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PubMed2026

Biallelic VPS41 Variants in Autosomal Recessive Spinocerebellar Ataxia 29 Resolved by Long-Read Sequencing and RNA Analysis.

BACKGROUND: Biallelic variants in VPS41, encoding a subunit of the HOPS complex, cause autosomal recessive spinocerebellar ataxia 29 (SCAR29), a rare neurodevelopmental disorder with an incompletely defined phenotypic and molecular spectrum. METHODS: We investigated a 24-year-old man with cerebellar ataxia, hypotonia, and intellectual disability. Exome sequencing identified four candidate VPS41 variants. Because maternal DNA was unavailable, long-read genome sequencing was performed to determine allelic configuration, followed by RNA and protein analyses. RESULTS: In addition to typical SCAR29 features, the patient showed previously unreported findings, including swan-neck deformities and pes cavus. Long-read genome sequencing demonstrated that two VPS41 variants were in trans. RNA analysis revealed distinct splicing consequences: one allele produced an out-of-frame transcript predicted to undergo nonsense-mediated decay, whereas the other generated an in-frame exon-skipped transcript. These complementary defects reduced VPS41 expression at both transcript and protein levels, supporting pathogenicity and variant reclassification. CONCLUSION: Our findings expand the phenotypic spectrum of VPS41-related disease and highlight the value of long-read allelic resolution in clarifying pathogenic mechanisms in rare genetic disorders.

Humans↗

PubMed2026

Compound Heterozygous PCDH15 Variants Associated With Cone-Rod Dystrophy in a Chinese Pedigree.

BACKGROUND: This study aimed to characterize the clinical and genetic features of a Chinese family with cone-rod dystrophy in which compound heterozygous PCDH15 variants were identified. METHODS: A Chinese pedigree with autosomal recessive cone-rod dystrophy was investigated. A comprehensive ophthalmic assessment was performed in the proband, a 42-year-old woman, together with genetic evaluation of her family members. Candidate variants were identified using whole-exome sequencing and subsequently assessed by Sanger sequencing and family segregation analysis. RESULTS: Ophthalmoscopic examination revealed pigmentary changes and atrophic lesions affecting the posterior pole and peripapillary area bilaterally. Optical coherence tomography (OCT) demonstrated bilateral outer retinal layer atrophy with disruption of the ellipsoid zone at the posterior pole. Multifocal electroretinography (mfERG) revealed attenuated central responses, while full-field electroretinography (ffERG) documented a more pronounced reduction in cone-mediated (photopic) responses. Two novel compound heterozygous variants in PCDH15, namely c.4903_4906del (p.Glu1635Lysfs*4) and c.3470C>A (p.Ala1157Glu), were identified in this autosomal recessive cone-rod dystrophy pedigree. Family co-segregation analysis provided supportive evidence for their potential association with the disease phenotype. Cross-species analysis revealed high evolutionary conservation of the PCDH15 protein. Three-dimensional structural modeling predicted potential alterations in protein structure. CONCLUSION: To our knowledge, this is the first report describing an association between compound heterozygous PCDH15 variants and cone-rod dystrophy, thereby providing preliminary evidence that may broaden the mutational spectrum associated with this gene.

Adult↗

PubMed2026

Severe Early-Onset Fetal Growth Restriction: The Yield of Antenatal and Postnatal Genetic Testing.

OBJECTIVES: We evaluated the diagnostic yield of karyotype (KT) and chromosomal microarray (CMA) with isolated severe FGR diagnosed before 32 weeks' gestation. Exome and genome sequencing (ES/GS) level data were available in a subset of this population. METHOD: We performed a retrospective review of singleton pregnancies (delivered 2022-2025) with estimated fetal weight or abdominal circumference < 3rd percentile before 32 weeks' gestation, no sonographic structural anomalies, and diagnostic testing (KT, CMA, ES, or GS) via amniocentesis or cord blood. Cases with abnormal cell-free DNA were excluded. RESULTS: Forty cases were included (mean diagnosis 26.8 weeks). Testing was performed via amniocentesis in 42% and cord blood in 58%. All KT (27/40) were normal. CMA (39/40) identified one pathogenic CNV (2.5%) and three (7.5%) variants of uncertain significance (VUS). Four (10%) showed ≥ 1 region of absence of heterozygosity (AOH) > 10Mb; one revealed maternal uniparental disomy of chromosome 6. Sequencing (N = 10) detected one VUS in COL1A1. Acute viral infection was not observed in any of the cases. CONCLUSIONS: CMA was diagnostic in 2/39 (5.1%) cases, a pathogenic CNV implicating the SHOX gene, and maternal UPD 6, which were consistent with FGR. There was a remarkable rate (10%) of AOH. Further investigation, including placental studies and genome sequencing, may elucidate whether AOH is a contributing factor for FGR.

Humans↗

PubMed2026

Prenatal Phenotypic Features of Five Fetal Cases With RNU4ATAC-Associated Microcephalic Osteodysplastic Primordial Dwarfism Type I.

OBJECTIVE: To present the prenatal sonographic features, genomic findings, and pregnancy outcomes of fetuses with biallelic pathogenic RNU4ATAC variants linked to microcephalic osteodysplastic primordial dwarfism type I (MOPD1). METHODS: This retrospective case series includes five prenatal cases with MOPD1. Diagnoses were established by prenatal ultrasound and genetic testing. Genome sequencing (GS) or targeted exome sequencing (ES) detected the variants either prenatally or after termination of pregnancy (TOP). Clinical data including parental demographics, ultrasound findings, and pregnancy outcomes were collected. RESULTS: All fetuses presented with consistent anomalies on ultrasound including intrauterine growth restriction (IUGR), microcephaly, agenesis of the corpus callosum (ACC), intracranial cysts, lissencephaly, and micrognathia. IUGR was the earliest anomaly detected in all five cases. Prenatal ultrasound findings suggestive of skeletal dysplasia were identified in one case. All cases carried biallelic pathogenic RNU4ATAC variants associated with MOPD1. TOP was chosen in four cases. One fetus was delivered at 39 + 1 weeks with genetic diagnosis confirmed at 27 weeks. CONCLUSION: IUGR, microcephaly and ACC can be detected in fetuses with MOPD1 at around 18 weeks of gestation. Interestingly, skeletal dysplasia was not a consistent prenatal finding. Variants in the non-coding RNU4ATAC gene need to be detected by GS or targeted approaches beyond standard ES.

Humans↗

PubMed1993

Identification and analysis of the Rhizobium meliloti exoAMONP genes involved in exopolysaccharide biosynthesis and mapping of promoters located on the exoHKLAMONP fragment.

Sequence analysis of a 7.494 kb DNA fragment from megaplasmid 2 of Rhizobium meliloti 2011 involved in exopolysaccharide I (EPS I) biosynthesis revealed the presence of five exo genes designated exoA, exoM, exoN, exoO, and exoP. ExoN was found to show strong homology to a UDP-glucose pyrophosphorylase from Acetobacter xylinum, whereas ExoO displayed weak homologies to the NodC proteins from R. meliloti and R. loti. Surprisingly, different mutations in exoP resulted in divergent phenotypes. One exoP mutant was able to establish an effective symbiosis with alfalfa, although no EPS I polymer could be detected. In contrast, other exoP mutations prevented the formation of an effective symbiosis. The transcriptional organization of the exoA-exoP gene region has been analysed in conjunction with the exoH, exoK and exoL genes. Using exo-lacZ transcription fusions in association with plasmid integration mutagenesis a strong promoter was identified upstream of exoH, which is able to direct transcription of the whole exoHKLAMONP gene cluster. A much weaker promoter upstream of exoL was found to be involved in the transcription of the exoLAMONP genes. In addition, weak promoters were identified upstream of exoK, exoA, exoN and exoP.

Amino Acid Sequence↗

PubMed2025

First clinical diagnosis of FAME3 via commercial Long-Read sequencing reveals mosaic repeat expansion in MARCHF6 gene.

Familial Adult Myoclonic Epilepsy type 3 (FAME3) is a rare autosomal dominant disorder characterized by cortical tremor and epilepsy, caused by a noncoding pentanucleotide repeat expansion (TTTTA/TTTCA)n in the MARCHF6 gene. Conventional genetic testing often fails to detect this expansion due to its repetitive structure and intronic location. We evaluated a 61-year-old woman with refractory myoclonic and generalized tonic-clonic seizures, whose prior genetic testing-including exome and genome sequencing-was non-diagnostic. Using PacBio HiFi long-read whole-genome sequencing and the tandem repeat genotyping tool TRGT, we identified a pathogenic MARCHF6 intronic expansion. The proband harbored one allele with 15 TTTTA repeats and a second allele with a compound expansion of 661 TTTTA and 12 TTTCA repeats. Three affected relatives shared similarly expanded alleles, but with increasing repeat size in the latter generations. Importantly, analysis using TRGT-instability revealed repeat mosaicism in all affected individuals, reflected by variability in motif counts across individual sequencing reads. This somatic heterogeneity may contribute to the phenotypic penetrance, variable expressivity and pleiotropism seen in FAME3 disease expression. To our knowledge, this is the first clinical diagnosis of FAME3 using a commercially available long-read sequencing platform, underscoring its diagnostic utility in resolving complex repeat expansion disorders and uncovering biologically relevant mosaicism.

Humans↗

PubMed2025

Detection of copy number variations by chromosomal microarray analysis in disorders of sex development of unexplained molecular etiology and association with clinical findings.

PURPOSE: Despite advances in genetic diagnostics, the molecular cause of a significant proportion of DSDs remains unknown. The aim of this study was to identify copy number variations (CNVs) using chromosomal microarray analysis (CMA) technology in DSD patients with previously undetected molecular genetic etiology and to investigate their phenotypic associations with these variations. METHODS: This study included DSD cases without chromosomal abnormalities and without any variants detected by sequence analysis methods, including whole-exome sequencing analysis. We evaluated variant pathogenicity according to the American College of Medical Genetics and Genomics guidelines and recorded the phenotypic findings of the cases. All pathogenic variants were subjected to segregation analysis. RESULTS: Of the 20 patients included in the study, 16 (80%) were classified as 46,XY DSD and 4 (20%) as 46,XX DSD. Initial clinical diagnoses in this 46,XX DSD group included gonadal dysgenesis in two patients (50%) and androgen excess in the remaining two (50%). Among the 46,XY DSD patients, five patients (31.25%) were presumed to be androgen insensitive, nine (56.25%) were diagnosed with defects in androgen biosynthesis, and two (12.5%) had gonadal dysgenesis. CMA detected 38 CNVs in 16 patients (80%), comprising 12 deletions (31.6%) and 26 duplications (68.4%). Three pathogenic CNVs were detected in 3 patients (15%), whereas 27 variants of uncertain significance were identified in 13 patients (65%). CONCLUSION: In selected cases, the diagnostic approach should incorporate CMA to elucidate the molecular etiology of DSD. Furthermore, CMA may prove to be an invaluable tool in the search for new genes responsible for DSD.

Humans↗

PubMed2025

The functional study of novel KLHL3 missense mutations associated with pseudohypoaldosteronism type II.

BACKGROUND: Pseudohypoaldosteronism type II (PHA II) is an inherited tubulopathy, clinically defined by three hallmark features, including secondary hypertension, hyperchloremic metabolic acidosis, and persistent hyperkalemia occurring despite maintained glomerular filtration function. Herein, we aim to investigate the association of kelch like family member 3 (KLHL3) gene mutations with PHA II. METHODS: Compound heterozygous KLHL3 mutations were identified through whole-exome sequencing and Sanger validation. AlphaFold-based structural modeling, site-directed mutagenesis of Flag-tagged plasmids, and co-immunoprecipitation (Co-IP)/immunoblotting in vivo were combined to analyze mutant protein interactions and ubiquitination effects. RESULTS: A Chinese patient was identified with two previously unreported KLHL3 variants (c.131G > A [p.R44Q] and c.744 C > G [p.Y248*]), exhibiting a biochemical triad of asymptomatic hyperkalemia, mild metabolic acidosis, and borderline hypertension. Administration of thiazide diuretics effectively normalized the patient’s hyperkalemia and hypertension. A p.R44Q missense mutation predicted as variants of uncertain significance (VOUS) by American College of Medical Genetics and Genomics (ACMG) guidelines, and a p.Y248* nonsense mutation predicted as variants of likely pathogenic. Functional study revealed that the two KLHL3 mutations impair its ubiquitination of with-no-lysine kinase 1 (WNK1) and with-no-lysine kinase 4 (WNK4), and further increase phosphorylation of both SPAK (sterile20/sporulation-specific protein-1 related proline/alanine-rich kinase)/OSR1 (oxidative stress response kinase-1) and Na-Cl-cotransporter (NCC). CONCLUSIONS: Our study characterized two previously unreported KLHL3 mutations, followed by comprehensive in vitro functional analyses to elucidate their pathophysiological contributions at the molecular level.

Humans↗

PubMed2026

A novel FLNA p.Pro2469Ser variant is associated with impaired T and NK cell function and immune dysregulation.

FLNA encodes filamin A, a ubiquitously expressed actin-binding cytoskeletal protein that cross-links actin filaments and links them to membrane-associated signaling complexes. Although FLNA has been implicated in T-cell signaling and regulatory T-cell development in murine models, its role in human immune-cell function remains incompletely understood. Here, we investigated the immunological phenotype associated with a novel hemizygous FLNA variant identified in a pediatric patient presenting with recurrent infections and inflammatory manifestations. Whole-exome sequencing revealed a hemizygous c.7405C>T (p.Pro2469Ser) variant in FLNA, which was confirmed by Sanger sequencing. Its potential impact on immune-cell function and cytoskeletal organization was evaluated using confocal microscopy, flow cytometry, and molecular assays. Patient-derived T cells showed impaired activation and proliferation following CD3/CD28 and IL-2 stimulation, accompanied by reduced CD25 and CD69 upregulation. CD4+ T cells also exhibited reduced IFN-γ, TNF-α, and IL-2 production after stimulation. Despite elevated basal phospho-STAT5 levels, IL-2-induced STAT5 phosphorylation and TCR-associated signaling responses, including pZAP70, pLCK, and p38 MAPK activation, were attenuated. Confocal imaging together with image-based quantification demonstrated altered cortical cytoskeletal organization in patient T cells despite preserved FLNA expression. In parallel, NK cells showed impaired activation responses and reduced cytotoxic activity under the assay conditions used. Increased apoptosis was observed in CD4⁺, CD8⁺, and NK-cell populations. Inflammatory cytokines were elevated in plasma and colonic tissue, whereas colonic ZO-1 and FLNA expression were reduced. Collectively, these findings indicate that the FLNA p.Pro2469Ser variant is associated with altered immune-cell signaling, disturbed cortical cytoskeletal organization, and immune dysregulation. This study expands the phenotypic spectrum linked to FLNA variants and supports a role for filamin A in human immune-cell regulation.

Humans↗

PubMed2026

AKR7A3 rs1738023 association with susceptibility to female hepatocellular carcinoma and its role in AFB1 metabolism and tumor.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancer worldwide. In this study, we performed a two-stage exome-chip association analysis and found that the aldo-keto reductase family7 member A3 (AKR7A3) rs1738023 may be a potential susceptibility locus for HCC in females. We aimed to explore its role and mechanism. METHODS: The association between genotype and phenotype was analyzed through GWAS method. The expression of AKR7A3 in cancer tissue and blood analysis by qRT-PCR. The relationship of AKR7A3 and aflatoxin B1 (AFB1) was also analyzed. The effect of AKR7A3 on the biological behavior of HCC cell line was investigated on proliferation and invasion. The potential mechanism was analyzed by transcriptome analysis and western blot. RESULTS: Through genome-wide association analysis (GWAS), AKR7A3 (rs1738023), KIF2C (rs4342887), and CYP3A5 (rs6977165 and rs4646450) were found to be associated with susceptibility to hepatocellular carcinoma (HCC) in women. Further expression quantitative trait loci (eQTL) analysis showed that only AKR7A3 (rs1738023) was significantly associated with gene expression. The expression of AKR7A3 was significantly lower in HCC than adjacent non-tumorous tissues (P < 0.001). The genotype of rs1738023 was significantly associated with AKR7A3 expression (P = 0.0085). Rs1738023[C] genotype had a low AKR7A3 expression level and limited detoxification ability of AFB1. Literature data showed that AKR7A3 is involved in the metabolism of aflatoxin B1 (AFB1). Functional experimental results showed that overexpression of AKR7A3 in the normal liver cell line HL-7702 could significantly reduce AFB1-induced ROS levels and DNA adduct formation, suggesting that it plays a protective role in AFB1 metabolic detoxification. Cell function test showed that overexpression of AKR7A3 inhibit the proliferation, migration and invasion of HCC cells, and block the cell cycle. Transcriptome sequencing and KEGG pathway enrichment analysis revealed that overexpression of AKR7A3 affected the PI3K signaling pathway and led to downregulation of HIF1A and its downstream VEGFA protein expression. The validation results were confirmed in HCC cell lines Huh-7 and SUN-387. CONCLUSION: Overexpression of AKR7A3 contributes to inhibition of HCC progression and reduction of aflatoxin toxicity. AKR7A3 may serve as a potential prognostic and therapeutic target for HCC patients, although further validation is needed.

AKR7A3↗

PubMed2025

Ataxia and oculomotor apraxia caused by a large-scale deletion in the senataxin gene.

Senataxin, an RNA/DNA helicase, is a key protein providing genome stability and one of the best characterized R-loop-binding factors playing an important role in transcription and DNA repair processes. Pathogenic SETX gene variants cause autosomal recessive spinocerebellar ataxia with axonal neuropathy (AOA2, MIM #606002) and autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4, MIM #602433), rare neurodegenerative disorders characterized by juvenile onset of progressive cerebellar ataxia, axonal sensorimotor peripheral neuropathy, combined upper and lower motor neuron symptoms, and increased serum alpha-fetoprotein (AFP; specific for AOA2). We report two cases of adult patients presenting with cerebellar syndrome, scanned speech, and exercise intolerance which started in the second/third decade of life and were followed by muscle weakness and impaired gait coordination. Whole exome sequencing (WES) was performed to analyze single nucleotide and copy number variants. A decreased coverage of a genomic region of around 16 kb on chromosome 9 (chr9:132,295,852-132,311,876), suggesting a deletion encompassing 5 exons of the SETX gene (exons 11-15, NM_015046.7) was observed. This homozygous SETX (9q34.13) deletion leads to a frame shift and consequently truncation of the helicase domain in the protein. Loss-of-function variants in the SETX gene are known to be pathogenic. Statistical analysis of NGS data from the Polish population identified a few heterozygous carriers, suggesting its region-specific origin.

Humans↗

PubMed2026

Pierson syndrome with numerous dilated tubules masquerading as autosomal recessive polycystic kidney disease: a case report.

Pierson syndrome, characterized by congenital nephrotic syndrome, ocular abnormalities, and neurological defects, is caused by biallelic pathogenic variants in LAMB2. LAMB2 encodes laminin β2, a key component of basement membranes that is predominantly expressed in the glomeruli, eyes, and neuromuscular junctions. The renal histopathology of Pierson syndrome typically shows diffuse mesangial sclerosis (DMS), with occasional tubulointerstitial atrophy and fibrosis. We report a case of Pierson syndrome characterized by DMS and prominent tubular dilatation. A fetal ultrasound at 23 weeks of gestation revealed hyperechoic kidneys, which gradually enlarged, accompanied by the onset of anhydramnios from 31 weeks. The patient was delivered at 39 weeks of gestation, weighing 3,132 g, without placentomegaly. Postnatal respiratory failure due to pulmonary hypoplasia required extracorporeal membrane oxygenation, and hemodialysis was initiated for anuria. Left nephrectomy was performed on day 8 of life, revealing replacement of the renal parenchyma by numerous irregularly dilated tubules with eosinophilic casts. The right kidney reached maximal enlargement by 1 month of age and subsequently began to shrink. Ocular findings included bilateral microcoria and cataracts. Whole-exome sequencing identified compound heterozygous truncating variants in LAMB2 (p.Gln1507Ter and p.Gln1622Ter). This case highlights the need to consider Pierson syndrome in the differential diagnosis of prenatally detected hyperechoic and enlarged kidneys, in addition to polycystic kidney disease.

Female↗

PubMed1993

Biosynthesis of succinoglycan, a symbiotically important exopolysaccharide of Rhizobium meliloti.

The exo genes of Rhizobium meliloti are needed for the synthesis of an acidic exopolysaccharide, succinoglycan. We have assigned biosynthetic roles to the products of the exo genes by characterizing succinoglycan biosynthetic intermediates from exo mutant strains. We propose a model of succinoglycan biosynthesis in which the products of the exoY and exoF genes function in the addition of the first sugar, galactose, to the lipid carrier; the products of the exoA, exoL, exoM, exoO, exoU, and exoW genes function in subsequent sugar additions; and the product of the exoV gene functions in the addition of pyruvate. The products of the exoP, exoQ, and exoT genes are required for polymerization of the octasaccharide subunits or transport of the completed polymer.

Acetylation↗

PubMed2026

Genome-wide detection of human 5' UTR variants that impact protein translation.

The 5' untranslated region (5' UTR) of messenger RNAs (mRNAs) plays a central role in regulating protein synthesis initiation, particularly through the Kozak sequence and upstream open reading frames (uORFs). Genetic variants within these regulatory elements could affect translation, altering gene expression and contributing to clinical phenotypes in humans. We developed a computational method called 5ULTRA (5' Untranslated Region Annotation) for analysis of whole-exome sequencing and whole-genome sequencing data to detect, annotate, and prioritize 5' UTR variants with potential translation impact. 5ULTRA identifies single-nucleotide variants, indels, and splicing variants that affect uORFs by creating or disrupting start/stop codons and that alter Kozak sequence strength of either the uORFs or the main coding sequence. 5ULTRA incorporates recent uORF databases and provides comprehensive annotations. 5ULTRA implements a machine-learning score to prioritize candidate variants with predicted effects on translation and also provides specific mechanistic predictions. The score correlates strongly with experimentally measured protein-level effects of 5' UTR variants. We applied 5ULTRA to multiple genetics datasets across diverse disease contexts, identifying candidate variants including potential cancer-driving somatic mutations predicted to decrease ABI1 level or increase NRAS abundance; common variants associated with traits such as multiple sclerosis, lung function, and cardiovascular function, by altering protein levels of TAGAP, VRTN, and SPAAR, respectively; and rare germline variants in our cohort, including a splicing variant of RPSA leading to 5' UTR sequence alteration that causes congenital asplenia and a variant of TNF that could predispose to tuberculosis.

Humans↗

PubMed2026

Shared inheritance reveals landscape of somatic and germline cancer risk in TP53.

Pathogenic variants in TP53, the key tumor suppressor gene underlying Li-Fraumeni syndrome (LFS), are among the best-established causes of inherited cancer predisposition. However, large-scale sequencing has revealed that many apparently pathogenic TP53 variants detected in blood are the result of somatic clonal expansions, complicating risk interpretation. Using blood-derived whole-exome data from 469,391 UK Biobank participants, we combined the variant allele fraction (VAF) with haplotype-sharing analysis to distinguish germline and somatic TP53 variants. Germline variants were concentrated at sites linked to partial loss of p53 function and lower disease penetrance, whereas classic LFS alleles appeared to be predominantly somatically acquired. Classic LFS alleles at high VAF conferred markedly increased risk of hematological malignancy but not solid tumors, indicating an important contribution from large TP53-mutant clonal expansions. The prevalence of somatic clonal expansion also correlated with missense variant pathogenicity, suggesting that somatic activity provides an informative in vivo proxy for functional impact. These results provide new insights into TP53-associated cancer risk at the population level, demonstrate that somatic rather than germline risk predominates in middle-aged healthy adults, and provide a scalable framework for variant classification in large-scale population genomics.

Humans↗

PubMed2026

Targeted sequencing reveals a distinct genetic alteration landscape in oral multiple primary squamous cell carcinomas.

OBJECTIVE: Oral multiple primary cancers (MPCs) are associated with poor clinical outcomes, yet their genomic characteristics remain insufficiently understood. DESIGN: Fifty-four formalin-fixed paraffin-embedded (FFPE) tumor samples from 30 patients with oral MPCs were analyzed using high-depth targeted sequencing of a customized 14-gene panel derived from prior whole-exome sequencing data. Detected alterations were analyzed after removal of synonymous mutations. RESULTS: Non-silent genomic alterations were identified in 59.3% (32/54) of samples, involving 19 patients. A total of 70 variant loci across 13 genes were detected. AKAP13 was the most frequently mutated gene at both the sample (22.2%, 12/54), with recurrent mutations observed across multiple patients. In contrast, TP53 mutations occurred at a substantially lower frequency (11.1%, 6/54). Marked inter- and intra-patient mutational heterogeneity was observed. CONCLUSIONS: FFPE-based targeted sequencing enabled an initial characterization of genomic alterations in oral MPCs. Recurrent alterations in AKAP13, GLI2, JMJD1C, and DNAH8, together with the relatively low frequency of TP53 alterations, identify candidate genomic features for further investigation and provide a basis for future studies of the molecular basis of oral MPCs.

Humans↗

PubMed2026

Early infantile developmental and epileptic encephalopathy: clinical spectrum, diagnosis, outcomes, and evolving treatment strategies.

Early infantile developmental and epileptic encephalopathy (EIDEE) is among the most severe epilepsy syndromes, with onset before three months of age and an estimated incidence of approximately 10 per 100,000 live births. The 2022 International League Against Epilepsy classification unified the historically distinct Ohtahara syndrome and early myoclonic encephalopathy under a single diagnostic framework defined by frequent drug-resistant tonic and/or myoclonic seizures, an abnormal neurological examination, and an abnormal interictal electroencephalogram-most characteristically a burst-suppression pattern. This narrative review synthesizes the clinical, electrophysiological, neuroimaging, genetic, and therapeutic literature within the EIDEE framework. The clinical phenotype is characterized by central hypotonia, postnatal microcephaly, cortical visual impairment, and age-dependent syndromic evolution toward infantile epileptic spasms syndrome or Lennox-Gastaut syndrome in the majority of patients. Electroencephalography remains essential for syndromic classification, while systematic metabolic screening and early trio whole-exome or whole-genome sequencing are central to the etiologic workup, achieving diagnostic yields of 60-65%. The most commonly identified genetic causes include STXBP1, KCNQ2, and SCN2A variants. Outcomes are poor overall and strongly etiology-dependent: vitamin-responsive disorders carry a substantially more favorable prognosis, whereas mortality reaches 25% in genetic cohorts. Genotype-guided pharmacotherapy is now applicable to a clinically meaningful subset of patients, with sodium channel blockers, potassium channel openers, and emerging antisense oligonucleotide therapies representing important therapeutic advances. Gene therapy trials are underway but have encountered early safety signals, underscoring the vulnerability of this population. Critical unmet needs include earlier molecular diagnosis, precision therapies targeting developmental outcomes beyond seizure control, and prospective international registries to characterize the long-term natural history of EIDEE.

Humans↗

PubMed2026

Frequent mutations in the BIRC3 gene promote metastatic potential of nasopharyngeal carcinoma cells through the TRAF2-NF-κB pathway.

Nasopharyngeal carcinoma (NPC) is a head and neck cancer characterized by highly locoregionally invasive behavior attributable to the latent infection with Epstein-Barr virus (EBV) and genomic instability. It is well established that EBV-encoded oncogenic molecules actively contribute to the malignant behavior of NPC cells. However, the mechanism by which aberrant genomic alterations enable NPC cells to become aggressive remains largely unknown. In the present study, whole-exome sequencing (WES) revealed that the gene encoding the baculoviral IAP repeat-containing 3 (BIRC3) protein was frequently mutated in circulating tumor cells (CTCs) but not in paired primary tumor cells from patients with metastatic NPC. A minigene assay indicated that the c.637 A > G mutation disrupted normal mRNA splicing, resulting in the partial deletion of Exons 2 and 3 and altered stability of BIRC3 mRNA. In vitro experiments demonstrated that ectopic expression of the BIRC3c.637A>G mutant enhanced NPC cell invasive properties, including proliferation, resistance to apoptosis, migration, and invasion. Furthermore, overexpression of wild-type BIRC3 promoted invasive characteristics in NPC cells through the TRAF2-NF-κB signaling axis. In summary, BIRC3 acts as a regulator of the malignant features of NPC cells. Frequent BIRC3 mutations in CTCs, such as the c.637 A > G mutation, further enhance the metastatic potential of disseminated NPC cells by inducing aberrant alternative splicing. These findings suggest the therapeutic feasibility of targeting the BIRC3/TRAF2/NF-κB axis in the treatment of NPC.

Humans↗