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Results for “variant interpretation”

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At least 19 recordsLinked to original sources

PubMed2024

Classification of variants of reduced penetrance in high-penetrance cancer susceptibility genes: Framework for genetics clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK).

PURPOSE: Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene as though having equivalent penetrance, despite increasing evidence of intervariant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants in which reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance. We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network. METHODS: A series of surveys and live polls were conducted during and between CanVIG-UK monthly meetings on various scenarios potentially indicating reduced penetrance. These informed the iterative development of a framework for the classification of variants of reduced penetrance by the CanVIG-UK Steering and Advisory Group working group. RESULTS: CanVIG-UK recommendations for amendment of the 2015 ACMG/AMP variant interpretation framework were developed for variants in which (A) active evidence suggests a reduced-penetrance effect size (eg, from case-control or segregation data) and (B) reduced penetrance effect is inferred from weaker/potentially inconsistent observed data. CONCLUSION: CanVIG-UK propose a framework for the classification of variants of reduced penetrance in high-penetrance genes. These principles, although developed for cancer susceptibility genes, are potentially applicable to other clinical contexts.

Humans↗

PubMed2025

Evaluating Language Models for Biomedical Fact-Checking: A Benchmark Dataset for Cancer Variant Interpretation Verification.

Accurate interpretation of genomic variants is critical for precision oncology but remains slow and dependent on specialized expertise. Public knowledgebases such as the Clinical Interpretation of Variants in Cancer (CIViC) help by curating literature-backed variant interpretations in a structured form, yet verification and review have become major bottlenecks. To address this, we developed CIViC-Fact, a benchmark dataset and pipeline for testing automated systems that verify the accuracy of cancer variant claims. CIViC-Fact links structured claims to sentence-level supporting or refuting evidence from full-text articles, and includes expert annotations and explanations. We evaluated multiple language models. Proprietary models performed well without training, but a smaller open-source model, fine-tuned on CIViC-Fact, achieved the highest accuracy (89%). Applying our fact-checking pipeline to real CIViC entries showed that reviewing less than 20% of content, focusing on flagged entries, would be sufficient to catch over half of all errors. This AI-assisted triage greatly accelerates the review process without replacing or reducing expert insight, ensuring that existing careful oversight remains in place while curators can work more efficiently. CIViC-Fact provides a realistic, high-consequence framework for biomedical fact-checking and a path toward more rigorous and efficient knowledgebase curation.

Journal Article↗

PubMed2024

CAGI, the Critical Assessment of Genome Interpretation, establishes progress and prospects for computational genetic variant interpretation methods.

BACKGROUND: The Critical Assessment of Genome Interpretation (CAGI) aims to advance the state-of-the-art for computational prediction of genetic variant impact, particularly where relevant to disease. The five complete editions of the CAGI community experiment comprised 50 challenges, in which participants made blind predictions of phenotypes from genetic data, and these were evaluated by independent assessors. RESULTS: Performance was particularly strong for clinical pathogenic variants, including some difficult-to-diagnose cases, and extends to interpretation of cancer-related variants. Missense variant interpretation methods were able to estimate biochemical effects with increasing accuracy. Assessment of methods for regulatory variants and complex trait disease risk was less definitive and indicates performance potentially suitable for auxiliary use in the clinic. CONCLUSIONS: Results show that while current methods are imperfect, they have major utility for research and clinical applications. Emerging methods and increasingly large, robust datasets for training and assessment promise further progress ahead.

Humans↗

PubMed2026

Optical genome mapping enhanced by refined variant interpretation in pediatric acute lymphoblastic leukemia.

Reliable detection of structural variants (SVs) and copy number variations (CNVs) is crucial in the contemporary diagnostics of pediatric B-cell acute lymphoblastic leukemia (B-ALL). However, limitations of commonly used conventional and molecular cytogenetic methods may hinder the accurate genetic characterization of patients. Optical genome mapping (OGM) offers a reliable alternative by enabling high-resolution, genome-wide detection of CNVs and SVs. Chromosomal aberrations were screened using OGM in 51 children with B-ALL. The results were compared with those of karyotyping, fluorescence in situ hybridization (FISH), digital multiplex ligation-dependent probe amplification (digitalMLPA), and targeted RNA sequencing (RNA-seq). OGM data showed high congruency with karyotyping and FISH findings, detecting clinically relevant variants beyond G-banding results and unraveling a complex KMT2A fusion undetected by FISH. Gene fusions involved in complex ETV6::RUNX1 translocations, but not detected by RNA-seq, were confirmed using FISH. Normalization of OGM copy number values with DNA-index-improved concordance with FISH-derived copy numbers in near-tri/tetraploid cases. In the peripheral regions of OGM variants (fringe-zones), a novel evaluation strategy called 'FriZone' was applied, which significantly improved the concordance between OGM and digitalMLPA. In addition, a co-segregation analysis revealed strong associations between ETV6::RUNX1 fusion and deletions of ETV6, RAG2, and NR3C2. OGM uncovered complex rearrangements undetected by widely used methods in 15% of cases, improving genetic classification and risk stratification in 10% of the patients. The FriZone analysis and normalization by DNA-index provide a refined, more accurate approach to OGM variant interpretation, facilitating the efficient application of OGM in clinical diagnostics. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Humans↗

PubMed2026

Deep DNA and protein level feature integration for robust clinical variant interpretation using probabilistic gradient boosting.

A major challenge in clinical genomics is to classify genetic variations correctly, since it directly affects disease diagnosis and personal care. The existing methods tend to be based on the combination of different factors, such as protein structure, population frequencies, phenotypic annotations, and sequence conservation. Nevertheless, these methods often cannot be used to achieve the necessary interpretability, quantify uncertainty, and address rare cases. This paper presents a probabilistic gradient boosting model on variant pathogenicity prediction. The suggested framework applies biological characteristics at both level of DNA and protein levels while also scaling the level of uncertainty in clinical decision making. Our machine learning aims to solve the issues of variant interpretation by managing the features and through probability-based pathogenicity prediction. The framework formulation is aimed at generalizing over various datasets and minimizing overfitting. At the same time, it can ensure reasonable performance to facilitate clinical experiments. The model has also been tested on three standard datasets and demonstrated to be more predictive of the pathogenic effect of variants, in comparison with a variety of existing tools. The probabilistic gradient boosting model proposed had ROC AUC values of 0.9293, 0.9610, and 0.9646 on ClinVar variants, GRCh37, and GRCh38 human genome respectively. Furthermore, the dataset was ensured to include both exonic and intronic variants, and Variants of Uncertain Significance were also taken into consideration for Performance Testing. Through this it also aims to provide better clinical significance which will lead to a good interpretable tool for priority of variants for a large variety of disease conditions.

ClinVar↗

PubMed2026

Clinical Variant Interpretation with the Integrative Genomics Viewer (IGV) for Molecular Pathologists.

The integrative genomics viewer (IGV) is a pivotal tool in clinical genomics, enabling the visualization and interpretation of complex sequencing data. Bringing clinical knowledge to bear with visual evaluation of sequencing results is the primary means by which molecular pathologists and other professionals assess and finalize cases. A variety of software tools can assist, but their relationship to the underlying data must be understood and applied systematically. This study includes essential background on next-generation sequencing (NGS) data file types (e.g., FASTQ, BAM, VCF) with a discussion of their format and purpose. We then describe features of IGV that derive nuances from these files. We utilize a series of curated practical cases based on clinical vignettes through which the reader will interact with clinical NGS sequencing data using the IGV software to review various types of clinically relevant variants relative to the human reference genome. These clinical vignettes have been curated to describe examples of some of the complexities of interpretation of genomic data, and how utilizing IGV as part of a routine workflow can provide additional interpretive information for variants beyond routine bioinformatic software algorithm variant calls. The visual inspection of genomic variants utilizing the tools within IGV can unmask subtle contextual cues (i.e., variant allele frequency, strand bias, tissue-specific context) that can influence the interpretation of genomic variants. Although this study focuses on using IGV for the detection and interpretation of somatic variants, the provided applications can be extrapolated for use in the germline setting, including analysis of complex variants and detection of mosaicism.

Humans↗

PubMed2025

AutoPM3: enhancing variant interpretation via LLM-driven PM3 evidence extraction from scientific literature.

MOTIVATION: Rare diseases affect over 300 million people worldwide and are often caused by genetic variants. While variant detection has become cost-effective, interpreting these variants-particularly collecting literature-based evidence like ACMG/AMP PM3-remains complex and time-consuming. RESULTS: We present AutoPM3, a method that automates PM3 evidence extraction from literatures using open-source large language models (LLMs). AutoPM3 combines a Text2SQL-based variant extractor and a retrieval-augmented generation (RAG) module, enhanced by a variant-specific retriever and fine-tuned LLM, to separately process tables and text. We curated PM3-Bench, a dataset of 1027 variant-publication evidence pairs from ClinGen. On openly accessible pairs, AutoPM3 achieved 86.1% accuracy for variant hits and 72.5% recall for in trans variants-outperforming other methods, including those using larger models. We uncovered the effectiveness of AutoPM3's key modules, especially for variant-specific retriever and Text2SQL, through the sequential ablation study. AutoPM3 located evidence in 76 s, demonstrating that open-source LLMs can offer an efficient, cost-effective solution for rare disease diagnosis. AVAILABILITY AND IMPLEMENTATION: AutoPM3 is implemented and freely available under the MIT license at https://github.com/HKU-BAL/AutoPM3.

Genetic Variation↗

PubMed2026

'Truthsets' for clinical validation of large-scale functional assays: Practice recommendations from Cancer Variant Interpretation Group UK (CanVIG-UK).

BACKGROUND: Large-scale functional assays, including multiplex assays of variant effect, have substantial potential to resolve variants of uncertain significance (VUS), particularly for rare missense variants where clinical and population evidence are limited. The ClinGen assay-level clinical validation framework described by Brnich et al provided baseline guidance for the use of functional data for variant classification. However, clear consensus regarding construction of variant 'truthsets' by which to clinically validate functional data remains lacking. METHODS: CanVIG-UK developed consensus recommendations for truthset construction through an iterative national consultation process involving the CanVIG Steering Advisory Group (CStAG), wider CanVIG-UK membership, and engagement with international functional genomics experts. Consultation was based on previous analyses of 2,120 truthset constructions examining the impact of truthset composition on evidence point allocation within the ClinGen assay-level clinical validation framework. RESULTS: Across several consultations, CanVIG-UK established nine guiding principles and seven best-practice recommendations for assay-level clinical validation, using the assumed context of an assay for a cancer susceptibility gene where loss-of-function is the mechanism of pathogenicity. The principal recommendation stipulates, where assays are intended for use in interpretation of largely missense variants, the truthset used to validate should comprise only missense variants. Rather than mixtures of different variant types which may serve to over-estimate assay performance. Additional recommendations support option for relaxation of truthset stringency to improve power, augmentation of benign missense truthsets with systematically derived 'proxy-clinical' benign variants, independent clinical validation separate from assayist-defined validation, and careful evaluation of missense score distributions against that of protein-truncating and synonymous variants. Guidance is also provided for scenarios with limited pathogenic truthset availability and for assays reporting multiple deleterious zones or readouts. CONCLUSIONS: The CanVIG-UK principles and recommendations for truthset construction upon the ClinGen assay-level clinical validation framework, while aiming to form a baseline for future discussion regarding other functional and disease contexts and helping to address the gap between publication of new data and routine clinical implementation.

Journal Article↗

PubMed2025

Utility of genome sequencing and group-enrichment to support splice variant interpretation in Marfan syndrome.

PURPOSE: To quantify the impact of noncanonical FBN1 splice site variants in undiagnosed Marfan syndrome (MFS), a connective tissue disorder associated with skeletal abnormalities and familial thoracic aortic aneurysm disease (FTAAD). METHODS: A systematic analysis of ultrarare FBN1 variants was performed using genome sequencing data from the 100,000 Genomes Project. Variants were annotated with SpliceAI and the significance of enrichment among individuals with FTAAD was assessed using Fisher's exact test. Experimental validation used RNA sequencing, reverse transcriptase polymerase chain reaction, minigene constructs, and replication analysis was with data from UK Biobank. RESULTS: Using aggregate data for 78,195 individuals, we identified 13,864 singleton single-nucleotide variants in FBN1 of which 21 were predicted to affect splicing (SpliceAI > 0.5). Incidence of candidate splice variants in individuals recruited with FTAAD (9/703) was significantly elevated compared with that seen in non-FTAAD participants (12/77,492; odds ratio = 84, P = 9.7 × 10-14). Additional analysis uncovered a further 14 families harboring 11 different FBN1 splice variants. A total of 20 candidate splice variants in 23 families were identified, of which 70% lay beyond the ±8 splice regions. RNA testing confirmed the predicted splice aberration in 16 of 20 and for 9 of 20, pseudoexonization was the likely splicing anomaly. CONCLUSION: Our findings indicate that noncanonical splice variants may account for approximately 3% of families with undiagnosed FTAAD, highlighting the importance of incorporating analysis of introns and confirmatory RNA testing into genetic testing for Marfan syndrome.

Humans↗

PubMed2022

Genetic structure correlates with ethnolinguistic diversity in eastern and southern Africa.

African populations are the most diverse in the world yet are sorely underrepresented in medical genetics research. Here, we examine the structure of African populations using genetic and comprehensive multi-generational ethnolinguistic data from the Neuropsychiatric Genetics of African Populations-Psychosis study (NeuroGAP-Psychosis) consisting of 900 individuals from Ethiopia, Kenya, South Africa, and Uganda. We find that self-reported language classifications meaningfully tag underlying genetic variation that would be missed with consideration of geography alone, highlighting the importance of culture in shaping genetic diversity. Leveraging our uniquely rich multi-generational ethnolinguistic metadata, we track language transmission through the pedigree, observing the disappearance of several languages in our cohort as well as notable shifts in frequency over three generations. We find suggestive evidence for the rate of language transmission in matrilineal groups having been higher than that for patrilineal ones. We highlight both the diversity of variation within Africa as well as how within-Africa variation can be informative for broader variant interpretation; many variants that are rare elsewhere are common in parts of Africa. The work presented here improves the understanding of the spectrum of genetic variation in African populations and highlights the enormous and complex genetic and ethnolinguistic diversity across Africa.

Africa, Southern↗

PubMed2024

Validating the splicing effect of rare variants in the SLC26A4 gene using minigene assay.

BACKGROUND: The SLC26A4 gene is the second most common cause of hereditary hearing loss in human. The aim of this study was to utilize the minigene assay in order to identify pathogenic variants of SLC26A4 associated with enlarged vestibular aqueduct (EVA) and hearing loss (HL) in two patients. METHODS: The patients were subjected to multiplex PCR amplification and next-generation sequencing of common deafness genes (including GJB2, SLC26A4, and MT-RNR1), then bioinformatics analysis was performed on the sequencing data to identify candidate pathogenic variants. Minigene experiments were conducted to determine the potential impact of the variants on splicing. RESULTS: Genetic testing revealed that the first patient carried compound heterozygous variants c.[1149 + 1G > A]; [919-2 A > G] in the SLC26A4 gene, while the second patient carried compound heterozygous variants c.[2089 + 3 A > T]; [919-2 A > G] in the same gene. Minigene experiments demonstrated that both c.1149 + 1G > A and c.2089 + 3 A > T affected mRNA splicing. According to the ACMG guidelines and the recommendations of the ClinGen Hearing Loss Expert Panel for ACMG variant interpretation, these variants were classified as "likely pathogenic". CONCLUSIONS: This study identified the molecular etiology of hearing loss in two patients with EVA and elucidated the impact of rare variants on splicing, thus contributing to the mutational spectrum of pathogenic variants in the SLC26A4 gene.

Humans↗

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

CanVar-UK: A collaborative platform for germline interpretation in cancer susceptibility genes.

Germline variants in cancer susceptibility genes (CSGs) are typically inherited rather than arising de novo. Hence, wide cascade testing of families across geographies is common, meaning consistency in variant classification is particularly critical. Variant interpretation requires collation of variant-level data from diverse sources, as well as assembly of comprehensive clinical data, often necessitating sharing of information between genomic testing centers. Here, we describe CanVar-UK, a freely accessible web platform bespoke designed to support interpretation of germline CSG variants. CanVar-UK contains variant-level data for over 1.1 million single-nucleotide variants (SNVs), comprising all possible coding SNVs in 116 established CSGs. The data sources with which variants are annotated include in silico scores from 11 clinically relevant tools, population allele frequencies from gnomAD v4.1, case counts from multiple cohorts, including National Health Service (NHS) clinical laboratory testing, variant-level readouts from 47 selected functional and splicing datasets across 19 CSGs, genetic epidemiology studies, and live linkage to existing consensus classifications in the ClinVar database. The diagnostic discussion forum is only available to registered diagnostic scientist users. Through this, a variant-tagged email message can be dispatched in real time across the diagnostic forum community of >1,500 users, with all exchanges and classifications captured and stored in the platform. Already widely used by NHS diagnostic clinical scientists in the UK, CanVar-UK has a rapidly growing international diagnostic user base (>800 UK and >600 non-UK registered users). Survey of the NHS diagnostic user community illustrates the wide-ranging utility of CanVar-UK within their clinical workflows for interpretation of germline CSG variants.

Journal Article↗

PubMed1979

The electroencephalogram (EEG) as a research tool in human behavior genetics: psychological examinations in healthy males with various inherited EEG variants. III. Interpretation of the results.

Interpretation of the results from psychological examinations of 298 probands with inherited EEG variants requires (1) critical evaluation of previous literature on psychological EEG correlates, (2) knowledge of the main concepts and experimental approaches for elucidating the basic mechanisms of EEG rhythms, (3) discussion of previous attempts to link psychological variation in human populations with corresponding variation in brain function, and (4) interpretation of results from considerations at these three levels with the data from our own study. At the first level (previous psychological studies), comparison with Schmettau's study proved to be especially revealing: Her conclusions about personality correlates with high alpha-index and with "flat" EEGs were very similar to ours with the monotonous alpha- (R) and low-voltage (N) EEGs, respectively. Her EEG type with high beta-index overlaps with our beta-diffuse (BD) type; a tendency to psychasthenia and low resistance to stress is less obvious in our group, but is expressed indirectly by reduced speed and accuracy in tests requiring attentiveness and persistence. The correlation between alpha-frequency and intelligence found in other studies was confirmed by the especially high intelligence scores of our group with occipital fast alpha-variants (BO). At the second and third levels of the discussion (EEG mechanisms; neurophysiological theories), the cooperation of cerebral cortex (EEG battery), thalamus (pacemaker), and ARAS (tonic arousal) is discussed, and the personality typologies of Eysenck and Claridge are mentioned. From this and other evidence, the following hypotheses are discussed: 1) The personality profiles of the R group are influenced by high activity and efficiency of the thalamic alpha-pacemaker(s), which leads to a high degree of modulation, selection, and amplification of afferent stimuli. 2) In the countertype of this EEG variant, the N EEG, a low modulation and amplification by the thalamic alpha-pacemaker is assumed. This leads to relatively low intensity of feeling and to low spontaneous activity, but to faster information processing. Combined with an increased level of tonic arousal in the ARAS, it may cause certain 'neurotic' complaints (our low-voltage borderline (NG) group). 3) The EEG with diffuse beta-waves (BD) is caused by a high level of tonic arousal in the ARAS, which tends to distrub the thalamocortical circuit. This leads to reduced stress resistance and to impairment of intellectual functions, especially space perception. Due to limited evidence, the next two hypotheses are advanced only tentatively: 4) alpha-rhythm with very high frequency 16--19 c/s) leads to improvement of information processing and, hence, to high intellectual performance and motor dexterity. 5) Probands with frontoprecentral beta-groups (BG) show no psychological signs of increased tonic arousal; therefore, these beta-groups are caused not by increased tonic arousal of the ARAS, but by a genetic variant of a thalamic subsystem.

Adult↗

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↗

PubMed2026

Expanding the Clinical Spectrum of DHX30-Related Neurodevelopmental Disorder: A Case Report and a Scoping Review.

BACKGROUND: Whole exome sequencing (WES) has improved diagnostic rates for neurodevelopmental disorders (NDDs) while introducing challenges in novel variant interpretation. DHX30-related NDD (DHX30-NDD) is a recently described condition with an evolving phenotypic spectrum. OBJECTIVES: To expand the understanding of the DHX30-NDD genotype-phenotype spectrum by integrating a case-based WES interpretation with a scoping review. METHODS: We performed comprehensive genetic analysis (karyotyping, microarray, WES) on a proband with global developmental delay (GDD). A systematic literature search of PubMed/MEDLINE, Scopus and Google Scholar from database inception to April 2026 identified 10 publications including 51 individuals with DHX30-NDD. Clinical and genetic data were extracted to characterize the genotype-phenotype spectrum. RESULTS: The proband presented with GDD and right microtia, harbouring a de novo heterozygous pathogenic DHX30 missense variant (c.1478G > A; p.Arg493His), confirming DHX30-NDD. To our knowledge, this is the first reported individual with DHX30-NDD and microtia. The scoping review confirmed DHX30 variants are formed predominantly de novo and affected both sexes (22 males; 29 females). Hallmark manifestations were motor delay (50/51; 98.0%), GDD/ID (48/49; 98.0%), hypotonia (48/51; 94.1%), feeding difficulties (38/51; 74.5%), ataxia (17/23; 73.9%), abnormal brain imaging (36/49; 73.5%) and absent expressive language (35/48; 72.9%). Digital anomalies (31/51; 60.8%), eye anomalies (28/51; 54.9%), autistic behaviours (24/44; 54.5%), sleep disturbances (26/51; 51.0%), joint hypermobility (25/51; 49.0%), microcephaly (23/51; 45.1%) and ear anomalies (22/51; 43.1%) were also frequent. CONCLUSIONS: This study potentially expands the phenotypic spectrum of DHX30-NDD, highlights the clinical utility of WES for diagnosing GDD and underscores the importance of ongoing WES reanalysis for evolving variant interpretation.

DHX30↗

PubMed2026

Genetic Research on Cardiac Channelopathies in African and African-Descent Populations: A Scoping Review.

Cardiac channelopathies are inherited arrhythmias that can lead to sudden cardiac death. Despite Africa's extensive genomic diversity, African and African-descent populations remain underrepresented in genetic research, creating gaps in variant interpretation and clinical care. This scoping review aims to map the extent, range, and nature of genetic research on cardiac channelopathies in these populations and to identify key geographic, thematic, and methodological gaps. Using the Joanna Briggs Institute scoping review methodology and the Population-Concept-Context framework, systematic searches in PubMed, Embase, and Web of Science identified original human studies on cardiac channelopathies with genetic data. Extracted variables included study characteristics, populations, types of channelopathies, and reported genes and variants. Forty-four studies met the inclusion criteria. Most studies originated from the United States and South Africa, while West, Central, and East Africa were largely underrepresented. US Black individuals and South African individuals of continental African or African-descended ancestry (excluding populations of European descent such as Cape Afrikaner people) were the most studied groups, with other continental African groups rarely included. Long QT syndrome was the predominant focus, and SCN5A, KCNQ1, and KCNH2 were the most frequently analyzed genes. Many of the genetic variants discussed remained of uncertain significance due to limited functional validation and the underrepresentation of African genomes in reference databases. Genetic research on cardiac channelopathies in populations of African ancestry is limited, restricting variant interpretation, counseling, and risk prediction. Broader African inclusion, expanded gene screening, and functional studies are essential to improve diagnostics and promote equity in genomic medicine.

Humans↗

PubMed2026

[Genetic and functional characterization of a novel KIT splicing variant in a Chinese three-generation pedigree with piebaldism].

OBJECTIVES: To investigate the genetic etiology of a three-generation pedigree affected with piebaldism. METHODS: Next-generation sequencing and Sanger sequencing were employed to detect and verify gene variants. Bioinformatics tools were used to predict the effects of candidate variants on splicing and protein function. RT-PCR and Sanger sequencing were further performed to validate the impact of the variant on RNA splicing, and homology modeling was applied to predict its effect on the three-dimensional structure of the KIT protein. The pathogenicity of the variant was then classified according to the guidelines of the American College of Medical Genetics and Genomics (ACMG) and the UK Association for Clinical Genomic Science (ACGS). RESULTS: A heterozygous insertion variant near the splice site, c.1990+8_1990+9insTGCACCATTGGAGGTAAA, was identified in the KIT gene in the proband and was found to co-segregate with the phenotype within the family. RT-PCR and cDNA sequencing revealed that this variant led to aberrant splicing during transcription, resulting in a 21 bp in-frame insertion in the mRNA, which encodes an extra 7 amino acids within the tyrosine kinase domain and may thus affect protein function. In silico predictions, together with the experimental findings, supported classification of this variant as likely pathogenic according to relevant variant interpretation guidelines. CONCLUSIONS: The heterozygous splice-site insertion variant KIT:c.1990+8_1990+9insTGCACCATTGGAGGTAAA is the genetic cause of piebaldism in this pedigree.

Genetics diagnosis↗