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PubMed2025

Automated Deep Learning-Based Detection of Early Atherosclerotic Plaques in Carotid Ultrasound Imaging.

BACKGROUND: Carotid plaque presence is associated with cardiovascular risk, even among asymptomatic individuals. While deep learning has shown promise for carotid plaque phenotyping in patients with advanced atherosclerosis, its application in population-based settings of asymptomatic individuals remains unexplored. METHODS: We developed a YOLOv8-based model for plaque detection using carotid ultrasound images from 19,499 participants of the population-based UK Biobank (UKB) and fine-tuned it for external validation in the BiDirect study (N = 2,105). Cox regression was used to estimate the impact of plaque presence and count on major cardiovascular events. To explore the genetic architecture of carotid atherosclerosis, we conducted a genome-wide association study (GWAS) meta-analysis of the UKB and CHARGE cohorts. Mendelian randomization (MR) assessed the effect of genetic predisposition to vascular risk factors on carotid atherosclerosis. RESULTS: Our model demonstrated high performance with accuracy, sensitivity, and specificity exceeding 85%, enabling identification of carotid plaques in 45% of the UKB population (aged 47-83 years). In the external BiDirect cohort, a fine-tuned model achieved 86% accuracy, 78% sensitivity, and 90% specificity. Plaque presence and count were associated with risk of major adverse cardiovascular events (MACE) over a follow-up of up to seven years, improving risk reclassification beyond the Pooled Cohort Equations. A GWAS meta-analysis of carotid plaques uncovered two novel genomic loci, with downstream analyses implicating targets of investigational drugs in advanced clinical development. Observational and MR analyses showed associations between smoking, LDL cholesterol, hypertension, and odds of carotid atherosclerosis. CONCLUSIONS: Our model offers a scalable solution for early carotid plaque detection, potentially enabling automated screening in asymptomatic individuals and improving plaque phenotyping in population-based cohorts. This approach could advance large-scale atherosclerosis research.

atherosclerosis↗

PubMed2025

Proteomics-enabled learning machine algorithms enhance the prediction of cardiovascular diseases in patients with type 2 diabetes mellitus.

BACKGROUND AND AIMS: Estimating the risk of cardiovascular disease (CVD) complications in type 2 diabetes mellitus (T2DM) patients is critical in the medical decision-making process. This study aimed to use a machine learning technique combined with proteomics to develop personalized models for predicting CVD in patients with T2DM. METHODS AND RESULTS: In total, 874 patients with T2DM and 2,920 Olink proteins obtained from the UK Biobank were used in this study. Proteins were screened using Cox regression and LASSO regression. A basic model containing clinical features and a full model combining proteome and clinical features were constructed using the random survival forest algorithm. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the predictive performance of the models and compare them with other CVD predictive models. Compared with the basic model, the full model performed better in predicting CVD, with time-dependent AUCs of 0.81 (3 years), 0.74 (5 years) and 0.74 (10 years) (0.77, 0.69 and 0.67). We calculated the risk scores of the Framingham, ASCVD and Score2-Diabetes models. The results revealed that the prediction performance of the full model was also better than that of the abovementioned models. In terms of differentiation accuracy, the results of the net reclassification improvement index and integrated discrimination improvement index showed that the full model can identify high-risk individuals more accurately (accuracy rate: 79% vs. 69%). CONCLUSIONS: Proteomics can be used to predict cardiovascular complications in diabetic patients. It is also necessary to consider the applicability of the model due to the limitations of the sample size and the constraints of proteomics in clinical applications.

Humans↗

PubMed2026

Proteomic Profiling Captures Residual Cardiovascular Risk Beyond the PREVENT Model in Individuals With Cardiovascular-Kidney-Metabolic Syndrome Stages 2-3.

BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome reflects complex pathobiological interactions among metabolic disorders, kidney injury, and cardiovascular disease (CVD). Stages 2 and 3 represent critical phases of disease progression characterised by high pathological heterogeneity. This study aimed to develop a CVD protein risk score (PRS) for this population and evaluate its incremental predictive value over the PREVENT model. METHODS: This study included 24 017 participants with CKM Stages 2-3 from the UK Biobank. Using 2923 plasma proteins measured via the Olink platform, a PRS was developed in a training set (n = 19 218) using the LASSO method. In the validation set (n = 4799), the incremental predictive performance of this score over the PREVENT model was assessed using Harrell's C-statistic, net reclassification improvement (NRI) and integrated discrimination improvement (IDI). RESULTS: A risk score comprising 63 proteins was constructed, primarily reflecting inflammation, kidney injury and matrix remodelling. Key proteins included growth differentiation factor 15 (GDF15), hepatitis A virus cellular receptor 1 (HAVCR1), matrix metallopeptidase 12 (MMP12) and NT-proBNP. In the validation set, after adjusting for PREVENT risk factors, individuals in the high PRS group had a 2.56-fold higher risk of CVD compared to those in the low score group (HR: 2.56, 95% CI: 1.96-3.37). Integrating the score into the PREVENT model improved the C-statistic by 0.034 (0.672-0.706) and achieved a 10-year NRI of 15.8% (95% CI: 9.5%-20.9%) and an IDI of 2.2% (95% CI: 1.3%-3.3%). CONCLUSION: Combining the PREVENT model with the PRS developed in this study enhances the prediction of future CVD events in the CKM Stages 2-3 population. This approach facilitates the capture of residual risk and supports precision risk stratification and management for this high-risk group.

Humans↗

PubMed2026

Large-Scale Plasma Proteomics Enhances Prediction of Liver-Related Events Among Individuals With Prediabetes and Type 2 Diabetes: A Prospective Cohort Study in the UK Biobank.

OBJECTIVE: To develop a protein risk score (ProRS) for predicting liver-related events (LREs) in patients with diabetes and compare its predictive performance with the Fibrosis-4 Index (FIB-4) and an established polygenic risk score. RESEARCH DESIGN AND METHODS: This prospective cohort study included 13 516 individuals with prediabetes and type 2 diabetes (T2D) from the UK Biobank. Cox proportional hazards models and LASSO regression were applied to identify proteins associated with incident LREs and construct the ProRS. Predictive performance was assessed using Harrell's C-index, time-dependent area under the receiver operating characteristic curve, net reclassification improvement and integrated discrimination improvement. RESULTS: Over a median follow-up of 13.5 years, 171 (1.3%) incident LREs occurred. We identified 877 proteins associated with LRE risk, primarily enriched in inflammatory signalling, extracellular matrix remodelling and complement/coagulation cascades. In the training set, we developed a 24-protein ProRS (C-index, 0.842; 95% CI 0.797-0.884) that stratified individuals into low-, medium- and high-risk groups, with 10-year cumulative incidences of LREs of 0.2%, 1.2% and 14.2%, respectively. Compared with the low-risk group, the hazard ratio for LREs was 57.1 (95% CI 31.9-102) in the high-risk group. In the internal validation set, the ProRS model (C-index, 0.876; 95% CI 0.827-0.920) accurately predicted both short- and long-term LREs and outperformed FIB-4 index (C-index, 0.733; 95% CI 0.657-0.807) and polygenic risk score (C-index, 0.636; 95% CI 0.564-0.706). CONCLUSIONS: The protein risk score demonstrated superior performance compared with the FIB-4 index and the polygenic risk score in predicting incident LREs among individuals with prediabetes and T2D. The score allows stratification of individuals according to liver-related risk, though external validation in multi-ethnic cohorts is warranted.

Humans↗

PubMed1992

An exploratory study of the sources of influence on the clinical decisions of community nurses.

This paper reports a small exploratory study which identifies what community nurses consider to be the scope of their practice and the sources of influence on their clinical decisions. The study was stimulated by the emergence of the nurse prescribing initiative, which is likely to bring clinical decision making to the centre of professional debate. The study was carried out over a 5-month period and data were collected from 47 community nurses in four district health authorities. A qualitative method was employed and field work involved observation of 40 home visits and five nurse-run clinics, individual interviews and group discussions with the nurses, and scrutiny of nursing records. The data were content analysed and classified, and the categories were validated by practitioners. Findings suggest that although community nurses consider that a large proportion of their work requires a scientific basis, their practice is largely founded on experiential knowledge, and on the whole they are not positively disposed to research knowledge. The findings are discussed in the context of nurse prescribing. Questions are raised about the nature of a 'professional' knowledge base and the reclassification of scientific knowledge as nursing or experiential knowledge once it has diffused into practice.

Attitude of Health Personnel↗

PubMed1992

Transoesophageal echocardiography in heart disease--old technologies, new tricks.

Cardiac ultrasound and upper gastrointestinal endoscopy are relatively old technologies. With the introduction of new ultrasound probes and by incorporating ultrasound technology into conventional endoscopes, 'new tricks' in cardiac imaging were discovered. Posterior structures of the heart are now able to be imaged clearly by the ultrasound probe from the oesophagus. Consequently, better resolution of cardiac anatomy allows more accurate diagnosis of cardiac pathologies which is not possible using conventional transthoracic (TT) approach. Over a period of two years, 1200 cases of transoesophageal echocardiography (TOE) were undertaken in our institution. The major indications were diseases of the aorta (10%), source of cardioembolism (28%), assessment of native and prosthetic valve function (20%), suspected endocarditis and its complication (17%), pre and post percutaneous transluminal mitral valvotomy (PTMV [13%], congenital heart disease (2%) and others (10%). The greatest impact with TOE is in the diagnosis of aortic dissection and transection. TOE is superior to conventional TT approach in detecting potential source of embolism, valvular vegetations and its complication, native and prosthetic valve dysfunction and LA thrombus prior to PTMV. Observations by TOE such as spontaneous echo contrast (SEC) in the left atrium open new challenges for further research in its role in the pathogenesis of LA thrombus and its association with cardioembolic event. Other areas of interest include; reclassification of distal aortic dissection and the use of TOE in intra-operative work.

Aortic Diseases↗

PubMed1992

The prognosis of adenosquamous carcinomas of the uterine cervix.

OBJECTIVES: Firstly, to identify a cohort of women with invasive adenosquamous carcinomas of the uterine cervix, including mucin-producing squamous cell carcinomas. Secondly, to compare the biological characteristics and behaviour of a cohort of adenosquamous carcinomas with a cohort of non-mucin-producing squamous cell carcinomas. DESIGN: Histological review, retrospective survival analysis. SETTING: Regional multidisciplinary gynaecological oncology service. SUBJECTS: 161 cases of stage 1B and above invasive cervical carcinoma presenting between 1 January 1980 and 31 July 1987. Thirty nine women with adenosquamous carcinomas were compared with 103 women with non-mucin-producing squamous cell tumours. RESULTS: Inclusion of routine stains for mucin in the assessment of histological material resulted in the reclassification of 38 (24%) of the cases, including the identification of 31 mucin-producing squamous cell carcinomas. The survival with adenosquamous tumours was significantly worse than with squamous cell cancers (P = 0.006), 5-year survival rates being 52% and 75% respectively. Multivariate analysis showed that this effect was explained by differences in clinical stage, pelvic lymph node metastasis and vascular invasion by tumour. CONCLUSIONS: The application of routine mucin stains to cervical tumours identifies a group of previously unrecognized adenosquamous cancers. Tumours so identified are likely to pursue a more aggressive clinical course associated with a poorer survival when compared to non-mucin-producing squamous carcinomas.

Adenocarcinoma↗

PubMed1978

Clinico-pathological correlations in the Kiel classification of non-Hodgkin's lymphomata in children.

The rapid development of chemotherapy and radiotherapy during the last decade makes an increasing demand for a reliable classification of malignant non-Hodgkin's lymphomas. This is especially important in children since in this age group the lymphomas show a much worse prognosis than in adults. An attempt at a modern classification is offered by the so-called Kiel classification. 38 children with non-Hodgkin's lymphomas previously classified according to Rappaport were re-evaluated according to the Kiel system. Reclassification was technically feasible in 26 patients. There was good agreement on typing between the two independently working cytopathologists. 3 patients proved to be cases of histiocytic medullary reticulosis. Among the remaining patients, a much larger variety of histological subgroups was seen than in the one published paediatric series of Lennert. 17 patients had high-grade malignant lymphomas with lymphoblastic lymphomas predominating. Some clinical correlations not detectable with the Rappaport classification were found using the Kiel system. 6 patients were judged as having low-grade malignant lymphomas but in this group the survival was poorer than expected and 1 patient showed leukaemic transformation. The Kiel classification makes high demands for adequate surgical techniques and preparatory routines. It seems to represent a step forward in the classification of non-Hodgkin's lymphomas but much more experience is needed, especially in children, in order to evaluate its role as a guide to differentiated therapy.

Child↗

PubMed2025

Chromosome-specific centromeric patterns define the centeny map of the human genome.

Centromeres are epigenetically specified by distinct chromatin, whereas their DNA varies between species and individuals. This extensive sequence divergence makes comparative analyses between centromeres challenging. In this study, we identified a chromosome-specific architectural pattern across the human genome, defined by the conserved spacing of a functionally relevant centromeric DNA motif. The distribution of these sites along chromosome arms constitutes the human "centeny map." By using a custom Genomic Centromere Profiling (GCP) pipeline, we leveraged the motif's position, orientation, and organization to construct structural models that enable reclassification of human chromosomal clusters, detection of centromere expansion, and identification of structural variants and misassembled regions. The high-resolution maps derived from this pattern not only provide a framework for comparative analysis of centromeres across evolution and disease but also offer a new dimension for chromosome annotation, assembly, and characterization.

Humans↗

PubMed2025

An update on clinically relevant, rare, and emerging Candida and Saccharomycotina yeasts that have been recently reclassified from Candida.

SUMMARYMany yeast species causing life-threatening invasive infections that were formerly classified in the genus Candida have been reclassified due to their evolutionary and phylogenetic relationships elucidated by DNA sequencing methods that are increasingly using whole genomes. This review explores the evolving taxonomy, epidemiology, and clinical implications of clinically relevant, rare, emerging Candida and Saccharomycotina yeasts that have recently been reclassified from Candida. This article highlights the urgent need for intensified research efforts to enhance knowledge and improve outcomes in the management of infections caused by these yeasts. Communicating results from molecular phylogenetic studies of yeasts, which lead to their reclassification, is of great importance to the medical mycology community to implement such results in clinical practice.

Humans↗

PubMed1978

Classification of the New Jersey serotype of vesicular stomatitis virus into two subtypes.

We propose a reclassification of five strains of the New Jersey serotype of vesicular stomatitis virus into two subtypes designated Concan and Hazelhurst. This subclassification into two subtypes is based on reciprocal differences in antibody neutralization of virion infectivity, nucleotide base sequence homology, oligonucleotide maps of virion RNA, and interference by defective-interfering particles.

Base Sequence↗

PubMed2026

Functional Validation of a Novel Homozygous TTN Splice-Site Variant Reveals Aberrant Splicing in Hypertrophic Cardiomyopathy.

The TTN gene encodes a crucial structural protein within cardiac sarcomeres, and its variants may contribute to hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy; however, phenotype and genotype are different. Whole-exome sequencing (WES) was conducted on a Chinese proband diagnosed with HCM. In silico splicing prediction tools and minigene assays were employed to investigate the impact of the identified variant on mRNA splicing. A literature review was performed to retrieve and analyze previously reported splicing variants in the TTN gene associated with HCM. A 42-year-old male proband presented with nonobstructive HCM and paroxysmal atrial arrhythmias. A novel homozygous TTN variant was found, predicted to cause a 14-base pair deletion at a splice acceptor site. Two asymptomatic offspring were found to carry the heterozygous variant. Based on variant interpretation guidelines, the variant met the PM2_supporting criterion and was classified as a variant of uncertain significance (VUS). The predicted aberrant splicing effect was subsequently confirmed by the minigene splicing assay, demonstrating altered pre-mRNA splicing leading to an in-frame insertion/deletion (p.Arg32498_Glu32504delinsGln). Functional verification confirmed that this mutation conforms to the PM4 criterion, suggesting that it can be reclassified as a tepid VUS (scoring 3 points). The functional result might provide pathogenic evidence. We also reviewed 28 previously reported splicing variants in TTN associated with HCM. Of these, 57.1% (16/28) localized to the I-band region, whereas 21.4% (6/28) were situated in the A-band domain of titin. Notably, 21.4% (6/28) co-occurred with pathogenic variants in other sarcomeric genes (MYH7 or MYBPC3), correlating with more severe clinical phenotypes. Reclassification and reinterpretation of the variants revealed that none met the level of likely pathogenic or higher. The present case contributes a homozygous splice-site variant with experimentally confirmed aberrant splicing and an in-frame protein alteration in titin. The focus of this report is the Mendelian genetic basis of the proband's cardiomyopathy phenotype, and our data provide additional case-level and functional evidence for a possible role of specific TTN splicing defects in HCM.

Humans↗

PubMed2026

Bayesian Integration of Tumor Mutational Signatures and Somatic Features Refines Pathogenicity Assessment of Germline Mismatch Repair Variants.

Variants of uncertain significance (VUS) in mismatch repair (MMR) genes represent a persistent bottleneck in germline interpretation for Lynch syndrome, creating a critical opportunity to leverage tumor biology to refine pathogenicity assessment. Although tumor features such as microsatellite instability (MSI) and immunohistochemistry (IHC) are routinely evaluated, they are typically interpreted separately from germline classification, and their quantitative contribution within ACMG/AMP frameworks remains poorly defined. We therefore analyzed paired germline and tumor sequencing data from 1110 tumors across 1073 patients with colorectal or endometrial cancer to determine whether mismatch repair-deficient (MMR-d) mutational signatures can be quantitatively integrated into Bayesian germline variant interpretation. Using COSMIC single-base substitution signatures, tumors were classified as MMR-d or MMR proficient, and an empirically derived likelihood ratio (LR) quantified the association between MMR-d signatures and pathogenic germline MMR variants. The presence of an MMR-d signature increased the likelihood of an underlying pathogenic germline MMR variant approximately eightfold (LR ≈ 8; log10 LR ≈ 0.90), whereas its absence provided moderate-to-strong benign evidence (LR ≈ 0.156; log10 LR ≈ -0.81). Applying this integrative framework to 45 germline MMR VUS, joint modeling of tumor mutational signatures with additional somatic and variant-level evidence resulted in clinically significant reclassification of 38 (84.4%) variants, including three reclassified as pathogenic or likely pathogenic and 35 as likely benign. A total of 16 downgraded variants were independently downgraded by Invitae. These findings demonstrate that tumor mutational signatures can be formally incorporated into Bayesian germline interpretation, transforming tumor data into quantitative pathogenicity evidence and offering a principled strategy to reduce VUS burden in hereditary cancer genetics.

Humans↗

PubMed1979

Therapy of urothelial bladder tumors. Results of a retrospective study of 615 cases.

615 urothelial bladder tumors are evaluated retrospectively after reclassification of histological and cytological specimens according to the recommendations of the World Health Organization (1973) and International Union Against Cancer (1974). The reason for a subdivision of the T1 category for exophytic noninfiltrating carcinomas is discussed. The importance of stage and grade is demonstrated as well as the different prognosis of patients with primary or recurrent tumors of the same T category. The results of the study demand a differentiated therapeutic regimen for urothelial bladder tumors.

Follow-Up Studies↗

PubMed2026

LDLR Variant Classification Through Activity-Normalized Prime Editing Screening.

BACKGROUND: Inherited variants in the LDL (low-density lipoprotein) receptor (LDLR) gene are the most common cause of familial hypercholesterolemia, significantly increasing coronary artery disease risk. Early identification of pathogenic LDLR variants enables prompt lipid-lowering therapy and cascade testing of at-risk relatives; however, most LDLR variants observed in the population have uncertain or absent clinical classifications, leaving many patients without actionable information. METHODS: We developed the first activity-normalized prime editing screening pipeline to measure the impact of 5184 LDLR coding variants on LDL-cholesterol (LDL-C) uptake. Each prime editing guide RNA is paired with a genotypic outcome reporter to correct for variable editing efficiency, overcoming a key limitation of previous pooled genome editing screens. A statistical framework further improves variant effect estimates by jointly analyzing all missense variants at each amino acid position. RESULTS: We show that prime editing of the reporter construct correlates with endogenous variant installation frequency, validating the activity normalization approach. The resulting scores capture a continuous spectrum of functional effects, robustly separate pathogenic versus benign ClinVar variants, and show concordance with LDL-C levels in UK Biobank participants. We calibrate functional evidence strengths to the ACMG/AMP variant interpretation framework, enabling integration into a clinical variant classification workflow. By combining functional, computational, population, and contextual evidence, 322 of 434 LDLR variants currently classified as variants of uncertain significance, conflicting, or absent from ClinVar appear to meet evidence thresholds for reclassification and can be prioritized for expert review, substantially expanding the pool of actionable variant classifications. The screen also reveals a cluster of gain-of-function variants in LDLR class A repeat 5, at least some of which enhance LDL-C uptake through increased apolipoprotein B interaction, with implications for therapeutic genome editing. Last, prime editing uniquely detects splice-altering coding variants missed by cDNA-based screens and pathogenicity predictors, revealing an advantage of endogenous variant installation. CONCLUSIONS: Altogether, activity-normalized prime editing provides a scalable framework for LDLR variant classification that substantially expands the proportion of variants with evidence for genetic diagnosis and reveals novel biology with therapeutic relevance.

CRISPR screening↗

PubMed1975

Subpopulations of lymphocytes: a review.

Human lymphocytes comprise a heterologous population of cells which can be sub-divided on functional criteria or on the basis of surface membrane markers. Although it is widely accepted that human lymphocytes are broadly divisible into thymus dependent (T) and thymus independent (B) cells, recent evidence suggests that at least in humans this distinction may not be as clear cut as previously thought. An assessment of the relative numbers of T and B cells in human peripheral blood and lymphoid tissues can be made utilizing these marker systems. This has led to a reclassification of human lymphoid diseases according to the T and B cell concept, which might be of value in characterising the immunological status in health and disease, and may allow a more rational approach to the therapy of immune deficiency states and lymphoid malignancies.

Agammaglobulinemia↗

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↗

PubMed2026

X-linked spondyloepiphyseal dysplasia tarda misdiagnosed as growth hormone deficiency: identification of a novel intronic TRAPPC2 variant by whole-genome sequencing.

BACKGROUND: X-linked spondyloepiphyseal dysplasia tarda (SEDT) is a rare skeletal dysplasia caused by pathogenic variants in TRAPPC2 and typically presents in late childhood or adolescence with short-trunk disproportion and vertebral dysplasia. CASE PRESENTATION: We describe a family series centered on an adolescent male initially diagnosed with GHD due to reduced height velocity and subnormal GH stimulation results, who received recombinant human GH (rhGH) therapy for three years with negligible improvement. During puberty, he developed progressive short-trunk disproportion and characteristic radiographic features, including platyspondyly and posterior hump-shaped vertebral endplates, suggestive of SEDT. Whole-exome sequencing (WES) was nondiagnostic, whereas whole-genome sequencing (WGS) identified a novel intronic TRAPPC2 variant, c.239-20_239-12delinsAATGAA, initially classified as a variant of uncertain significance (VUS). Segregation analysis across the family enabled reclassification of the variant to likely pathogenic, confirming X-linked SEDT. The proband's younger brother exhibited earlier radiologic abnormalities and, notably, a favorable response to rhGH, whereas the younger sister-an asymptomatic heterozygous carrier-showed normal spinal morphology, consistent with expected female carrier phenotypes. CONCLUSIONS: This family-based report underscores the generally limited therapeutic effect of rhGH in SEDT while highlighting potential interindividual variability, as evidenced by the younger male sibling's response. It further emphasizes the diagnostic utility of WGS for detecting deep intronic variants missed by WES and the importance of segregation analysis in resolving VUS in rare skeletal dysplasias.

Humans↗