has continued to uncover a wide range of functionally divergent proteins. However, several orphan transporters remain in the C-subfamily, and the physiological function and substrates of ABCC5, ABCC11, and ABCC12 remain elusive. This review explores the emerging understanding of human ABCC5. Unlike other ABC transporters with well-defined drug export functions, ABCC5’s physiological roles remain only partially understood. While it is known for its involvement in multidrug resistance in cancers, recent studies suggest broader implications in development, metabolism, neurobiology, and male fertility. ABCC5 exports various endogenous substrates, including cyclic nucleotides (cAMP and cGMP), glutamate conjugates like NAAG, and possibly haem. Knockout models in mice, zebrafish, and sea urchins reveal ABCC5’s role in gut formation, brain function, eye development, and iron metabolism. In mice, its deletion results in lower adipose tissue mass, enhanced insulin sensitivity, and neurobehavioral changes resembling schizophrenia, highlighting its role in glutamatergic signalling and circadian regulation. Functionally, ABCC5 appears to impact adipocyte differentiation and GLP-1 release, implicating it in type 2 diabetes susceptibility in humans. Structural studies using human ABCC5 revealed a novel autoinhibitory mechanism involving a peptide segment (C46–S64) that blocks substrate binding, offering new potential for selective inhibitor development. However, this review emphasises caution in targeting ABCC5 for cancer therapy due to its underappreciated physiological function(s), particularly in the brain and male reproductive system. Understanding ABCC5’s substrate specificity, regulatory mechanisms, and functional redundancy with its paralog ABCC12 remains critical for successful therapeutic strategies in humans. Full article

Introduction: Metabolic dysfunction associated steatotic liver disease (MASLD), previously termed as nonalcoholic fatty liver disease (NAFLD), is a growing global health concern, particularly in South Asia. While PNPLA3 is a well-recognized genetic contributor to MASLD, the role of other metabolic genes, such as ABCC8, remains unexplored in South Asian populations. In this study, we aim to investigate the genetic association and potential synergy between PNPLA3 (rs738409) and ABCC8 (rs146378237) variants in MASLD pathogenesis in a Pakistani cohort. Methods: A two-phased case–control study was conducted. Whole Exome Sequencing (WES) was performed on 6 MASLD cases and 6 healthy controls to identify relevant variants, followed by validation via Sanger sequencing in an extended MASLD cohort (n = 52). Variant frequencies were compared with 96 ethnically matched controls from the 1000 Genomes Project. Furthermore, the association of the variants with clinical, biochemical, and fibrotic parameters was assessed. Results: The PNPLA3 rs738409 G allele (MAF = 0.47) and ABCC8 rs146378237 T allele (MAF = 0.36) were significantly enriched in MASLD cases and strongly associated with cirrhosis. The TT genotype of ABCC8 was also linked to T2DM and low HDL levels. Importantly, eight MASLD patients harbored both GG (PNPLA3) and TT (ABCC8) genotype, and all were known cases of diabetes, suggesting a synergistic genetic interaction. Conclusions: This is the first report of ABCC8 rs146378237 in a South Asian MASLD cohort, revealing population-specific risk and a gene–gene interaction that may inform targeted screening and personalized management of MASLD in high-risk diabetic individuals. Full article

Feed efficiency is a key economic trait that affects the cost of production in broiler farming. Reducing broiler feed costs contributes to reducing excessive feed consumption and increasing the productivity of broiler breeding. Therefore, identifying genetic regions associated with feed efficiency is crucial for broiler breeding. In this study, we performed genome-wide association (GWAS) analyses of feed conversion ratio (FCR) and residual feed intake (RFI) traits for four growth cycles (72–81, 81–89, 89–113, and 113–120 days of age) using 55K single-nucleotide microarray genotypic data of 4493 Wenchang chickens from two generations. In the single-trait GWAS, a total of 59 SNPs were identified, and 36 genes were annotated within the ±50 kb regions surrounding candidate loci (including ABCC6, CLDN10, DGKB, EXT2, FOXO1, IFT140, JAG2, among others. These candidate loci explained 1.4–7.0% of the phenotypic variance explained, and applying a filtering criterion that required a deleteriousness score greater than 8, one locus-Gallus gallus chromosome (GGA) 5:3550350 (chCADD score = 12.51524) was located within intron 3 of ANOX3. In the FCR and RFI traits in the longitudinal GWAS (LONG-GWAS) model, 80 SNPs and 191 SNPs were identified, respectively, and a total of 43 genes and 121 genes were annotated. A total of 33 candidate loci were screened by combining the locus deleteriousness scores, and 25 candidate genes were annotated within the upper and lower 50 kb ranges. Through KEGG signaling pathway analysis, it was found that the candidate genes were highly enriched mainly in autophagy, mitochondrial phagocytosis, and other pathways. In conclusion, the SNPs and potential genes identified in this study will be helpful for chicken breeding and provide fundamental data for the genetic basis of chicken feed efficiency-related traits. Full article

Background/Objectives: Cantú syndrome is a rare autosomal dominant genetic disorder caused by gain-of-function variants in the ABCC9 or KCNJ8 genes. Although its phenotypic expression is variable and can go unnoticed postnatally, certain ultrasound findings may raise suspicion during pregnancy. This article presents a case of prenatal diagnosis through exome sequencing, which also enabled retrospective diagnosis in the mother and a previously undiagnosed child, highlighting the clinical and emotional value of diagnostic certainty in fetal medicine. Methods: We conducted a descriptive observational study based on a case identified at the Fetal Medicine Unit of the Regional University Hospital of Málaga. The patient underwent high-resolution ultrasound and trio-based exome sequencing (fetus and both parents). Results: Prenatal exome sequencing revealed a heterozygous pathogenic variant in ABCC9, consistent with Cantú syndrome, identified simultaneously in the fetus and the mother as part of a trio-based analysis, confirming maternal inheritance. The same variant was later detected in the patient’s older daughter, who had been under pediatric evaluation for a suggestive phenotype but had not received a genetic diagnosis until this study. The prenatal diagnosis allowed for obstetric and neonatal planning, genetic counselling, and a reinterpretation of the clinical and emotional meaning of previous pregnancies. Conclusions: Prenatal diagnosis of Cantú syndrome enables anticipation of perinatal complications, planned clinical interventions, and also provides emotional relief and a coherent narrative for families. In scenarios of variable phenotypic expressivity, fetal medicine may represent a gateway to family diagnosis, with significant clinical and psychosocial implications. Full article

Arsenic (As) contamination has significantly increased in recent decades due to anthropogenic activities. This is a serious challenge for human health, environmental quality, and crop productivity. Biochar (BC) is an important practice used globally to remediate polluted soils. Likewise, melatonin (MT) has also shown tremendous results in mitigating metal toxicity and improving crop productivity. Nevertheless, the mechanism of combined BC and MT in alleviating As toxicity in rice (Oryza sativa L.) remains unexplored. In this study, we investigated how As affected rice and how the combined BC and MT facilitated As tolerance. The study comprised a control, As stress (100 mg kg⁻¹), As stress (100 mg kg⁻¹) + BC (2%), As stress (100 mg kg⁻¹) + MT (100 µM) and As stress (100 mg kg⁻¹) + BC (2%) + MT (100 µM). Arsenic significantly decreased rice growth and yield by increasing electrolyte leakage (EL), malondialdehyde (MDA), and hydrogen peroxide (H₂O₂). Co-applying BC and MT substantially enhanced rice growth and yield by increasing chlorophyll synthesis (48.12–92.42%) leaf water contents (40%), antioxidant activities (ascorbate peroxide: 56.43%, catalase: 55.14%, peroxidase: 57.77% and superoxide dismutase: 57.52%), proline synthesis (41.35%), MT synthesis (91.53%), and phytochelatins synthesis (125%) nutrient accumulation in rice seedlings and soil nutrient availability. The increased rice yield with BC + MT was also linked with reduced H₂O₂ production, As accumulation, soil As availability, and an increase in OsAPx6, OsCAT, OsPOD, OsSOD OsASMT1, and OsASMT2 and a decrease in expression of OsABCC1. Biochar + MT enhanced residual OM- and Fe, ((Fe₂As) and Mn (Mn₃(AsO₄)₂) bound forms of As leading to a substantial increase in rice growth and yield. Thus, the combination of BC and MT is an eco-friendly approach to mitigate As toxicity and improve rice productivity. Full article

ABCC6, a key regulator in ectopic calcification, plays a crucial role in mineralization through the modulation of extracellular purinergic pathways and production of inorganic pyrophosphate (PPi), which inhibits calcification. Inherited deficiencies in ABCC6 lead to pseudoxanthoma elasticum (PXE) and related conditions, characterized by calcification in various tissues, particularly affecting the skin, eyes, and cardiovascular system. Although PXE does not directly impact the nervous system, secondary neurological issues arise from cerebrovascular complications, increasing the risk of strokes linked to arterial blockages resembling atherosclerosis. This review investigates the connection between ABCC6 mutations and cerebral small vessel disease (SVD), expanding the understanding of PXE and related phenotypes. Mutations in ABCC6, identified as causing PXE, contribute to systemic metabolic dysfunction, with significant implications for cerebrovascular health. An association between ABCC6 mutations and cerebral SVD has been suggested in various studies, particularly in populations with distinct genetic backgrounds. Emerging evidence indicates that pathogenic mutations increase the risk of ischemic strokes, with both homozygous and heterozygous carriers showing susceptibility. Mechanistically, ABCC6 deficiency is implicated in dyslipidemia and atherosclerosis, further exacerbating cerebrovascular risks. Increased arterial pulsatility, linked to carotid siphon calcification, may also contribute to microvascular damage and subsequent brain injury. Understanding these mechanisms is vital for developing targeted diagnostic and therapeutic strategies for managing cerebrovascular risks in PXE patients. This review emphasizes the need for comprehensive genetic screening and the consideration of traditional vascular risk factors in patient management, highlighting the complex interplay between genetic mutations and environmental influences affecting cerebrovascular health. Future research should focus on longitudinal studies to elucidate the causal pathways linking arterial calcification, pulsatility, and brain damage in PXE. Full article

Cadmium (Cd) contamination in agricultural soils severely threatens rice production and food safety. To address this issue, this study developed transgenic rice lines co-expressing three Vitis vinifera genes: the ABCC transporter Vvmrp1 and metallothioneins Vvmt1 and Vvmt2. AlphaFold computational modeling confirmed the conserved ABCC-type transporter domain in VvMRP1. Under hydroponic conditions, transgenic rice showed remarkable Cd tolerance, surviving 30 mM Cd (lethal to wildtype, WT) without growth penalties, and exhibited 62.5% survival at 1 mM Cd vs. complete wild-type mortality. Field-relevant Cd exposure (1 mM) reduced Cd accumulation to 35.8% in roots, 83% in stems, and 76.8% in grains compared to WT. Mechanistic analyses revealed that Vvmrp1 mediates cellular Cd efflux while Vvmt1 and 2 chelate free Cd ions, synergistically inhibiting Cd translocation. Transgenic plants also maintained better Fe, P, and Mg homeostasis under Cd stress. This study pioneers the co-expression of a transporter with metallothioneins in rice, demonstrating their complementary roles in Cd detoxification without pleiotropic effects from endogenous gene modification. The findings provide an effective genetic strategy for cultivating low-Cd rice in contaminated soils, offering significant implications for food safety and sustainable agriculture. Full article

Here, we present a unique case of the combination of two rare hereditary diseases—a familial form of dilated cardiomyopathy (DCM) and arterial calcification (AC)—in a 10-month-old boy. DCM was caused by a novel pathogenic nucleotide variant (NV) c.542G>T in the MYH7 gene, and AC was caused by biallelic nucleotide variants c.3421C>T and c.4015C>T in the ABCC6 gene. NVs were identified by the next-generation sequencing (NGS) of a broad panel of 404 genes potentially involved in cardiovascular disorders and subsequently validated by Sanger sequencing in the proband and his parents. Cardiologic examinations confirmed the familial nature of cardiomyopathy and the pathogenicity of variant c.542G>T in MYH7 gene. This case highlights the clinical utility of NGS in identifying complex co-existing hereditary conditions and emphasizes the need for the comprehensive genetic testing of patients with atypical clinical presentations. Full article

The standard immunosuppressive treatments in heart transplantation are calcineurin inhibitors, corticosteroids, and antimetabolite agents or inhibitors of the mammalian target of rapamycin. Pharmacogenetic studies show the impact on clinical course of genetic variability in genes that encode transporters, metabolizers, or molecular targets of immunosuppressants. The aim of this systematic review is to elucidate the role that pharmacogenetics of immunosuppressant drugs plays in clinical outcomes upon heart transplantation. PubMed, EMBASE, the Cochrane Central Register, and the Database of Abstracts of Reviews of Effects were searched without restrictions. The 64 studies analyzed followed these criteria: (1) were based on clinical data on heart transplantation patients; (2) analyzed the associations between polymorphisms and clinical response; (3) analyzed the impact of polymorphisms on immunosuppressant safety. CYP3A4/5 variants were associated with higher doses of tacrolimus, whereas POR*28 variants with lower doses—ABCB1, ABCC2, SLCO1B1, and SLC13A1—contribute to interindividual variability in drug absorption, distribution, and toxicity. An ABCC2 polymorphism (rs717620) was related to higher risk of graft rejection in pediatrics. Variations in HLA-G, TNF-α and TGF-β genes influence transplant rejection risk and immune response. Implementing pharmacogenetic screening of polymorphisms could enhance therapeutic outcomes by improving drug efficacy, reducing toxicity, and ultimately increasing heart graft survival rates. Strong evidence supports genotyping for CYP3A5 and TPMT, but further research is required for transporter genes and cytokine polymorphisms. Full article

Hepatocellular carcinoma (HCC) is still a leading cause of cancer-related mortality worldwide, characterized by poor prognosis and limited therapeutic efficacy of conventional chemotherapeutics such as doxorubicin. Phytochemicals are promising adjuvants in cancer therapy due to their multi-targeted effects. In this in vitro study, we investigated the impact of a methanol–water extract (70:30 v/v, MET70) from Muscari comosum bulbs, rich in polyphenols and flavonoids, on doxorubicin-treated HepG2 human hepatoma cells. Co-treatment with MET70 increased intracellular reactive oxygen species (ROS) associated with downregulation of Nrf2 signaling, suppression of antioxidant enzymes (SOD2, GPX-1) and decreased mitochondrial UCP2 expression. MET70 modulated the inflammatory response induced by doxorubicin by decreasing TNF-α and increasing IL-6 expression. MET70 also promoted protein homeostasis through PDIA2 upregulation without exacerbating endoplasmic reticulum stress and inhibited autophagy by reducing Beclin-1 levels, contributing to increased chemosensitivity. Moreover, MET70 downregulated ABCC1 expression, suggesting a role in overcoming multidrug resistance. All these findings demonstrate that Muscari comosum extract enhances doxorubicin efficacy by targeting redox balance, inflammatory signaling, autophagy, and drug resistance, offering a promising redox-based strategy for improving HCC therapy. However, further studies should be performed in vivo. Full article

Background/Objectives: Systemic therapy with hedgehog pathway inhibitors (HHIs) and anti-programmed cell death protein 1 (PD-1) antibodies represent the first- and second-line treatment options for advanced basal cell carcinoma (aBCC), respectively. A shift in the treatment paradigms toward the neoadjuvant approach is gaining increasing interest in aBCC management, whereby prior systemic therapy followed by surgery is likely to yield more favorable outcomes. The aim of this narrative review is to summarize the current evidence on systemic treatment options and the neoadjuvant approach for aBCC management. Methods: We performed a non-systematic review of the literature based on PubMed as search engine. Results: The pivotal phase II trials ERIVANCE and BOLT investigated the efficacy and safety profile of vismodegib and sonidegib, respectively, with reported objective response rates (ORRs) of 60.3% and 56% in laBCC patients, respectively. The pivotal phase II trial NCT03132636 investigated the efficacy and safety profile of cemiplimab in patients who progressed or were intolerant to prior HHI therapy, with an ORR of 32.1% in laBCC patients. Real-life studies confirmed the effectiveness and safety profile of HHI and anti-PD-1 immunotherapy. Several phase I/II clinical trials are currently investigating HHIs and immune-checkpoint inhibitors in the neoadjuvant setting followed by surgery for aBCC patients, with the aim of providing more favorable treatment outcomes, especially when upfront surgery would result in functional and/or aesthetic sequelae. Conclusions: Advanced BCC treatment is challenging, and the neoadjuvant approach followed by surgery is expected to reduce surgical complexity, increase tissue preservation, and improve patients’ satisfaction. Full article

Background: Oral mucositis (OM) is a painful inflammation resulting from chemotherapy. It is dependent on factors such as age, gender, chemotherapy regimen, oral health, immunological and nutritional status, and genetics. Objectives: The aim of the study was to conduct a narrative review to compile studies on the contribution of genetic and epigenetic aspects to the pathogenesis of OM in children with haematological malignancies undergoing chemotherapy treatment. Methods: The literature search was performed in Pubmed, Scopus, Web of Science, Cochrane, Lilacs, and grey literature databases covering articles published since 2010. Results: Twenty-two studies investigating polymorphisms and four studies investigating DNA methylation were included. Polymorphisms in the MTHFR, ABCB1, ABCC2, ABCG2, SLCO1B, miR-1206, miR-3683, CAT, and VDR genes were associated as risk factors for OM and polymorphisms in the TYMS and miR-4268 genes were associated as protective factors. With regard to DNA methylation, associations such as protection or susceptibility to OM have not yet been proven. However, studies have shown that DNMT1 methylation and hypomethylation in total DNA and in the TNF-α gene are associated with recovery of the oral mucosa. Conclusions: Genetic variants are associated with OM in various biological pathways, such as folate metabolism, transport proteins, epigenetic machinery, oxidative stress, and vitamin D metabolism. The DNA methylation profile, which is still poorly understood in the pathogenesis of OM, is associated with mucosal recovery (inflammation and epigenetic machinery). Genetic and epigenetic markers may be tools to indicate a patient’s susceptibility to developing OM, and epigenetic markers may be a target for therapies. Full article