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PubMed1977

Bilateral mandibular condylysis-a morphanalytic diagnosis.

Four cases of bilateral mandibular condylysis are presented. The condition does not appear to be included in current teaching or existing nomenclature and consists of an acquired absence of the mandibular condyles, unassociated with temporomandibular ankylosis or aural/facial anomalies. In the literature of condylar maldevelopment four published cases appear to justify reclassification as bilateral mandibular condylysis, bringing the recorded total to eight. Whereas previous writers have regarded the condition as a prenatal condylar aplasia or hypoplasia, morphanalysis studies of the four current cases have shown that the probable aetiology is postnatal local disturbance in the condylar region. The term condylysis has been chosen to emphasise the locally destructive (or lytic) mechanism which appears to be involved. Mandibular condylysis is distinguished from condylar aplasia by its non-association with aural/facial anomalies and because normal development appears to proceed until the lytic event occurs. It is further distinguished from primary and secondary condylar hypoplasia because the condyle is absent rather than small, because normal development appears to proceed until the lytic event occurs and because of its non-association with aural/facial anomalies or temporomandibular ankylosis.

Adolescent↗

PubMed1979

Stage A2 prostatic carcinoma: should staging system be reclassified?

Seventy patients with clinically localized prostatic carcinoma were studied for histologic differentiation of primary tumor and the incidence of lymph node metastasis. Also the urologic literature was reviewed regarding the survival of such patients under similar treatment. The results indicate that clinically staged A2 tumors are more aggressive biologically than tumors staged as B1, reaffirming the need for a change in the current staging system. The authors propose reclassification of clinically unsuspected, diffuse carcinoma from the A to the B2 stage.

Adenocarcinoma↗

PubMed2026

Routine methods misidentify Serratia spp.: Limitations of MALDI-TOF MS revealed by whole-genome sequencing.

Accurate species-level identification within the genus Serratia remains challenging due to extensive phenotypic overlap and high genomic relatedness among closely related and recently described taxa. This study presents an evaluation of routine and genome-based identification approaches applied to clinical Serratia isolates, integrating phenotypic assays, MALDI-TOF MS (Bruker Daltonics), 16S rRNA gene sequencing, and Whole-Genome Sequencing (WGS). A total of 103 isolates collected from a teaching hospital were analyzed. WGS was performed on a subset of isolates. Conventional biochemical methods classified all isolates as Serratia marcescens, whereas MALDI-TOF MS identified 60.1% as S. marcescens, 11.6% as S. ureilytica, and 28.1% just at the genus level. Peak analysis from MALDI-TOF MS revealed specific peaks associated with S. marcescens and S. ureilytica, but limited discriminatory power. WGS of six isolates initially identified as S. ureilytica by MALDI-TOF MS revealed reclassification as Serratia sarumanii (n = 5) and Serratia montpellierensis (n = 1), supported by Average Nucleotide Identity (ANI), Average Amino Acid Identity (AAI), and Digital DNA-DNA Hybridization (dDDH) thresholds. In contrast, 16S rRNA analysis showed limited species-level resolution. Phylogenomic and SNP-based analyses confirmed these classifications with strong support. Overall, this study underscores the critical role of high-resolution genomic approaches for precise species identification and highlights the need for continuous expansion and curation of MALDI-TOF MS reference databases to support reliable clinical diagnostics and epidemiological surveillance of emerging Serratia species.

Spectrometry, Mass, Matrix-Assisted Laser Desorpti↗

PubMed2024

Microduplications of ARID1A and ARID1B cause a novel clinical and epigenetic distinct BAFopathy.

PURPOSE: ARID1A/ARID1B haploinsufficiency leads to Coffin-Siris syndrome, duplications of ARID1A lead to a distinct clinical syndrome, whilst ARID1B duplications have not yet been linked to a phenotype. METHODS: We collected patients with duplications encompassing ARID1A and ARID1B duplications. RESULTS: 16 ARID1A and 13 ARID1B duplication cases were included with duplication sizes ranging from 0.1 to 1.2 Mb (1-44 genes) for ARID1A and 0.9 to 10.3 Mb (2-101 genes) for ARID1B. Both groups shared features, with ARID1A patients having more severe intellectual disability, growth delay, and congenital anomalies. DNA methylation analysis showed that ARID1A patients had a specific methylation pattern in blood, which differed from controls and from patients with ARID1A or ARID1B loss-of-function variants. ARID1B patients appeared to have a distinct methylation pattern, similar to ARID1A duplication patients, but further research is needed to validate these results. Five cases with duplications including ARID1A or ARID1B initially annotated as duplications of uncertain significance were evaluated using PhenoScore and DNA methylation reanalysis, resulting in the reclassification of 2 ARID1A and 2 ARID1B duplications as pathogenic. CONCLUSION: Our findings reveal that ARID1B duplications manifest a clinical phenotype, and ARID1A duplications have a distinct episignature that overlaps with that of ARID1B duplications, providing further evidence for a distinct and emerging BAFopathy caused by whole-gene duplication rather than haploinsufficiency.

Humans↗

PubMed2025

Pathogenicity assessment of genetic variants identified in patients with severe hypertriglyceridemia: Novel cases of familial chylomicronemia syndrome from the Dyslipidemia Registry of the Spanish Atherosclerosis Society.

PURPOSE: Genetic testing is required to confirm a diagnosis of familial chylomicronemia syndrome (FCS). We assessed the pathogenicity of variants identified in the FCS canonical genes to diagnose FCS cases. METHODS: 245 patients with severe hypertriglyceridemia underwent next-generation sequencing. Preliminary variant pathogenicity criteria and classification, based on the American College of Medical Genetics and Genomics guidelines, were obtained online and verified. Phenotype evaluation was based on lipoprotein lipase activity deficiency, a clinical score, and/or type I hyperlipoproteinemia determined in 25 patients. RESULTS: Twenty-four biallelic variants were analyzed. Evidence-based criteria allowed the reclassification of 8 likely pathogenic (LP) variants in the LPL, APOA5, and LMF1 genes into pathogenic (P) and the change of 2 variants of uncertain significance (VUS) to LP. Conversely, 2 variations in LMF1 remained as VUS. Additionally, 1 variant in LPL and 2 in GPIHBP1 were likely benign. Twenty FCS cases had biallelic P/LP variants and 1 patient, with an FCS phenotype, harbored biallelic VUS. FCS was excluded from 4 patients with pathogenic/likely benign combinations. CONCLUSION: The analysis of the clinical and biochemical features of patients with variants in the FCS canonical genes allowed a confident variant classification that helped in the diagnosis of novel FCS cases.

Humans↗

PubMed2026

RNU4ATAC-opathy: Clinical, molecular, and transcriptomic insights from a large cohort.

PURPOSE: We aim to better define the genotype and phenotype spectrum of RNU4ATAC-opathy, demonstrate the utility of RNA sequencing (RNA-seq) for variant classification, and highlight the challenges in detecting variants in this noncoding gene. METHODS: Sixty individuals with molecularly confirmed RNU4ATAC-opathy were recruited from multiple clinical and research centers internationally. RNA-seq was available for 7 affected individuals. RESULTS: We report the clinical and molecular findings of 60 individuals, including 42 not previously described, and 33 distinct RNU4ATAC variants, 13 of which are novel. Core features in this cohort-present in most individuals assessed and varying in severity-include microcephaly, short stature, skeletal anomalies, developmental delay, cerebral anomalies, skin conditions, and immune deficiency. Additional findings, such as diabetes, holoprosencephaly, and the absence of various core features in some individuals, highlight the broad phenotypic spectrum. All individuals who underwent RNA-seq showed a consistent pattern of minor intron retention. In 6 individuals, RNA-seq enabled the reclassification of variants of uncertain significance as likely pathogenic. Although RNU4ATAC variants are generally covered by clinical exomes, they are often overlooked in analysis because of their noncoding nature. CONCLUSION: This study highlights the variability of phenotypes and genotypes associated with RNU4ATAC-opathy. Laboratories should ensure RNU4ATAC and other noncoding genes are appropriately assessed by their analysis pipelines.

Lowry-Wood syndrome↗

PubMed2026

Proteomic signatures for sudden cardiac death and related intermediate phenotypes.

BACKGROUND: Novel markers for sudden cardiac death (SCD) are needed. OBJECTIVE: This study aimed to explore whether a protein risk score derived from a large-scale proteomics dataset improves risk prediction of SCD in the general population. METHODS: A total of 52,705 individuals with 1459 unique plasma protein measurements were included from the UK Biobank Pharma Proteomics Project. A protein risk score was developed using lasso-penalized Cox regression on 40,722 participants enrolled at the English centers and validated on 11,983 participants enrolled at the remaining centers. RESULTS: The protein risk score formula developed from the derivation set comprised 64 unique plasma proteins including latent-transforming growth factor beta-binding protein 2, protein tyrosine phosphatase receptor sigma, and spondin-1. In the test set, a per standard deviation increase in protein risk score was associated with a hazard ratio of 2.60 (95% confidence interval [CI] 2.12-3.18) for SCD. Adding a protein risk score to SCD clinical risk factors resulted in a concordance index increase of 0.063 (95% CI 0.037-0.105) for SCD. For ventricular arrhythmia-mediated SCDs, an increase in concordance index when a protein risk score was added to SCD clinical risk factors was 0.070 (95% CI 0.010-0.188). A protein risk score added to SCD clinical risk factors resulted in a risk reclassification of 16.9% (95% CI 9.0-24.7) at a 10-year risk threshold of 5%. A protein risk score was significantly associated with intermediate phenotypes of SCD including corrected QT prolongation, an increase in left ventricular mean myocardial thickness, and a decrease in left ventricular global longitudinal strain. CONCLUSION: A protein risk score derived from a single plasma sample significantly improved risk prediction of SCD and related intermediate phenotypes.

Humans↗

PubMed2026

Lactate Dehydrogenase and Outcomes in Patients With HF and Reduced Ejection Fraction: Insights From GALACTIC-HF.

BACKGROUND: Lactate dehydrogenase (LDH) is a cytoplasmic enzyme found in most cells. Increased LDH levels are a nonspecific measure of cellular injury and may be prognostically important in heart failure (HF). OBJECTIVES: This study aims to assess the relationship between LDH and clinical characteristics and outcomes in heart failure and reduced ejection fraction (HFrEF). METHODS: Using data from GALACTIC-HF, a phase 3, randomized, placebo-controlled trial evaluating the efficacy and safety of omecamtiv mecarbil (OM) in patients with HFrEF, the relationship between LDH and clinical outcomes was analyzed. The incremental value of LDH added to a validated prognostic model (PREDICT-HF) was also calculated using Harrell's C statistic, integrated discrimination index (IDI), and net reclassification index (NRI). RESULTS: In GALACTIC-HF, baseline LDH data were available for 8,179 patients, including 6,138 outpatients. Patients with higher LDH were more frequently female and had worse HF status. They were also more likely to have elevated serum creatinine, liver enzymes, creatine kinase, NT-proBNP, and high-sensitivity troponin I. Compared with patients in the lowest LDH (Q1: 155 U/L [25th-75th percentile: 144-163 U/L]), the HRs for the primary outcome (first HF event or cardiovascular death) were Q2: 183 U/L (25th-75th percentile: 177-188 U/L); HR: 1.15 [95% CI: 1.02-1.31]; Q3: 207 U/L (25th-75th percentile: 201-215 U/L); HR: 1.39 [95% CI: 1.23-1.58]; and Q4: 253 U/L (25th-75th percentile: 236-280 U/L); HR: 1.84 [95% CI: 1.62-2.08], respectively. Even after adjustment, elevated LDH remained independently associated with higher HR. When added to the PREDICT-HF risk model, baseline LDH improved Harrell's C statistic, IDI, and NRI for the primary outcome. CONCLUSIONS: In GALACTIC-HF, higher LDH levels were independently associated with a higher risk of clinical outcomes in HFrEF. (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure [GALACTIC-HF]; NCT02929329; EudraCT number: 2016-002299-28).

Humans↗

PubMed2025

Optical Genome Mapping in Myelodysplastic Syndromes: Clinical Value and Limitations Derived From a Cohort of 236 Patients.

Identification of cytogenetic abnormalities is critical for the classification and risk stratification of myelodysplastic syndromes (MDS). Optical genome mapping (OGM) is an emerging cytogenomic platform that enables high-resolution genome-wide cytogenetic analysis. We analyzed bone marrow specimens of 236 MDS patients, 149 newly diagnosed and 87 with relapsed/refractory disease, using OGM, conventional karyotyping, and next-generation sequencing analysis. OGM and karyotyping showed concordant results in 68% of cases, including 34% with normal findings by both assays. OGM provided additional information in 27% of patients. Common abnormalities detected exclusively by OGM included chromoanagenesis (n = 33), KMT2A partial tandem duplication (n = 7), and MECOM rearrangement (n = 4). These OGM findings led to disease reclassification and/or changes in risk stratification in 14 patients (9.4%) with newly diagnosed MDS. In contrast, OGM failed to detect small clones or subclones in 5% of patients, resulting in risk group changes in 2% of newly diagnosed MDS patients. We conclude that OGM enhances the cytogenetic assessment of MDS in approximately 25% of patients and leads to a change in disease classification and/or risk stratification in approximately 10% of patients. However, low sensitivity for detecting small clones or subclones remains a limitation of OGM.

Humans↗

PubMed2025

DNA Methylation-Based Classification of Kidney Neoplasms.

Renal neoplasms are morphologically and molecularly heterogeneous, with their diagnosis often hindered by interobserver variability and overlapping microscopic features. A subset of cases is unclassifiable despite immunohistochemical, mutation, and cytogenetic-based diagnostic workup. Through examination of the genome-wide DNA methylation signatures of over 2000 renal neoplasms, we identified 23 coherent groups that correlate with known neoplasm types and identified novel clinically relevant subtypes of existing neoplasm types. We used machine learning models to develop and validate a classifier trained on DNA methylation profiles of 1284 samples. The classifier was tested on an external data set of 287 renal neoplasms with >90% concordance between expected neoplasm type and high-score DNA methylation-based classification. Discordance between the original histologic label and methylation class led to potential reclassification of some cases. This work demonstrates proof of principle for the feasibility of a DNA methylation classifier as a clinically useful tool to assist in the diagnosis of renal neoplasms.

Humans↗

PubMed2025

Optical Genome Mapping Is a Powerful Diagnostic Tool in Non-Hodgkin Lymphoma.

Non-Hodgkin lymphoma (NHL) is a diverse and heterogeneous group of hematological malignancies. These lymphomas arise from the clonal proliferation of either B/T or natural killer lymphocytes, and their correct classification relies partly on identifying characteristic structural variants and copy number alterations. Current standard-of-care technologies for detecting these genomic features, chromosome banding analysis (CBA) and fluorescent in situ hybridization (FISH), are labor intensive and have specific limitations. CBA has low resolution and relies on viable cell culture, whereas the targeted approach of FISH does not provide the whole genome view required for comprehensive disease characterization. This highlights the need for higher-resolution nontargeted genomic methods. Previous studies have evaluated optical genome mapping (OGM) as a whole genome alternative for cytogenomic characterization in NHL diagnostics but were restricted in number and to cases with peripheral blood and/or bone marrow invasion. Here, we selected a comprehensive cohort of 110 NHL cases (79 B-NHL and 31 T-NHL/natural killer-NHL) derived from different types of tissue biopsies, all with established histopathological diagnoses. Seventy-eight samples were genomically well characterized at diagnosis by CBA and FISH. The remaining 32 cases were included because of previous CBA failure, although FISH data were available for 20 cases. OGM provided informative results in 94% of the cohort, with a high concordance rate of 97.6% compared with CBA/FISH in detecting clinically relevant aberrations. The 2 variants that were missed were both present at the detection threshold of OGM. In contrast, OGM successfully resolved 26 samples with previous CBA failure and detected 3 additional disease-defining events, resulting in diagnostic reclassification of 1 patient. Finally, OGM identified novel recurrent aberrations that warrant further investigation into their pathogenetic implications. To conclude, OGM robustly detects clinically relevant structural variants and copy number alterations and presents a promising alternative to CBA and FISH in routine diagnostic evaluation of NHL.

Humans↗

PubMed2026

Generation of two homozygous iPSC lines carrying variants of uncertain significance in LMNA associated with cardiomyopathy.

Variants of uncertain significance (VUS) in the LMNA gene represent a major challenge in clinical genetics, as insufficient functional evidence limits their interpretation and clinical decision-making in laminopathies, including dilated cardiomyopathy (DCM). Here, we generated two isogenic induced pluripotent stem cell (iPSC) lines carrying homozygous LMNA variants, c.293A > G (p.Glu98Gly) and c.439G > A (p.Ala147Thr) by prime editing of a healthy donor iPSC line. Both variants are located within Coil 1B domain of lamin A. The edited iPSC lines retain normal morphology, pluripotency, genomic integrity, and trilineage differentiation capacity, providing a valuable platform for functional characterization and potential clinical reclassification of LMNA VUS.

Humans↗

PubMed2026

Targeted reflex RNA sequencing for enhanced variant classification on exome and genome sequencing improves patient outcomes.

RNA sequencing (RNA-seq) has been utilized to provide functional evidence regarding the impact of splicing variants. This study explores the utility of targeted reflex RNA-seq to inform classification of predicted splicing variants identified through clinical exome sequencing (ES) and genome sequencing (GS). A retrospective analysis was conducted on consecutive ES/GS cases completed at a single center in which targeted reflex RNA-seq was performed following identification of eligible variants. There were 131 cases (4.1%) that had at least one RNA-seq eligible variant reported, with eight of these cases having two unique eligible variants. Of the 139 eligible variants, 125 were classified as variants of uncertain significance (VUS). Sixty-four cases had targeted reflex RNA-seq completed with 27 cases having at least one variant reclassified (42.2%). After reclassification, 23 cases had positive results, and two cases had a likely diagnosis of an autosomal recessive condition. Clinical outcomes data regarding positive RNA-seq cases showed that 71% (10/14) had clinical management changes and 43% (6/14) had treatment changes. Incorporation of targeted reflex RNA-seq analysis into the diagnostic pipeline of rare diseases enhances variant classification and resolves uncertainty regarding predicted splice variants, leading to an estimated 1.6% increase in diagnostic yield of clinical ES/GS.

Journal Article↗

PubMed1979

Development of a classification rule for four clinical therapeutic psychotropic drug classes with EEG power-spectrum variables of human volunteers.

An objective rule for the classification of psychotropic substances has been developed. Classification is based on data from five basic studies simultaneously designed and performed and involving 75 healthy volunteers who ingested 20 different psychotropic drugs and 5 placebos in single oral dosages. Each volunteer took one psychostimulant, one antidepressant, one neuroleptic, one minor tranquilizer and one placebo in a double-blind Latin square cross-over design. The variables were 6 frequency bands, based on power spectrum estimates and determined by factor analysis, plus total power in the 1.5-30.0 Hz range. An objective classification rule was established by multi-group (5 groups) linear discriminant analysis. Reclassification of the substances by the new rule yielded correct results for 17 out of 20 psychotropic drugs and 4 out of 5 placebos. Of placebos from various studies not used for the establishment of the classification rule, 7/9 were classified correctly. The validity of the rule for other classes of substances will have to be verified in independent studies.

Adult↗

PubMed2026

A Quantitative Lung Mucin Score to Identify Chronic Bronchitis.

BACKGROUND: We previously demonstrated that sputum total mucin concentration is an objective marker for chronic bronchitis (CB). This current study introduces a novel Mucin Quantitative Score (MUCQ) that combines total mucin concentration and mucin composition to improve the assessment of risk, onset of clinically diagnosed disease, and progression of muco-obstructive lung diseases. METHODS: Patients from the SPIROMICS (SubPopulations and InteRmediate Outcome Measures in COPD Study) cohort were classified as having CB, or not, based on clinical questionnaires. Using the measured total mucin, MUC5AC, and MUC5B concentrations in sputum samples, we calculated MUCQ as [Total mucin]×([MUC5AC]÷[MUC5B])÷100 μg/ml, which is a unitless, weighted concentration score. Our primary outcome was the net reclassification of patients with a diagnosis of CB, or not, based on total mucin concentrations in their sputum compared with using the MUCQ score. Participants were first classified as CB- positive or -negative using a total mucin concentration threshold of 2306 μg/ml, then reclassified using the MUCQ threshold of 4.30. Associated z statistics and a P value for the primary outcome are reported. RESULTS: Among 164 patients in the SPIROMICS cohort with clinically defined CB, using the MUCQ score up-classified 18 patients who were currently smoking to a diagnosis of CB and down-classified 5 patients who were currently smoking and 3 control participants who had never smoked, compared with the classification of CB was based on total mucin concentrations alone (P=0.001). In addition, MUCQ correlated with other clinical and pathological indices of chronic airway disease and airway obstruction. CONCLUSIONS: The MUCQ metric was superior in distinguishing patients with CB compared to a total mucin concentration. Trials are needed to ascertain the prospective use of MUCQ metrics in research and clinical settings for assessment, management, and tracking therapeutic responses in CB and potentially other muco-obstructive conditions. (Funded by the National Institutes of Health and others.).

Humans↗

PubMed1979

Quantitative studies of saccadic and pursuit eye movements in multiple sclerosis.

Ocular movements were studied in 108 patients with established or suspected multiple sclerosis using an on-line computer-based electro-oculographic technique. In one group of patients peak eye movement velocities alone were measured during horizontal refixation saccades. In a second group saccade reaction times and accuracies were measured in addition to velocities, while in a subgroup a quantitative analysis of horizontal pursuit eye movements was also carried out. With the saccade velocity test abnormalities were present in 44 per cent of cases studied and were subclinical in 18 per cent. Abnormalities were found in 57 per cent of cases in whom the detailed saccade analysis was performed, including 48 per cent of patients with clinically normal eye movements. Saccade reaction time and accuracy were more sensitive parameters than saccade velocity, and the highest yield of abnormalities was obtained when all three were taken into consideration. Abnormalities of pursuit movements were found in 71 per cent of cases studied and were frequently subclinical. Abnormalities of saccadic and pursuit movements were not always present together in the same patient, and the overall yield of abnormalities was higher when the results of both types of study were taken into account. The yield of abnormalities with the eye movement studies was somewhat lower than with the pattern-reversal VEP in the clinically definite multiple sclerosis group, but was higher in patients in the other categories. Subclinical abnormalities of eye movement were found in a significant number of patients with normal VEPs. The finding of such an abnormality in patients with spinal cord syndromes allowed reclassification of 14 patients to a category with a higher degree of diagnostic certainty. It is concluded that quantitative electro-oculography is a valuable adjunct to the clinical evaluation of eye movements and has an important role in the investigation of patients suspected of multiple sclerosis.

Adult↗

PubMed2026

Comprehensive assessment of vasospastic angina using coronary computed tomography angiography: synergistic value of the presence of myocardial bridge, perivascular inflammation, and myocardial extracellular volume fraction.

AIMS: Coronary computed tomography angiography (CCTA) has evolved beyond anatomical assessment to include sophisticated tissue characterization. While an elevated perivascular fat attenuation index around the right coronary artery (FAI-RCA) is known to reflect coronary inflammation in vasospastic angina (VSA), recurrent vasospasms may also induce chronic subclinical myocardial injury and subsequent remodelling, potentially associated with an increased myocardial extracellular volume fraction (ECV). However, the diagnostic integration of ECV and FAI-RCA for identifying VSA in patients with angina with non-obstructive coronary arteries (ANOCA) remains to be elucidated. METHODS AND RESULTS: This study included consecutive ANOCA patients who underwent CCTA with a dedicated ECV protocol, followed by an invasive spasm provocation test. Comprehensive CCTA analysis quantified both FAI-RCA and the transmural ECV gradient (the difference between endocardial and epicardial ECV: ECVEndo - ECVEpi). Of the 100 patients analysed (mean age: 65.3 ± 11.8 years; 55% male), 27 were diagnosed with VSA. Multivariable logistic regression analysis identified transmural ECV gradient [odds ratio (OR): 1.12, 95% confidence interval (CI): 1.01-1.25], presence of myocardial bridging (MB) (OR: 3.49, 95% CI: 1.25-9.74), and high FAI-RCA (> -70.95 Hounsfield units [HU]) (OR: 5.79, 95% CI: 2.06-16.30) as significant independent predictors of VSA (all P < 0.05). Notably, the integration of transmural ECV gradient provided incremental diagnostic value beyond FAI-RCA and MB, as assessed by the Net Reclassification Improvement and Integrated Discrimination Improvement. CONCLUSION: A multi-parametric CCTA approach potentially identifies patients at high risk for VSA. The significant association of the transmural ECV gradient with VSA suggests that myocardial remodelling imaging provides a novel diagnostic window into the cumulative myocardial impact of vasospasm, independent of active adipose tissue inflammation and the presence of MB.

Humans↗

PubMed2026

Automated patch clamp data improve variant classification and penetrance stratification for SCN5A-Brugada syndrome.

BACKGROUND AND AIMS: Brugada Syndrome (BrS) is an inherited arrhythmia disorder that causes an elevated risk of sudden cardiac death. Approximately 20% of patients with BrS have rare variants in SCN5A, which encodes the cardiac sodium channel NaV1.5. Genetic workup of BrS is often complicated by SCN5A variants of uncertain significance (VUS) and/or incomplete penetrance. This study deployed an SCN5A-BrS functional assay at cohort scale to facilitate the implementation of genetic and precision medicine. METHODS: All 252 missense and in-frame insertion/deletion SCN5A variants from a previously published large cohort of BrS cases (n = 3335 patients) were analysed using a calibrated high-throughput automated patch-clamp (APC) assay. Variant functional Z-scores were assigned evidence levels ranging from BS3_moderate (normal function) to PS3_strong (loss-of-function), as defined by American College of Medical Genetics and Genomics criteria. Functional evidence was combined with population frequency, hotspot, case counts, protein-length changes, and in silico predictions. Odds ratios of BrS case-control enrichment and penetrance for BrS were calculated from variant frequencies in the BrS cohort and in gnomAD. RESULTS: Most variants (146/252) were functionally abnormal (Z ≤ -2), with 100 having severe loss-of-function (Z ≤ -4). Functional evidence enabled the reclassification of 110 of 225 VUS; 104 to likely pathogenic and 6 to likely benign. SCN5A variants with loss-of-function were mainly localized to the transmembrane domains, especially the regions comprising the central pore. SCN5A variant penetrance was proportional to the severity of loss-of-function; variants with Z ≤ -6 had penetrance of 24.5% (15.9%-37.7% CI) and an odds ratio of 501 for BrS. CONCLUSIONS: This cohort-scale APC dataset stratifies SCN5A variants found in BrS patients into normal function 'bystander' variants that have a low risk of BrS and loss-of-function variants that have a high risk for BrS. Functional data can be integrated with other criteria to reclassify a substantial fraction of VUS. The dataset helps clarify the SCN5A-BrS relationship and will improve the diagnosis and clinical management of BrS probands and their families.

Humans↗