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PubMed1987

Scapulothoracic dissociation (closed avulsion of the scapula, subclavian artery, and brachial plexus): a newly recognized variant, a new classification, and a review of the literature and treatment options.

Scapulothoracic (ST) dissociation is a closed complete traumatic forequarter amputation manifested by a flail pulseless arm and well-defined roentgenographic findings. These roentgenographic findings were previously reported to be lateral displacement of the scapula and either acromioclavicular separation (17) or displaced clavicular fracture (20). In this paper we present four patients with ST dissociation who had a previously unreported combination of roentgenographic findings: lateral displacement of the scapula and sternoclavicular separation. Polytrauma was present in all previously reported cases of patients with ST dissociation. We present one patient, however, in whom ST dissociation is an isolated finding. A review of the literature, and a review of treatment options that includes some combination of amputation, shoulder arthrodesis, prosthetic fitting, and reconstructive tendon transfers, are presented.

Adult↗
PubMed1990

Classification of glucose-6-phosphate dehydrogenase variants by multivariate statistical analysis.

Using principal component analysis a two-dimensional presentation of kinetic parameters from various G6PD-variants was obtained from which similarities between individual enzymes became detectable. Conclusions could be drawn as to how far the kinetic parameters contribute to the discrimination between different variants. An objective classification of G6PD-variants was achieved by application of cluster analysis. The proposed methods provide an effective means for differential elucidation of G6PD-variants and other heterogeneous enzymopathies.

Cluster Analysis↗
PubMed2026

Genome-wide variation analysis of two Salvia hispanica L. genotypes and implication for associations with metabolic and adaptive traits.

BACKGROUND: Advances in next-generation sequencing have accelerated genome-wide exploration of genetic diversity in underutilized oilseed crops. Salvia hispanica L. (chia), a high-nutrient pseudocereal rich in omega-3 fatty acids, is increasingly valued for its health benefits and commercial potential, yet it remains poorly characterized at the genomic level. Understanding the scale and nature of genomic variation is essential for improving complex traits such as oil yield, stress tolerance, and seed quality. METHODS: Two contrasting chia genotypes, Black-chia (CACH-B) and White- chia (CACH-W), were resequenced using the Bio-Resequencing Toolkit (BRT) pipeline. High-coverage sequencing, with a mapping rate exceeding 99% and an average depth of approximately 28×, facilitated the detection and annotation of single-nucleotide polymorphisms (SNPs), insertions and deletions (InDels), copy-number variations (CNVs), and structural variants (SVs). The functional classification of variant impacts enabled the identification of genes potentially linked to metabolic and adaptive traits. RESULTS: A total of 1.97 million SNPs, 401,493 InDels, 836 CNVs, and 15,288 SVs were identified across the chia genome. Notably, approximately 53% of exonic SNPs were non-synonymous (dN/dS ≈ 1.28), predominantly affecting lipid metabolism, transcriptional regulation, and stress response pathways, potentially altering key agronomic traits. In addition, CNV hotspots were concentrated in chromosomes 3 and 6, overlapping MYB, WRKY, and bZIP transcription factor loci, may potentially be involved in stress tolerance and yield. Furthermore, structural rearrangements, including inversions and duplications within the FAD2, FAD3, and CYP450 gene clusters, were potentially associated with seed pigmentation and omega-3 biosynthesis, pointing to their potential breeding relevance. Observed heterozygosity (Hₒ ≈ 0.71) and nucleotide diversity (π ≈ 7 × 10-3) indicated moderate to high allelic richness. In addition, the low FST value (0.038) indicates substantial genomic similarity between the two genotypes. CONCLUSION: This study presents the first comprehensive map integrating SNPs, CNVs, and SVs in S. hispanica L. The results reveal a structurally dynamic genome characterized by substantial sequence and structural variation, providing valuable insights into genomic diversity and potential adaptive mechanisms in chia. The coexistence of high SNP diversity and abundant structural variation underpins chia's nutritional specialization and environmental resilience. These results deliver a foundational genomic resource for marker-assisted breeding, genome-wide association studies, and the development of climate-resilient chia cultivars.

Copy-number variation, structural variation↗
PubMed2026

Reinforcement learning-based dynamic ensemble for missense variant effect prediction and tiered prioritization of VUS.

BACKGROUND: Accurate classification of missense variants remains a challenging task despite major advances in genomics. Numerous computational models have been developed to assist in variant classification, but often require repeated integration and benchmarking efforts. Ensemble methods have been proposed to overcome the limitations of single predictors, but mostly rely on fixed, predefined weights that constrain their ability to capture interactions among predictive signals. METHODS: We present GenixRL, a dynamic ensemble framework that reformulates model fusion as a reinforcement learning optimization problem. GenixRL uses a Q-learning agent to learn a policy that dynamically weights the probabilistic outputs of complementary predictors, including BayesDel (addAF and noAF), ClinPred, and MetaRNN. Replacing static weighting with policy learning allows GenixRL to adaptively identify optimal weightings and substantially improve classification accuracy. RESULTS: In benchmark evaluation against 25 state-of-the-art predictors, GenixRL achieved an AUROC of 0.9644 on an independent ClinVar dataset. On saturation genome editing assays for BRCA1 and BRCA2, GenixRL achieved the best performance and ranked highest on 14 of 17 clinically significant genes in a zero-shot evaluation. Applied to uncertain and conflicting ClinVar variants, GenixRL enabled tiered, evidence-based prioritization of hundreds of thousands of variants as likely pathogenic or pathogenic with high confidence, supported by orthogonal population evidence from gnomAD. CONCLUSION: GenixRL advances pathogenicity prediction for missense variants and provides an adaptive ensemble that sorts variants of uncertain significance into tiered candidates for expert curation and functional validation.

Mutation, Missense↗
PubMed2026

RNA splicing evidence enables robust classification of BRCA1 exon 18 variants: Results from the ENIGMA consortium.

The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) research consortium conducted a comprehensive study to characterize spliceogenic variants in BRCA1 exon 18. The absence of systematic RNA-based assessment for these variants has led to inconsistent interpretation, limiting accurate classification and management of individuals and their families. The splicing profile of 166 variants was assessed using minigene assays; 32 were additionally analyzed in blood-derived RNA from 51 individuals and 18 in mouse embryonic stem cell (mESC)-based assays to evaluate homology-directed repair (HDR) capacity. mRNA assessment by RT-PCR in blood samples and minigene assays showed a significant positive correlation, with splicing analysis in mESCs displaying highly concordant results. The mESC-based HDR assay showed that the in-frame exon 18 skipping (&#x394;18) transcript encodes a non-functional protein lacking rescue activity. Linear regression analysis using mESC splicing and functional data indicated that &#x2265;59% of full-length (FL) levels and <34% of &#x394;18 were associated with benign HDR activity. These thresholds differ from those recommended by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) specifications for applying BP7_strong(RNA): >30% functional transcripts or <70% non-functional transcripts. Incorporation of RNA splicing evidence into variant interpretation increased pathogenic (28.6%-31.7%) and benign (3.7%-24.4%) classifications while reducing likely pathogenic (19.5%-17.7%), uncertain (18.9%-8.5%), and likely benign (29.3%-17.7%) categories. Experimental mRNA profiling impacted the interpretation of 34% of variants and resolved uncertainty in approximately 10% of cases. Exon 18 skipping was less tolerated, indicating that the degree of splice perturbation required to impair BRCA1 function may depend on the nature of the resulting non-functional transcript.

Humans↗
PubMed1989

Surgical significance of popliteal arterial variants. A unified angiographic classification.

Distal popliteal arterial variations may influence the success of femorodistal popliteal and tibial arterial reconstructions. Two patients whose bypass procedures were initially unsatisfactory because of a poor choice for anastomosis stimulated a review of variations in the distal popliteal artery in 1000 femoral arteriograms. The popliteal arterial anatomy could be assessed in 605 extremities and the tibial arterial anatomy in 495 extremities. Seventy-five variant cases were identified. Normal branching of the popliteal artery was present in 92.2%. Among the 7.8% incidence of variants, the majority (72%) were either high origin of the anterior tibial artery or a trifurcation pattern. Of variant patterns to the foot (5.6%), the most common was that in which the supply to the distal posterior tibial artery arose from the peroneal artery. We propose a unified classification of the popliteal and tibial arterial variations that encompasses both anatomic areas. Variant arterial supply to the foot can be suspected when the infrapopliteal vessels show a hypoplastic or aplastic anterior or posterior tibial artery and compensatory hypertrophy of the peroneal artery. Knowledge of these variants is important to angiographers and vascular surgeons.

Angiography↗
PubMed1987

Cloacal exstrophy and cloacal exstrophy variants: a proposed system of classification.

A coding system that documents the abnormalities within the cloacal exstrophy complex is presented. Analysis allows the classification of these abnormalities into classical and variant series in a logical manner. The application of the coding system to selected reported material is described and it demonstrates the similarities between apparently divergent cases.

Abnormalities, Multiple↗
PubMed2026

Systematic functional evaluation of CNGA1 missense variants associated with retinitis pigmentosa.

BACKGROUND: Missense variants are frequently classified as variants of uncertain significance (VUS) according to the guidelines of the American College of Medical Genetics and Genomics and the Association of Molecular Pathology (ACMG/AMP). Consequently, disease relevance remains elusive, impeding molecular genetic diagnostics, patients` and family genetic counseling, and identification of patients eligible for clinical trials. Functional studies are critical for resolving the clinical significance of VUS. CNGA1 encodes the main subunit of the rod cyclic nucleotide-gated (CNG) channel, a vital component of the phototransduction cascade. Variants in CNGA1 are a rare cause of autosomal recessive retinitis pigmentosa and a phase I/II gene augmentation trial (NCT06291935) is currently ongoing highlighting the necessity to differentiate benign from pathogenic variants. METHODS: CNGA1 missense variants compiled from retinal disease patient cohorts, public databases and literature were functionally investigated using a medium-throughput aequorin-based assay and in vitro minigene splice assays for predicted exonic spliceogenic variants. Functional data were correlated with the in silico prediction of five variant effect predictors (VEPs) and applied to support or revise variants' ACMG/AMP classification. RESULTS: Data mining revealed 86 missense CNGA1 variants - including three novel - most of them lacking functional data; 65.1% of the variants were initially classified as VUS. The aequorin-based assay showed that 72.1% of tested variants significantly impaired CNG channel function and were classified as functionally abnormal, while 23.3% were functionally normal and 5% remained functionally uncertain. Correlation of the functional data with in silico predictions identified AlphaMissense and CPT-1 to be the most suitable tools for assessing CNGA1 missense variants. Using in vitro minigene splice assays, two putative missense variants were shown to induce missplicing. Based on the functional findings, 62.1% of the variants initially classified as VUS were re-categorized as likely pathogenic or likely benign. Furthermore, 93.3% of the variants initially classified as likely pathogenic showed an effect on CNGA1 channel function, confirming their disease relevance and supporting their reclassification as pathogenic. CONCLUSION: This study represents the first comprehensive functional assessment of disease-associated CNGA1 missense variants, thus significantly advancing the understanding of their disease relevance and improving molecular genetic diagnostics in patients.

Humans↗
PubMed1987

Human albumin genetic variants: an attempt at a classification of European allotypes.

The relative mobility of albumin and proalbumin genetic variants was estimated by means of cellulose acetate electrophoresis performed with three buffer systems at different pH (8.6, 5.0, and 6.9) after addition of a reference protein and dilution of sera. Numerous experiments using samples of reference variants corroborated the accuracy and reproducibility of this technique. The estimation of the variants' relative mobility at three pH allowed us to distinguish three fast-moving variants (Gent, Vanves, and Reading) and five slow-moving variants (Sondrio, Roma, Christchurch, Lille, and B) in the French population. The frequency of alloalbuminemia in this population is .0004 and is characterized by the high occurrence of albumin B and of the two proalbumin variants, Christchurch and Lille. In order to classify the variants of European origin, the methodology that we developed, owing to its more resolutive possibilities, should be employed as a first step in their identification until establishment of a structural nomenclature making mention of the amino acid substitution characterizing each variant.

Albumins↗
PubMed2025

Extracting and calibrating evidence of variant pathogenicity from population biobank data.

Genomic medicine requires a robust evidence base of variant phenotypic impacts, which remains incomplete even in extensively studied genes with monogenic disease associations. Here, we evaluated the broad potential of using population cohort data to identify evidence that can be used in variant assessment. Across 41 genes related to 18 clinically actionable monogenic phenotypes, we calculated variant-level odds ratios of disease enrichment using data from 469,803 UK Biobank participants. We found significant differences in odds ratio values between ClinVar-labeled pathogenic and benign variants in 11 phenotypes, spanning both common and rare disorders. To facilitate clinical translation, we calibrated the strength of evidence provided by variant-level odds ratios to align with American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) interpretation guidelines (PS4 criterion) and found that odds ratios may reach "moderate," "strong," or "very strong" evidence, varying by phenotype and gene. Overall, we found that 2.6% (N = 12,350) of participants harbor a rare variant of uncertain significance (VUS) with at least moderate evidence of pathogenicity-an indication of potentially unrecognized disease risk. Finally, by incorporating computational and functional data alongside population-based odds ratios, we identified variants that met the criteria for clinical reclassification. Notably, using this approach, we identified that 12.4% of rare VUSs in LDLR seen in participants meet diagnostic criteria to be classified as likely pathogenic, demonstrating its potential to scale the reclassification of VUSs.

Humans↗
PubMed1977

[The problem of the cardiomyopathies].

The author criticizes the tendency to broaden continuously the notion of "cardiomyopathy" and the attempts to cover by this term almost all etiological and pathogenetic variants of myocardial lesions. Classification of these variants by two groups is proposed: 1) idiopathic cardiomyopathies, etiology of which are either not known, or not established yet; 2) symptomatic cardiomyopathies the causes of which are known. The first group comprises congestive and hypertrophic cardiomyopathies. Their essential clinico-anatomical features and considerations concerning pathogenesis are set forth. Every variant of the second group of cardiomyopathies (symptomatic) is analysed separately according to the character of the pathogenic agent. The need for comprehensive study of myocardial pathology in the so-called cardiomyopathies is emphasized.

Cardiomegaly↗
PubMed1986

[Heat exposure differentiates 2 electrophoretically equal allo-albumins].

An alloalbumin characterized by thermolability at 56 degrees C of its slow migration band is described in this paper. The comparison between this new variant and correspondent standard of the "Comitato Italiano per la Standardizzazione dei Metodi Ematologici e di Laboratorio" (CISMEL) allow some remarks upon classification of variants based on the electrophoretic mobility.

Blood Protein Electrophoresis↗
PubMed1989

Temporal lobe syncope: clinical variants.

Temporal lobe syncope (TLS) is a term coined by Landolt. Characteristically, the patient has psychomotor and drop attacks, and the interictal electroencephalogram (EEG) shows temporal lobe epileptic abnormalities. TLS is synonymous with type III complex partial seizures (CPSs) in the Delgado Escueta classification. Several variants of TLS can be recognized including atonic akinetic, simple akinetic, atonic, atonic-tonic complex (automatisms), sexual seizures, stress-induced convulsions, and gelastic atonic seizures. TLS must be distinguished from drop attacks of vertebrobasilar insufficiency and associated EEG abnormalities, and from hereditary tachyarrhythmias mimicking stress-induced convulsions. Epileptic falls and drop attacks are discarded by ictal EEG recordings. Recognition of TLS variants is important in the prospective evaluation of the surgical treatment of epilepsy given the past conflicting reports on the differential outcome of surgically treated CPSs. TLS is an attractive clinical term, easy to remember, and with pathophysiologic relevance to the clinician confronting the patient with a history of syncope and whose EEG discloses temporal lobe paroxysmal activity. The detailed ictal electrophysiology of TLS is unknown.

Adult↗