Search Results (1,042)

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication deficits and repetitive behaviors, now affecting approximately 1 in 31 children. While traditionally defined behaviorally, ASD is increasingly understood as a disorder of brain connectivity arising from altered synaptic formation and refinement. This narrative review synthesizes evidence on neuroimmune dysregulation in ASD, focusing on immune-mediated synaptic pruning mechanisms. We conducted a comprehensive literature search in PubMed, Scopus, and Web of Science (2010–2026), prioritizing high-impact peer-reviewed research. Convergent findings suggest that the classical complement cascade (C1q-C3) tags specific synapses for elimination, while microglia participate in the phagocytic removal of tagged connections. Genetic studies have reported associations between ASD and variants in complement-related genes (C1q, C3, CR3, and C4A, although the strongest evidence for C4A-mediated pruning comes from schizophrenia research), as well as in microglial function genes (TREM2, PTEN, SHANK3). Neuroimaging reveals a dynamic pattern of local hyperconnectivity transitioning to long-range hypoconnectivity during development, particularly affecting prefrontal, insular, and cerebellar regions. Systemic inflammation, including gut–brain axis dysbiosis and maternal immune activation, may amplify neuroimmune dysregulation. We conclude that ASD can be understood, in part, as a disorder of synaptic immunology, where disrupted neuroimmune communication during critical developmental windows may contribute to altered connectivity. The complement–microglia axis therefore represents a potential mechanistic target for future therapeutic investigation. Full article

Background/Objectives: Atrial fibrillation (AF), the most prevalent form of clinical cardiac arrhythmia globally, is associated with markedly increased morbidity, mortality, and socio-economic expenditure. Accumulating strong evidence highlights genetic abnormalities underpinning its etiopathogenesis. A recent investigation has demonstrated that mutations in the TBX20 gene, which codes for a T-box transcription factor essential for proper cardiovascular development and structural remodeling, contribute to familial AF. Nevertheless, the mutational prevalence and spectrum of this gene in patients with sporadic AF remain unknown. Methods: A cohort of 352 individuals suffering from sporadic AF and a group of 376 healthy subjects without AF history were recruited prospectively. Sanger sequencing examination of TBX20 was implemented in all research participants. The functional impacts of the discovered TBX20 variations were quantitatively measured by dual-reporter gene analysis. Results: Two novel heterozygous truncating TBX20 variations, NM_001077653.2: c.725C>A; p.(Ser242*) and NM_001077653.2: c.826A>T; p.(Lys276*), were detected in two of the 352 cases with sporadic AF, respectively, with a mutational prevalence of approximately 0.57%. The two TBX20 variants were absent from the 752 control chromosomes. Functional measurements revealed that both Ser242* and Lys276* variants lost transactivation on KCNH2 and NPPA, two genes responsible for AF. In addition, each of the two variations abrogated the synergistic transactivation of NPPA by TBX20 together with NKX2.5, another gene reported to cause AF. Conclusions: The current data indicate haplo-insufficient TBX20 variations as new genetic defects predisposing to sporadic AF and hence are conducive to improving the prophylaxis and treatment strategies of sporadic AF in a subset of patients. Full article

Background/Objectives: The brachial plexus is a complex network of nerves responsible for the sensory and motor functions of the upper limbs. While extensively studied, the typical configuration taught only sometimes matches what is found in individuals, as numerous variations have been documented. These variations can have significant clinical and surgical implications. This study explored the prevalence and types of brachial plexus variations in donor bodies from the Midwestern United States. Methods: Using bodies donated through the Gift of Body Donation program at A.T. Still University’s Kirksville College of Osteopathic Medicine, the brachial plexuses of 32 donors were analyzed. Results: Among the 64 plexuses examined, 33 (52%) had a typical M-shaped median nerve formation without additional variations, 18 (28%) had a typical M-shaped formation with additional variations, 6 (9%) had an abnormal M without other variations, and 7 (11%) had an abnormal M with other variations. Thus, 31 plexuses (48%) showed atypical branching patterns. The most common variations were extra communicating branches, observed in 17 (55%) of the 31 variant plexuses. These branches were most often found between the medial and lateral cords (13/17, 76%) and between the musculocutaneous and median nerves (4/17, 24%). Other, less common variations included variant nerves, small branches, and rejoining nerves. Conclusions: This study highlights the significant prevalence of variations in the brachial plexus, which may impact clinical and surgical practices. Further research is needed to fully understand the implications of these variations, especially in procedures like nerve blocks and reconstructive surgeries. Full article

The Transport Protein Particle (TRAPP) complex is a highly conserved multi-subunit tethering complex that plays a critical role in membrane trafficking. Mutations in TRAPP complex subunits have been implicated in a growing spectrum of rare genetic disorders, yet the molecular mechanisms underlying variant pathogenicity often remain unclear. Here, we developed a humanized yeast platform to enable systematic functional characterization of TRAPP complex variants of uncertain significance. Using a stepwise gene replacement strategy in Saccharomyces cerevisiae, we constructed a strain in which five yeast TRAPP core subunits were replaced with their human orthologues. The integration of human subunits was validated through quantitative RT-PCR and Western blotting. Growth assays revealed that partial humanization of the core complex recapitulates key functional aspects of TRAPP assembly and enables the functional investigation of variants of uncertain significance in vivo. Structural modeling and clash analysis provided insights into the impact of specific mutations on complex stability and subunit interactions. TRAPPC3 has not yet been definitively associated with human disease. Introduction of TRAPPC3 variants of uncertain clinical significance into the humanized strain resulted in pronounced growth defects and predicted structural clashes. This work demonstrates the power of humanized yeast as a model for elucidating potential genotype–phenotype relationships in TRAPPopathy disorders and provides a versatile platform to support variant interpretation, mechanistic studies, and potential therapeutic screening. Full article

Background/Objectives: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by impaired ciliary function, leading to chronic airway disease. Loss-of-function mutations in ODAD3 (CCDC151) represent an established cause in patients, and Odad3-deficient mice recapitulate key disease traits. However, the impact of Odad3 ablation on upper airway development and function remains unexplored. This study investigated the consequences of Odad3 disruption on upper airway structures during development and in adult animals. Methods: Constitutive (Odad3^−/−) and inducible conditional (Odad3^icKO) mouse models were analyzed alongside heterozygous and wild-type littermates during embryonic, postnatal, and adult stages. Optimized high-resolution 3D micro-computed tomography (micro-CT or µCT) combined with histology was utilized to conduct systematic genotype-phenotype evaluations, map upper airway anatomical architecture, and assess PCD disease onset. Results: Genetic dissection revealed a marked dependence of the phenotype on whether Odad3 loss occurred during development or in adulthood. Constitutive Odad3 deletion resulted in pervasive craniofacial remodeling and turbinate hypoplasia during embryonic stages and early postnatal development. Conversely, adult-induced conditional ablation produced localized caudal atrophy of the nasal turbinates accompanied by massive mucus accumulation, consistent with impaired mucociliary clearance and providing a 3D structural and morphological characterization of chronic rhinosinusitis-like pathology in PCD mouse models. Heterozygous Odad3^icKO/+ and Odad3^+/− mice were phenotypically indistinguishable from wild-type controls, indicating that single-allele loss does not disrupt upper airway morphology. Conclusions: This study characterizes the structural timeline of upper airway pathology in PCD and validates the Odad3^icKO model as a robust 3D structural phenotyping platform for investigating airway disease in ciliopathies. Combining targeted genetic disruption with 3D µCT virtual histology offers a powerful framework for comprehensive studies of human genetic variants and gene knockouts in mouse models of PCD. Full article

Primary dystrophin deficiency, caused by X-chromosome mutations within the DMD gene, encompasses a continuous clinical spectrum of neurological, muscular, and cardiac disorders known as dystrophinopathies that exhibit profound phenotypic variability driven by specific mutation profiles and epigenetic factors. This comprehensive review analyzes the clinical and molecular characteristics of seven primary classifications: Duchenne muscular dystrophy (DMD), a severe childhood myopathy caused by a complete absence of the protein that leads to loss of ambulation and fatal cardiorespiratory failure in youth; Becker muscular dystrophy (BMD), a milder variant with partial protein deficiency that preserves walking capabilities into adulthood and prolongs life expectancy; pseudometabolic dystrophinopathic syndrome, featuring exercise intolerance, cramps, and recurrent rhabdomyolysis that mimics metabolic diseases; asymptomatic dystrophinopathy, representing the mild end of the spectrum identified incidentally through chronically elevated creatine kinase levels; brain dystrophin-related syndrome, where the disruption of distal isoforms like Dp140 and Dp71 results in neurodevelopmental and neuropsychiatric comorbidities such as ADHD, autism, and intellectual disability; X-linked dilated cardiomyopathy (XLDCM), a cardiac-selective condition causing severe heart failure and arrhythmias while sparing skeletal muscle function; and female dystrophin-related syndrome, distinguishing between familial carriers—who can manifest symptoms due to skewed X-chromosome inactivation—and rare sporadic females who develop an exceptional, severe, Duchenne-like phenotype due to cytogenetic accidents such as Turner syndrome or chromosomal translocations. Ultimately, advancements in molecular testing (NGS and WGS) have significantly optimized diagnostic precision, proving essential for implementing early cardioprotective care, accurate genetic counseling, and the development of future tissue-specific targeted gene therapies. The present study also discusses the psychosocial impact that the disease has on patients. Full article

Background/Objectives: Non-syndromic orofacial clefts (NSOFCs) are among the most common congenital craniofacial anomalies, with genetic factors playing a major role in their etiology. Transforming growth factor-β-induced (TGFBI) protein is an extracellular matrix protein implicated in cell adhesion and apoptosis. Although experimental studies have implicated TGFBI in palatal fusion, its contribution to human NSOFCs remains unclear. This study investigated the genetic basis of hereditary NSOFCs in a Chinese family. The functional consequences of the identified TGFBI variant were subsequently evaluated. Methods: Whole-exome sequencing was performed in a Chinese NSOFC pedigree, followed by Sanger validation and ophthalmological evaluation. The functional impact of the identified variant was investigated through evolutionary and structural analyses, TGFBI expression analysis during mouse palatal development, and cellular functional assays. Results: A novel heterozygous stop-gain variant in TGFBI (NM_000358.3:c.230C > A; p.Ser77X) was identified in affected family members but not in the unaffected father. No corneal abnormalities were observed in variant carriers. TGFBI was expressed in the midline epithelial seam during palatal fusion. The p.Ser77X variant generated a truncated protein lacking all four FAS1 domains and the C-terminal RGD motif, resulting in abnormal localization, impaired cellular apoptosis and proliferation, and altered p38-MAPK signaling. Conclusions: This study identifies a rare loss-of-function TGFBI variant associated with NSOFCs and provides genetic and functional evidence supporting a role for TGFBI variation in human palatal development. Full article

Background: Systemic autoinflammatory phenotypes can clinically overlap with Familial Mediterranean Fever and other monogenic autoinflammatory diseases, yet some cases remain unclassified in the absence of pathogenic variants in MEFV or other related genes. In this study, we aimed to investigate the genetic and molecular basis of an unclassified autoinflammatory phenotype in a two-generation family comprising four affected members and one unaffected member. Methods: We performed whole-exome sequencing in all family members and prioritized variants according to rarity, predicted functional impact, segregation pattern, and biological relevance to inflammatory pathways. Downstream molecular analyses were performed using PBMCs from affected individuals and the unaffected family member. Results: Whole-exome sequencing identified a novel splice-site variant in PSMB10 (NM_002801; c.56+1G>A) affecting the canonical splice donor site. The variant segregated with the autoinflammatory phenotype and was associated with reduced full-length PSMB10 transcript levels in patient-derived PBMCs, supporting a predicted loss-of-function effect. Although pathogenic variants in PSMB10 have previously been implicated in proteasome-associated autoinflammatory syndrome (PRAAS), the clinical presentation in this family differed from the classical PRAAS phenotype. Molecular analyses showed altered immunoproteasome-related gene expression and a severity-associated interferon-related response. Severely affected individuals showed increased expression of interferon-related genes, including ISG15, IFI35, and SIGLEC1, whereas mildly affected individuals showed lower or reduced expression patterns. Notably, the extent of these molecular alterations differed among family members and broadly reflected the observed clinical heterogeneity. Conclusions: We report a novel PSMB10 splice-site variant as a strong potential contributor to an unclassified autoinflammatory disease, with a predicted disruption of canonical splicing and loss of protein function. Our findings expand the clinical spectrum of immunoproteasome-associated disorders and suggest that immunoproteasome-related dysregulation and variable interferon responses may contribute to disease severity. The intrafamilial variability observed in this family suggests that additional genetic or immunogenetic factors may modify disease expression, even in autoinflammatory disorders that appear to follow a monogenic inheritance pattern. Full article

Maraviroc (MVC), a CCR5 antagonist, has been proposed as a potential antiviral agent against SARS-CoV-2; however, its mechanism of action across viral variants remains unclear. Here, we evaluated the antiviral activity of MVC against SARS-CoV-2 wild-type (WT) and Omicron BA.1 variants using single-round infectious particles (SRIPs), virus-like particles (VLPs), and cell-based assays, with a focus on its impact on viral entry and Mpro function. MVC potently inhibited infection of both WT and BA.1 SRIPs in Vero E6 cells, exhibiting EC₅₀ values of 0.0065 μM and 0.016 μM, respectively. Time-of-addition assays revealed that MVC primarily targets the early phase of infection, with the strongest inhibition observed at the viral entry stage, while moderate effects were detected during attachment and post-entry stages. Fluorescence-labeled VLP imaging demonstrated distinct entry pathways, with WT predominantly entering via plasma membrane fusion and BA.1 via endocytosis, independent of cell type. MVC altered WT-VLP trafficking by promoting internalization and lysosomal localization, whereas it had minimal impact on BA.1 internalization. In spike-mediated cell–cell fusion assays, MVC preferentially inhibited WT spike-driven syncytium formation but showed limited effects on BA.1 or BA.4 fusion, while more effectively reducing Omicron spike-mediated binding. At the post-entry stage, MVC inhibited SARS-CoV-2 main protease (Mpro) activity, with BA.1 Mpro (P132H) exhibiting greater sensitivity (IC₅₀ = 0.496 µM) than WT (1.869 µM). Collectively, these findings demonstrate that MVC exerts variant-dependent antiviral effects by targeting viral entry, modulating trafficking pathways, and inhibiting Mpro activity. This study highlights MVC as a multi-stage inhibitor with differential efficacy against SARS-CoV-2 variants, providing insights into its potential therapeutic application. Full article

Systolic anterior motion (SAM) of the mitral valve can occur either in association with or in the absence of hypertrophic obstructive cardiomyopathy (HOCM). SAM induces dynamic left ventricular outflow tract obstruction (LVOTO) and, in the majority of cases, is associated with a substantial degree of mitral regurgitation (MR) that significantly impacts patient morbidity and mortality. This narrative review explores the contemporary understanding of the pathophysiology, diagnosis, and management of SAM, focusing particularly on surgical strategies and the novel therapeutic class of cardiac myosin inhibitors. Extended septal myectomy remains the gold-standard treatment for HOCM-related SAM, yielding superior long-term outcomes compared to alcohol septal ablation (ASA). Advanced imaging modalities, including three-dimensional transesophageal echocardiography (3D-TEE), enable precise pre-operative characterization of the mitral valve apparatus. Some patients may benefit from septal reduction strategies while concomitant mitral valve interventions are generally reserved for highly selected cases with intrinsic valve pathology or persistent residual SAM, thereby avoiding unnecessary valvular manipulation and its potential hemodynamic risks. Mavacamten, a selective cardiac myosin inhibitor, represents an important advance in pharmacological management, achieving a mean LVOT gradient reduction of 37.2 mmHg in symptomatic patients. Furthermore, data from the MARVEL registry confirm the real-world clinical efficacy of mavacamten in obstructive hypertrophic cardiomyopathy, with 86% of patients successfully down-staged to NYHA functional class I–II. Although ASA serves as a viable alternative to surgery, it entails a higher risk of conduction abnormalities requiring permanent pacemaker implantation and subsequent re-intervention. Beyond classical hypertrophic SAM, this review addresses the diagnosis and management of post-mitral repair complications and non-hypertrophic variants. Optimal management and risk stratification remain an evolving field requiring a multidisciplinary Heart Team approach, leverage of advanced imaging, and adoption of novel medical therapies. Interventional strategies must be carefully tailored to maximize the efficacy-to-safety profile on an individualized patient basis. Full article

Neurodevelopmental disorder, speech impairment, and dysmorphic facies (NEDSID) is an autosomal dominant condition primarily driven by SETD1A haploinsufficiency. While most documented cases are sporadic, genomic mechanisms underlying intrafamilial phenotypic heterogeneity remain poorly understood. This study presents a comprehensive clinical, neurophysiological, and molecular characterization of a two-generation Mexican family segregating a novel heterozygous missense SETD1A variant. Whole-exome sequencing (WES) identified a c.1604G>A (p.Gly535Glu) substitution localized within the critical Functional Location on SETD1A (FLOS) domain, which was validated via automated Sanger sequencing across all family members and 100 ethnically matched controls. The proband exhibited a moderate NEDSID phenotype, including global developmental delay, macrocephaly, borderline IQ (79) with pronounced information-processing deficits, and abnormal EEG sharp waves. Conversely, first-degree relatives carrying the identical variant presented with mild, non-intellectually disabling phenotypes characterized primarily by isolated psychiatric disorders (bipolar disorder, depression) and minimal dysmorphism. Structural 3D modeling and multi-algorithmic in silico profiling confirmed high evolutionary conservation and a deleterious impact (CADD: 22.2, SIFT: 0.00, GERP: 2.924), classifying the variant as a Variant of Uncertain Significance (VUS)/Likely Pathogenic according to ACMG/AMP criteria (PM2, PP1, PP3, PP4). Furthermore, epigenetic dysregulation and chromatin remodeling defects increasingly link these histone-modifier variants to broader psychiatric landscapes. Emerging transcriptomic profiling confirms that dosage-sensitive COMPASS complex disruptions alter downstream neurodevelopmental gene cascades. Our findings present observational evidence of intrafamilial clinical variability in a single pedigree with a SETD1A missense alteration, supporting the hypothesis that non-catalytic domain substitutions may contribute to diverse neurodevelopmental outcomes. Full article

The use of invertebrates for sewage sludge bioconversion offers a sustainable strategy for waste valorization, yet species-specific effects on microbial communities and biosafety remain unclear. Here, we compared the impacts of the earthworm Eisenia andrei (Ea) and the mealworm Tenebrio molitor (Tm) on the bacteriomes and mycobiomes of sewage sludge (ss) using 16S rRNA and ITS amplicon sequencing. Gut passage in both Ea and Tm markedly altered bacterial and fungal composition relative to ss, but produced distinct community profiles with differential shifts across multiple taxa. Both invertebrates reduced bacterial richness by ~40%, while fungal responses diverged: Ea largely preserved mycobiome richness despite reduced evenness, whereas Tm caused a near-complete collapse (~83% Amplicon Sequence Variant loss). Beta diversity analyses revealed clear, non-overlapping separation among ss, Ea, and Tm for both microbial domains. Tm frass showed strong enrichment of clinically relevant bacterial pathogens, while Ea casts exhibited no such enrichment. For fungi, Ea reshaped pathogen composition, whereas Tm largely eliminated fungal pathogens through broad community collapse. Both treatments reduced predicted antibiotic resistance gene abundance, but functional profiles differed, with Ea showing greater functional stability. These findings demonstrate that microbiome restructuring during bioconversion is species-dependent, with contrasting ecological and biosafety implications for downstream environmental use. Full article

Background. Breast and ovarian cancer are among the most common neoplasms in women, and germline variants in the BRCA1 gene markedly increase the risk of developing them. Despite existing studies, the frequency and spectrum of BRCA1 variants in women from Jalisco, Mexico, remain underexplored. Objective. To identify and characterize BRCA1 variants in a cohort of Mexican women with breast and ovarian cancer, and to assess their functional and splicing consequences through computational analysis. Methodology. Genomic DNA from 228 women with breast and/or ovarian cancer, selected by clinical criteria suggestive of hereditary cancer, was analyzed by next-generation sequencing. The functional impact of point variants was predicted with Ensembl VEP, SIFT, PolyPhen-2, REVEL, CADD, and AlphaMissense, and their effect on splicing was evaluated with SpliceAI, using the MANE Select canonical transcript (NM_007294.4). Results. BRCA1 variants were identified in 14.0% of this screening-enriched cohort, with carrier proportions of 16.2% in ovarian and 13.6% in breast cancer; these figures reflect a selected series and do not represent population prevalence. Breast cancer carriers showed a younger age at diagnosis, a higher proportion of the triple-negative phenotype, and a stronger family history. Fourteen-point variants and four large rearrangements were detected, with a predominance of truncating loss-of-function alterations. The recurrent missense variant c.5123C>A (p.Ala1708Glu), located in the BRCT1 domain, was the most relevant finding, present in 28.1% of carriers (9/32). The computational analysis did not reclassify variants on its own but provided complementary evidence (PP3/BP4) consistent with current classifications: it allowed reannotation of c.5243G>A from nonsense to missense, supported the pathogenic nature of the intronic splice variant c.4987-3C>A, and was concordant with the likely benign interpretation of c.2735A>G, while c.3367G>T remained of uncertain significance. Conclusions. This cohort from Western Mexico harbors a distinctive spectrum of BRCA1 variants, including the recurrent c.5123C>A variant, which may reflect a regional founder effect warranting haplotype analysis. These findings underscore the need for local evidence and for genetic panels adapted to the Mexican population, to enable accurate and equitable variant interpretation and access to targeted therapies such as PARP inhibitors. Full article

Clutch length is a key determinant of egg production in geese and has a direct impact on breeding efficiency. However, the genetic and molecular mechanisms underlying variation in clutch length remain largely unclear in Zi geese. In this study, we integrated whole-genome resequencing with ovarian transcriptomic and proteomic analyses to identify candidate genes and functional single nucleotide polymorphisms (SNPs) associated with clutch length. A total of 200 female Zi geese were monitored throughout a 230-day laying period, from which 20 individuals with the longest clutch length and 20 with the shortest clutch length were selected for multi-omics analyses. Comparative analyses identified 424 differentially expressed genes and 856 differentially expressed proteins between the two groups. Integration of population-differentiated SNPs, genome-wide association study signals, transcriptomic, and proteomic datasets converged on two key candidate genes, INHA (inhibin subunit alpha) and FNDC1 (fibronectin type III domain containing 1). INHA expression was negatively associated with clutch length, whereas FNDC1 expression showed a positive association. Eight missense SNPs were detected across these two genes. Notably, structural modelling and molecular docking analyses demonstrated that the Gly10Cys substitution in INHA markedly increased the binding affinity of INHA homodimerisation (binding energy: −10.4 kcal/mol versus −8.6 kcal/mol for the wild-type protein), promoting the formation of more stable but functionally inactive INHA–INHA homodimers. This finding provides a plausible molecular explanation for the reduced INHA mRNA and INHA protein expression observed in geese with longer clutch lengths. These structural analyses suggest that the biological effects of these identified missense SNPs are primarily mediated through protein conformational changes. Collectively, our findings identify INHA and FNDC1 as key regulators of clutch length in Zi geese and reveal a previously unrecognised structural mechanism by which an INHA missense variant may influence reproductive performance. These results provide valuable molecular markers and mechanistic insights for the genetic improvement of egg production in geese. Full article

Background: Founder mutations in MYBPC3 may contribute substantially to the genetic burden of hypertrophic cardiomyopathy (HCM) and provide important insights into genotype–phenotype correlations and population-specific disease mechanisms. In this study, we investigated two recurrent canonical splice-site variants, MYBPC3 c.1458-1G>A and c.3331-1G>A, identified in patients with HCM from the Emilia-Romagna region of Northern Italy. Methods: Ninety-one unrelated patients with HCM carrying either MYBPC3c.1458-1G>A or c.3331-1G>A were analyzed. Haplotype reconstruction was performed to assess a possible founder effect and estimate the approximate age of the shared ancestral allele. Functional characterization was carried out by RNA sequencing of myocardial tissue to evaluate the impact of the variants on splicing. Clinical and phenotypic data were compared with those of carriers of other truncating MYBPC3 variants or pathogenic variants in other sarcomeric genes. Results: Both variants, classified as pathogenic according to ACMG criteria, shared a conserved variant-specific core haplotype. Founder age was estimated at approximately 10.5 generations (~262 years), consistent with a regional founder effect. RNA sequencing demonstrated aberrant splicing for both variants, resulting in premature termination codons and presumably subsequent nonsense-mediated mRNA decay. Clinically, carriers showed delayed disease onset, with a mean onset in the fifth decade of life, and a comparatively milder phenotype, including a lower incidence of sudden cardiac death, than patients carrying other truncating MYBPC3 variants or pathogenic variants in other sarcomeric genes. Both variants exhibited partial penetrance (approximately 63–67%) and age-dependent variable expressivity. Conclusions:MYBPC3 c.1458-1G>A and c.3331-1G>A represent novel founder alleles associated with HCM in Northern Italy. Identification of these locally prevalent variants improves molecular diagnosis, family screening, and supports the development of variant-targeted therapeutic approaches. Full article