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PubMed2026

Single-cell and spatial transcriptomics define a progenitor subpopulation and fibroinflammatory niche at the leading edge of parathyroid carcinoma.

Parathyroid carcinoma (PC) is a rare but clinically aggressive endocrine malignancy with limited treatment options and a poorly defined tumor microenvironment (TME). To elucidate its cellular heterogeneity and spatial architecture, we integrated single-cell and spatial transcriptomic profiling with whole-exome sequencing and multiplex immunohistochemistry on eight parathyroid neoplasm specimens, including PC, parathyroid adenoma, and atypical parathyroid tumor. We identified a distinct progenitor-like endocrine subpopulation (Ca-1) enriched in CDC73-mutant PC, exhibiting stem-like properties, elevated cell cycle activity, and pronounced genomic instability. Spatial mapping revealed that Ca-1 cells preferentially localize at the leading edge, forming a fibroinflammatory niche characterized by the enrichment of inflammatory cancer-associated fibroblasts (iCAFs) and SPP1+ macrophages. Within this niche, the dipeptidyl peptidase 4 (DPP4) is selectively expressed in Ca-1 cells and iCAFs, implicating a potential paracrine axis driving stromal remodeling and immunosuppression. These findings suggest that a spatially organized ecosystem may promote PC progression through TME remodeling and highlight the DPP4-CXCL2 axis as a candidate pathway for future investigation in aggressive parathyroid neoplasms.

Humans↗

PubMed2026

Clinical relevance of HRD score in pheochromocytomas and paragangliomas: molecular cluster distribution and prognostic implications.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with variable metastatic potential across molecular clusters. While the homologous recombination deficiency (HRD) score has been established as a surrogate for HRD-related genomic instability to guide prognostic evaluation and therapeutic options in multiple solid tumors, its relevance in PPGLs remains unexplored. Here, data from 133 PPGL patients in the TCGA database were extracted to assess relationships between the HRD score and molecular clusters, metastasis, metastasis-free survival (MFS), and other clinical characteristics. Subsequently, a real-world cohort of 54 matched blood-tumor pairs was subjected to whole-exome sequencing, with HRD scores calculated to confirm the prior observations. The median HRD score was 7.0 and 9.0 in the TCGA-PPGL dataset and the clinical cohort, respectively. In the TCGA dataset, an elevated HRD score significantly correlated with metanephrine secretion, C2 cluster, and metastasis. Multivariate analysis identified a higher HRD score as an independent risk factor for shorter MFS (HR = 1.33, P = 0.008). Patients with HRD scores ≥ 7 exhibited significantly shorter MFS (P = 0.037), which was observed exclusively within the C1A cluster (P = 0.007). Analyses of our clinical validation cohort corroborated this cluster-specific distribution and further revealed higher HRD scores in three temozolomide-treated PPGLs compared with those treatment-naive C1A tumors (P = 0.043). In conclusion, despite exhibiting lower levels in C1A clusters, an elevated HRD score emerges as a promising indicator for refined metastatic risk stratification in PPGLs. Futhermore, the substantial increase in HRD score following temozolomide treatment provides a rationale for PARP inhibitor sequential or combination therapy in metastatic PPGLs.

Humans↗

PubMed2026

Molecular subtyping of adrenocortical carcinoma reveals distinct subtypes with prognostic and therapeutic implications.

Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with poor survival and limited treatment options. To comprehensively characterize its molecular landscape and identify clinically relevant subtypes, we performed an integrated genomic analysis - including whole-exome sequencing, RNA sequencing, and copy number variation profiling - on 61 Chinese patients with ACC. We identified recurrent mutations in TP53 (25%), CTNNB1 (15%), ZNRF3 (10%), and MEN1 (8%). Unsupervised clustering of transcriptomic data revealed four distinct molecular subtypes: cortisol-driven (CD, 14%), immune-suppressed (IS, 40%), cell cycle-altered (CCA, 22%), and immunomodulatory (IM, 24%). The CD subtype exhibited steroidogenic pathway activation; the IS subtype showed T cell receptor downregulation and the worst disease-free survival; the CCA subtype was marked by chromosomal instability and cell cycle gene overexpression; and the IM subtype displayed enriched immune signaling and favorable outcomes. Copy number analysis further uncovered focal amplifications (e.g. TERT, CDK4) and HLA-II deletions. This study establishes a novel molecular classification of ACC, providing a framework for subtype-specific therapeutic strategies, such as CDK4/6 inhibition for CCA and immunotherapy for IM tumors, while highlighting the clinical challenges of immune-cold IS tumors.

Humans↗

PubMed2026

PSIP1::TBL1X: a recurrent gene fusion in pancreatic neuroendocrine tumors.

Effective treatment of metastatic neuroendocrine tumors (NETs) is limited by a lack of targeted therapies and clinically useful predictive biomarkers. We applied complementary genomic profiling technologies, including optical genome mapping (OGM) and whole exome sequencing (WES), to 70 liver metastases of NETs from multiple anatomical primary sites to identify actionable genomic alterations. We detected recurrent fusions involving TBL1X (PSIP1::TBL1X) and BEND2 (CHD7::BEND2 and NEO1::BEND2) by OGM in pancreatic neuroendocrine tumors (pNETs). The expression of the PSIP1::TBL1X fusion was confirmed by PacBio Iso-Seq long-read transcriptome sequencing and nested rtPCR, and fusion protein expression was established by western blotting. Expression of the PSIP1::TBL1X fusion was also assayed in a separate cohort of 31 specimens from 28 pNET cases by rtPCR. Across both cohorts, PSIP1::TBL1X was identified in 11% of pNET patients with available metastatic tissue, but was not detected in primary tumor specimens. All PSIP1::TBL1X fusion isoforms were found to retain early exons of PSIP1 and the complete coding sequence of TBL1X. Consistent with prior reports, BEND2 fusions were associated with high-grade tumors and may represent a clinically useful biomarker for aggressive disease. Notably, TBL1X and BEND2 fusions did not co-occur with ATRX/DAXX mutations, defining a distinct molecular subgroup of pNETs. This study highlights the importance of structural variant profiling in molecular profiling studies and supports a revised view of the role of gene fusions in neuroendocrine malignancies.

Humans↗

PubMed2026

Preimplantation genetic testing for concurrent Meckel Syndrome and hereditary breast cancer in a Chinese family harboring a novel NPHP3 pathogenic variant and a canonical BRCA2 frameshift variant.

Meckel syndrome (MKS) is a lethal autosomal recessive disease with high phenotypic and genetic heterogeneity. Defects in NPHP3 cause MKS type 7. Herein, we report a case of a Chinese family with a newborn male proband presenting with occipital encephalocele and polycystic kidneys. Whole-exome sequencing was performed on genomic DNA extracted from peripheral blood. Potential variants were assessed for pathogenicity. Two compound heterozygous variants of NPHP3 (c. 950T>C, p. Phe317Ser, and c.2694-2_2694-1delAG) were identified, which were inherited from both parents, with c.950T>C representing a novel variant. Two BRCA2 variants (c.5576_5579delTTAA, p. Ile1859Lysfs*3, and c.9357A>C,p. Leu 3119 Phe) were identified, which were inherited from the father. After the proband was diagnosed with MKS7, the couple chose preimplantation genetic testing for monogenic disorders (PGT-M) to simultaneously prevent the transmission of NPHP3 and BRCA2 pathogenic variants, leading to a successful pregnancy. Our study expands the NPHP3 variant spectrum and contributes to the molecular diagnosis and genetic counseling of MKS. This case indicates that PGT-M is a viable option for NPHP3-related MKS and BRCA-positive patients to avoid transmission while maintaining their families. Successful application of PGT-M provides a potential approach for treating other monogenic diseases.

Journal Article↗

PubMed2026

Genomic landscape of autism spectrum disorder in Brazil.

Genomic studies of autism spectrum disorder (ASD) have largely excluded admixed populations. To address this gap, we characterized the genomic landscape of ASD in Brazil by combining a systematic literature review with whole-exome sequencing analysis of 441 Brazilian individuals and their families. Our analysis revealed a conclusive molecular diagnosis in 13.1% of probands. The diagnostic yield was higher among individuals with clinical features, particularly comorbid signs of intellectual disability, hypotonia, and seizures, providing a basis for prioritizing genetic testing. The sample presented a diverse ancestry, with major European, African, and Native American contributions. Notably, more than half of the identified rare risk variants were located on non-European haplotypes. Both de novo and inherited variants contributed to ASD risk, and we reinforce NPAS3 as a candidate ASD risk gene. This study provides the first comprehensive genomic overview of ASD in a large Brazilian cohort, reinforcing the critical need to include diversely admixed populations in genomic research to expand the understanding of ASD architecture and improve diagnostic strategies in resource-limited settings.

Journal Article↗

PubMed2026

Deconvolution of evolutionary architecture unmasks a high-risk, subclonal-rich subtype in treatment-naive small cell lung cancer.

BACKGROUND: Intratumoral heterogeneity (ITH) drives therapeutic resistance in small cell lung cancer (SCLC). However, conventional single-sample analysis has limited horizontal, cross-patient comparisons, leaving the overarching evolutionary architecture in treatment-naive tumors poorly understood. This study aims to deconvolve these architectures to identify clinically relevant evolutionary subtypes. METHODS: We analyzed whole-exome sequencing data from 41 treatment-naive SCLC patients. To overcome the cross-patient comparability bottleneck, we developed a novel probabilistic framework using a refined Gaussian Mixture Model (GMM). This standardized subclonal structures into four hierarchical strata, enabling the identification of evolutionary subtypes via unsupervised clustering. To address the scarcity of SCLC public data, prognostic concordance was robustly explored in The Cancer Genome Atlas (TCGA) lung squamous cell carcinoma (LUSC) based on shared smoking etiology, with lung adenocarcinoma (LUAD) serving as a negative control. RESULTS: The cohort robustly segregated into "Clonal-dominant" (Group 1, n=28) and "Subclonal-rich" (Group 2, n=13) subtypes. Group 1 evolution was primarily driven by tobacco signatures (SBS4). Conversely, Group 2 exhibited late-stage acquisition of a DNA mismatch repair deficiency (MMRd) signature (SBS15), fueling trace subclonal diversification. Clinically, Group 2 demonstrated a significantly lower objective response rate (ORR) to platinum-based regimens (25.0% vs. 81.3%, P=0.02). Furthermore, the Subclonal-rich architecture independently predicted inferior overall survival (OS) [adjusted hazard ratio (adj. HR) =2.93, P=0.02], driven predominantly by limited-stage disease. Cross-cancer analysis validated this histology-dependent, high-heterogeneity adverse pattern in early-stage LUSC but not in LUAD. CONCLUSIONS: This hypothesis-generating study demonstrates that a "Subclonal-rich" architecture, driven by acquired MMRd, identifies high-risk, chemo-resistant SCLC. Our GMM approach suggests that pre-existing heterogeneity may serve as a potential, histology-dependent prognostic marker that warrants prospective validation for tailoring future therapeutic regimens.

Gaussian Mixture Model (GMM)↗

PubMed2026

Integrating rare and common variation in epilepsy genetics: from genetic architecture to penetrance and clinical expressivity.

Epilepsy genetics has often been interpreted through a useful but simplified dichotomous framework in which severe epilepsies, particularly developmental and epileptic encephalopathies, are attributed mainly to rare, high-effect variants, whereas more common epilepsies are viewed as arising largely from the cumulative effects of common, small-effect variation. Although this framework has been instrumental for gene discovery, molecular diagnosis, and mechanism-based treatment, it does not fully explain incomplete penetrance, intrafamilial phenotypic heterogeneity, or marked differences in severity among individuals sharing the same molecular diagnosis. Evidence from exome sequencing, copy number variant (CNV) studies, and genome-wide association studies increasingly suggests that rare SNVs/indels, CNVs, and common variant should not be interpreted as entirely independent risk sources, but may partially converge on shared genes, pathways, cell types, and neurobiological processes relevant to neuronal excitability, network stability, and seizure susceptibility. Here, we review evidence across epilepsy subtypes, focusing on convergence and divergence across the allelic spectrum, and discuss how polygenic background and other modifiers may influence penetrance and clinical expressivity among carriers of rare pathogenic variants and CNVs. We also consider implications for variant interpretation, genetic counseling, risk stratification, and precision medicine, while emphasizing that most rare-common integrated models remain insufficiently validated for routine clinical decision-making.

common variants↗

PubMed2026

Longitudinal analysis of genomic and immune differences between primary and metastatic nasopharyngeal carcinoma for precision oncology.

INTRODUCTION: Nasopharyngeal carcinoma (NPC) is a common malignancy with a high incidence in Southern China and Southeast Asia. Distant metastasis remains a major cause of poor prognosis. This study aims to explore the genomic and immune microenvironmental changes in primary and metastatic NPC through longitudinal analysis, to provide insights for guiding precision treatment strategies. METHODS: We analyzed tumor samples from 11 male NPC patients with distant metastasis. Paired primary and metastatic samples underwent targeted whole-exome sequencing (551 genes) and RNA sequencing (289 genes). Multiplex immunohistochemistry was performed to assess immune cell composition and immune response markers. Genomic alterations and immune features were compared between primary and metastatic tumors, and their associations with clinical outcomes were evaluated. RESULTS: Metastatic tumors exhibited distinct chromosomal changes, including frequent 1q gain, while 6p gain showed a trend toward prolonged survival. Primary tumors showed stronger immune suppression characterized by increased B-cell and Treg infiltration and elevated CTLA4 and IDO1 expression, whereas metastatic lesions displayed more active immune responses. Liver metastases presented a distinct immune landscape with lower CD8+ T-cell density compared to non-liver metastases. In locoregionally advanced NPC, high expression of oncogenic genes such as EGFR and MYC correlated with shorter disease-free survival, while elevated PANCK expression and enhanced cytotoxicity were linked to better outcomes. These results delineate the molecular and immune evolution of NPC and provide a foundation for developing precision therapeutic strategies. CONCLUSION: This study identifies key molecular and immune features associated with NPC survival. Primary tumors show an immunosuppressive phenotype, suggesting potential benefits from combining CTLA4 or IDO1 inhibitors with PD-1 blockade. Liver metastases exhibit distinct immune features, supporting the need for site-specific precision therapies. These findings contribute to personalized management strategies in NPC, guiding treatment based on molecular and immune profiles.

distant metastasis↗

PubMed2026

Case Report: Early infantile drug-resistant epilepsy and gastrointestinal dysmotility associated with a de novo GNAO1 variant and a 16p13.11 microdeletion.

BACKGROUND: The GNAO1 gene is located on the long arm of chromosome 16 (16q13) and is associated with Developmental and Epileptic Encephalopathy 17. It encodes a protein involved in regulating various neurotransmitters and neuronal growth and development. The 16p13.11 microdeletion is a genomic deletion in the p13.11 region of the short arm of chromosome 16, previously reported to predispose individuals to neurodevelopmental disorders. These two regions do not overlap on the chromosome, and the 16p13.11 microdeletion does not involve the GNAO1 gene locus. CASE PRESENTATION: We reports a 1-month-old infant presenting with concurrent GNAO1 (p. G203R) gene variation and a 16p13.11 microdeletion. The patient initially presented with recurrent abdominal distension in the neonatal period, which gradually progressed to include focal seizures and intractable epileptic spasms. Interictal EEG showed multifocal discharges and burst-suppression patterns. Brain MRI revealed no abnormalities. A full gastrointestinal series suggested intestinal obstruction and gastro-esophageal reflux. Improved whole-exome sequencing identified: 1) A single nucleotide variantion: GNAO1, NM_020988.3:exon6: c.607G > A (p.Gly203Arg). 2) A copy number variation: A pathogenic 1.453 Mb deletion in the 16p13.11 region. CONCLUSIONS: We describe the developmental trajectory of an infant with overlapping features of gastrointestinal symptoms and drug-resistant epilepsy, carrying a GNAO1 variant and a 16p13.11 microdeletion. This case provides insights into the contribution of both single nucleotide variant and copy number variant to the phenotype.

16p13.11 microdeletion↗

PubMed2026

Long-Term Outcomes and Paired Immune and Genomic Exploratory Analyses After Neoadjuvant Dose-Dense MVAC in Muscle-Invasive Bladder Cancer: A Single-Centre Case Series.

Background/Objectives: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy has been the standard of care for muscle-invasive bladder cancer (MIBC) for two decades, yet a substantial proportion of patients derive no benefit. As antibody-drug conjugates and immune checkpoint inhibitors reshape perioperative treatment, it is unclear which patients retain meaningful benefit from platinum. We describe long-term outcomes and exploratory paired immune and genomic analyses in a single-centre cohort treated with dose-dense MVAC (dd-MVAC). Methods: We retrospectively identified 54 consecutive patients with MIBC treated with neoadjuvant dd-MVAC between November 2013 and November 2019. Forty-two underwent radical cystectomy and are assessable for pathologic response. Immunohistochemistry for CD3, CD8, FOXP3, PD-1, PD-L1, PD-L2, and NY-ESO-1 was evaluable in 31 baseline specimens and 22 paired specimens; paired genomic profiling was evaluable in 12 cases, with paired tumour mutational burden (TMB) in 10 by whole-exome sequencing and 7 by TSO-500. Paired analyses necessarily exclude patients achieving a pathologic complete response (pCR), who have no residual tumour, and most early progressors. Results: pCR was achieved in 11/42 operated patients (26%, 95% CI 15-41). Median follow-up was 87 months (IQR 24-104). Hydronephrosis was the only baseline factor associated with absence of pCR (p = 0.016). Within the operated cohort, pCR was associated with longer recurrence-free survival (log-rank p = 0.017), but the difference in overall survival did not reach significance (p = 0.121). NAC reduced intratumoral FOXP3 (q = 0.001), NY-ESO-1 (q = 0.013), PD-L2 (q = 0.013), and CD3 (q = 0.043) after correction for multiple comparisons, whereas TMB showed no significant change (TSO-500 p = 0.67; WES p = 0.86). No statistically significant association was detected between any baseline immune marker, including PD-L1, and pCR. The mutational landscape was largely concordant before and after NAC. Conclusions: This study was exploratory and was not powered to validate predictive biomarkers. In this long-term cohort, dd-MVAC was associated with measurable depletion of intratumoral immune populations in chemoresistant tumours, while paired genomic profiles remained broadly concordant. No pre-treatment biomarker identified platinum-refractory patients, but the small evaluable subsets mean these are hypothesis-generating rather than negative findings, and prospective studies with pre-specified biomarker endpoints are required.

chemoresistance↗

PubMed2026

Ocular Nystagmus as the Initial Presenting Feature in a Patient with Complete CLTC Deletion: Expanding the Genotype-Phenotype Spectrum of CLTC-Related Disorder.

Background: CLTC-related neurodevelopmental disorder is a rare condition primarily characterized by global developmental delay (GDD) and intellectual disability (ID). To date, approximately 41 cases involving CLTC gene alterations have been reported. We present the first individual with a complete deletion of the CLTC gene. Methods: The proband is a male from a non-consanguineous family, presenting with congenital nystagmus, hypotonia, GDD, and autism spectrum disorder (ASD). Chromosomal microarray analysis and trio exome sequencing were performed. A systematic review of previously reported CLTC variant cases was conducted to delineate the phenotypic spectrum. Results: A de novo 363-kb heterozygous deletion at 17q23.1 spanning the entire CLTC gene was identified. The systematic review confirmed GDD/ID as core features and revealed various ocular abnormalities in a subset of cases. These findings indicate that the clinical phenotype extends beyond neurodevelopment, with multi-system involvement. Conclusions: The phenotypic heterogeneity of CLTC-related disorders underscores the need for comprehensive physical examination to identify extra-neurological manifestations. Accurate diagnosis relies on integrating detailed clinical phenotyping with comprehensive genomic testing. Early, precise diagnosis facilitates multidisciplinary management, informed genetic counseling, and the establishment of long-term surveillance protocols.

Humans↗

PubMed2026

A Novel SLC25A4 Variant Causing Mitochondrial Dysfunction, Myopathy and Cardiomyopathy: A Functional and Molecular Characterization.

SLC25A4, solute carrier family 25 member 4, gene is a member of the mitochondrial carrier subfamily within the solute carrier protein family. Pathogenic variants in SLC25A4 are associated with a spectrum of mitochondrial disorders that exhibit variable inheritance patterns and clinical manifestations. Specifically, dominantly inherited variants are typically associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, recessively inherited variants are linked to myopathy and cardiomyopathy, and de novo variants can result in early-onset fatal disease presentations. In this study, we aimed to identify and characterize the disease-causing mutation(s) in a nine-year-old female patient from a consanguineous Saudi family. The patient was asymptomatic until the age of 3 years, when she presented with cardiomyopathy and myopathy. Comprehensive genetic analysis inclusive of whole exome sequencing and segregation analysis using Sanger sequencing identified an SLC25A4 variant (NM_001151.4: exon 2: c.112-1G>C) as the most likely cause of the disease. To assess transcript-level effects, we performed RT-PCR on RNA extracted from the patient's cultured lymphoblast cell lines (LCLs) and fibroblast cell lines (FCLs). RT-PCR analysis demonstrated that the variant causes aberrant splicing, resulting in a 6 bp in-frame deletion (p.Gln37_Val38del) in the ANT1 protein. Quantitative RT-PCR demonstrated reduced SLC25A4 transcript levels in both FCLs and LCLs. Quantitative PCR analysis of mitochondrial DNA demonstrated a trend toward increased mtDNA copy number in patient-derived FCLs compared with controls, suggesting a possible compensatory response to mitochondrial dysfunction. Furthermore, Seahorse assays revealed marked reductions in both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in patient-derived FCLs compared with controls. These findings expand the molecular and functional spectrum of SLC25A4-associated disease and may inform clinical practice, including genetic interventions such as preimplantation genetic diagnosis, premarital genetic screening, targeted genetic counseling, and cascade testing of at-risk family members.

Humans↗

PubMed2026

Biallelic EZH1 Nonsense Novel Variant in Two Siblings with Neurodevelopmental Disorder and Central Precocious Puberty: A Case Report from a Consanguineous Saudi Family.

Neurodevelopmental disorders (NDDs) are a group of conditions that impair the development and function of the central nervous system. Recently, variants in the EZH1 gene have been associated with neurodevelopmental disorders. Here, using whole-exome sequencing coupled with confirmatory Sanger sequencing, we identified a homozygous nonsense variant in EZH1 in two affected siblings. Both parents were heterozygous carriers of the variant. The variant is predicted to result in a 44-amino acid C-terminal truncation within the catalytic SET domain, leading to loss of protein function. RT-qPCR analysis revealed significantly reduced EZH1 mRNA expression in patient-derived peripheral blood cells. The index patient (female) also exhibited elevated gamma-glutamyl transferase (GGT) levels and hypoalbuminemia, whereas the affected male presented with central precocious puberty. This study further expands the clinical, genetic, and molecular spectrum of EZH1-associated neurodevelopmental disorders by demonstrating that reduced EZH1 expression is consistent with a loss-of-function disease mechanism.

Child↗

PubMed2026

[Pathogenicity analysis and prenatal genetic counseling for five Chinese pedigrees harboring a hemizygous c.-32C>G variant of FGF13 gene].

OBJECTIVE: To explore the pathogenicity and prenatal counseling strategies for five Chinese pedigrees harboring a hemizygous c.-32C>G (NM_001139500.2) variant of fibroblast growth factor 13 (FGF13) gene. METHODS: Five Chinese pedigrees found to carry a hemizygous c.-32C>G variant of the FGF13 gene at the Prenatal Diagnosis Center of Henan Provincial People's Hospital between January 2024 and January 2025 were selected as study subjects. The pedigrees had undergone prenatal diagnosis for a family history of genetic disorders, abnormal fetal ultrasound findings, or advanced maternal age. A retrospective analysis was carried out, wherein clinical data for all members of the pedigrees were obtained through the medical records system and outpatient visit system. Peripheral blood samples were collected from all pedigree members, and amniotic fluid samples were obtained from the probands. Following extraction of genomic DNA, prenatal diagnosis was performed using chromosomal microarray analysis (CMA) and trio whole-exome sequencing (trio-WES). Sanger sequencing was used to determine the carrier status for the candidate variant, and Mini-Mental State Examination (MMSE) was used to assess the cognitive function of hemizygous individuals carrying the FGF13 gene c.-32C>G variant. Pathogenicity of candidate variant was assessed based on guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: 2021-171). RESULTS: CMA and trio-WES revealed no pathogenic variants in all probands, whilst trio-WES and Sanger sequencing had identified 11 male individuals carrying a hemizygous c.-32C>G variant of the FGF13 gene from the five pedigrees, which included six adult males, a young boy, and four fetuses. One fetus had undergone termination of pregnancy due to hydrocephalus, one was born pre-term at 34+1 weeks of gestation owing to maternal hypertension, and other two were delivered at full term. Follow-up of the survived males revealed no phenotypic manifestations related to language or intellectual impairment. Among these, three adult males underwent the MMSE assessment, all of whom showed normal cognitive function. Search of the gnomAD database suggested the carrier frequency of FGF13 c.-32C>G variant in the East Asian population to be 0.125%, with 11 hemizygous males documented. Three male patients harboring the variant showed severe intellectual disability. Both in vitro and in vivo studies suggested that it could reduce the translation levels of FGF13 protein. Based on the ACMG guidelines, it was classified as variant of uncertain significance (BS4+PS3_Supporting). CONCLUSION: There is insufficient evidence to classify the FGF13 c.-32C>G as a pathogenic variant in clinical practice, and its presence should not be considered an indication for pregnancy termination due to major birth defects.

Adult↗

PubMed2026

[Study of a patient with azoospermia due to variant of MOV10L1 gene].

OBJECTIVE: To explore the clinical and genotypic characteristics of a patient with Sertoli cell-only syndrome (SCOS) due to variants of MOV10L1 gene. METHODS: A 27-year-old patient with Non-obstructive azoospermia (NOA) underwent routine semen analysis. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P), estradiol (E2), prolactin (PRL), and testosterone (T) were determined by chemiluminescence assays. Peripheral blood samples were collected for G-banded karyotyping analysis. Multiplex PCR fluorescence detection was used to screen for AZF gene microdeletions. Whole exome sequencing (WES) and Sanger sequencing were performed simultaneously. Testicular biopsy tissues were subjected to Hematoxylin-Eosin (HE) staining to assess seminiferous tubule cell composition, and MOV10L1 protein expression was detected by immunohistochemical staining. Bioinformatics tools were employed to predict the pathogenicity of variants and their impact on protein structure and function. This study was approved by the Medical Ethics Committee of the Guangdong Institute of Reproductive Sciences [Ethics No.: 2023(01)]. RESULTS: The patient's two semen analyses had failed to detect any sperm. Hormone tests indicated elevated FSH (22.32 mIU/mL) and PRL (397.6 mIU/mL), while T (3.68 nmol/L) and E2 (38.32 pmol/L) were reduced. Chromosomal karyotyping revealed 46,XY, and no AZF gene deletion was detected. WES and Sanger sequencing detected compound heterozygous variants of the MOV10L1 gene, including a c.345C>A (p.C115X) nonsense variant and a c.3323C>T (p.T1108I) missense variant, with the former being unreported previously. HE staining showed only Sertoli cells in the seminiferous tubules, confirming the diagnosis of SCOS. Immunohistochemical staining revealed absent MOV10L1 protein expression in the testicular tissue. Based on the guidelines from American College of Medical Genetics and Genomics (ACMG), the c.345C>A (p.C115X) was classified as a pathogenic variant (PVS1+PM2_Supporting+PP4), while the c.3323C>T (p.T1108I) was deemed variant of uncertain significance (PM2_Supporting+PP3_Supporting+PP4). Bioinformatics analysis demonstrated that c.345C>A (p.C115X) may cause premature termination of protein translation, while c.3323C>T (p.T1108I) may disrupt the hydrophobicity of the RNA helicase domain, reducing the active pocket volume and decreasing its affinity for MILI protein. CONCLUSION: This study has diagnosed a case of SCOS due to compound heterozygous variants of the MOV10L1 gene, which also enriched its mutational spectrum.

Humans↗

PubMed2026

[A case of bilateral open-lip schizencephaly with West syndrome due to variant of PAFAH1B1 gene and literature review].

OBJECTIVE: To report the clinical manifestations, genetic features, diagnosis, treatment, and prognosis of a child with bilateral open-lip schizencephaly complicated by West syndrome due to a variant of PAFAH1B1 gene, and review the relevant literature. METHODS: Clinical data of a 4-month-old boy were retrospectively analyzed, and 35 previously reported cases were systematically reviewed. This study was approved by the Medical Ethics Committee of Gansu Provincial People's Hospital (Ethics No.: 2025-871). RESULTS: The 4-month-old boy presented with clustered flexor spasms, hypsarrhythmia on electroencephalography, and developmental regression. Brain magnetic resonance imaging revealed bilateral pachygyria, schizencephaly, and dysgenesis of the corpus callosum. Trio whole-exome sequencing identified a de novo heterozygous NM_000430.4: c.703_704delAG (p.Glu235Metfs*20) frameshift variant in the PAFAH1B1 gene. Sanger sequencing confirmed that neither parent carried this variant. Based on the guidelines from American College of Medical Genetics and Genomics (ACMG), the variant has met the criteria for PVS1+PS2_Moderate+PM2_Supporting, and was classified as pathogenic. After treatment with adrenocorticotropic hormone combined with vigabatrin and other antiseizure medications, the epileptic spasms were controlled and the electroencephalographic abnormalities had improved. However, global developmental delay persisted at the 12-month follow-up. Analysis of the present case and 35 previously reported cases showed that PAFAH1B1-related phenotypes were highly consistent, mainly including infantile spasms (28/36), developmental delay/intellectual disability (29/36), and abnormal brain MRI findings (30/36), predominantly cortical malformations. The reported variant types included deletions, frameshift variants, nonsense variants, missense variants, and splice-site variants. CONCLUSION: PAFAH1B1 gene variants are an important cause for cortical malformations, including schizencephaly, and may lead to secondary West syndrome. This study has systematically summarized the genotypic and phenotypic features of bilateral open-lip schizencephaly complicated by West syndrome associated with a frameshift variant of the PAFAH1B1 gene. For infants with epileptic spasms or early-onset epilepsy accompanied by structural brain abnormalities, early genetic evaluation should be performed, and antiseizure treatment should be integrated with neurodevelopmental rehabilitation to facilitate long-term management.

Humans↗

PubMed2026

A Case Report of a Pedigree with Distal Hereditary Motor Neuropathy Caused by a Homozygous c.1124G>A Variant an the /*9Vaccinia-Related Kinase 1 Gene.

This study aimed to analyze the clinical phenotypes, neurophysiological characteristics, and pathogenicity of gene variants in a pedigree with distal hereditary motor neuropathy (dHMN) caused by VRK1 variants, and to provide evidence to support clinical diagnosis and genetic counseling for this disease. We report a Chinese consanguineous family with dHMN caused by a homozygous c.1124G>A variant in the VRK1 gene. Clinical and electrophysiological data of the proband were collected. Whole-exome sequencing (WES) and validation by Sanger sequencing were performed to identify the variant site, and pathogenicity interpretation was conducted in accordance with American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. The proband was a 24-year-old male who presented with 2 years of progressive weakness and atrophy of the distal lower limbs, accompanied by slender upper limbs and no sensory disturbance. Electrophysiological examination showed decreased compound muscle action potential (CMAP) amplitude in motor nerves of both upper and lower limbs, indicating peripheral neurogenic damage, while sensory nerve conduction was normal. Genetic testing detected a homozygous c.1124G>A (p.Trp375Ter) variant in the VRK1 gene. His parents and elder sisters were heterozygous carriers, and the pedigree conformed to autosomal recessive inheritance. According to ACMG guidelines, this variant was classified as pathogenic (evidence: PVS1, PM2, PP1). The homozygous VRK1 c.1124G>A variant causes adult-onset dHMN, rather than pontocerebellar hypoplasia type 1A (PCH1A) as annotated in some genetic databases. This pedigree presents distinctive phenotypes, including slender upper limbs and diffusely decreased CMAP amplitudes in both upper and lower limbs, thereby expanding the clinical and genetic spectrum of VRK1-related dHMN in the Chinese population.

Humans↗