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PubMed2026

Type I Interferon Signature is Associated With Lung Disease, Drug-Associated Immune Reactions, and Genetic Variation in Interferon-Linked Pathways in Still Disease.

OBJECTIVE: To evaluate the relationship across type I interferon (IFN-I)-stimulated gene (ISG) expression, Still disease, and the development of lung disease (LD) and drug-associated immune reactions (DAIR) to interleukin-1 (IL-1) and/or IL-6 inhibitors. METHODS: Whole blood ISG expression was quantified by NanoString array. ISG-28 scores were calculated in consecutive patients with Still or Still-like disease. Exome sequencing with family-based variant prioritization identified candidate genes harboring rare candidate causative variants. Lists of candidate genes were subjected to functional enrichment analysis. RESULTS: Among 57 patients (32 children, 25 adults), 16 had elevated ISG-28 scores. This group exhibited higher prevalence of LD (0.44 vs 0.1, P = 0.007) and DAIR (0.63 vs 0.17, P = 0.003) and lower IL-6 inhibitor use (0 vs 0.25, P = 0.048) compared to others. No significant differences were found in the rates of macrophage activation syndrome, active disease, elevated IL-18, or current IL-1 inhibition. The combination of HLA-DRB1*15 with high ISG-28 scores is associated with LD and DAIR with high specificity, whereas absence of both biomarkers had high negative predictive value. Candidate genes from high ISG-28 individuals were enriched in IFN-related pathways, including autophagy, IFN-I production, toll-like receptor signaling, macrophage activation, cytoskeletal organization, and responses to stress. CONCLUSION: High IFN-I expression correlates with LD and DAIR in Still disease, linked to rare genetic variation in immune pathways. Combining high ISG-28 with HLA-DRB1*15 significantly improves post hoc stratification of patients for these complications. If prospectively validated, these findings may guide molecular risk assessment and targeted therapies, including IFN-I directed treatments in Still disease with IFN-I signature.

Humans↗

PubMed2026

Identification of the Genomic Etiology of Unexplained Congenital Problems in Pediatric Patients: First Reported Case With Coffin-Siris Syndrome and Sialuria From India.

Coffin-Siris syndrome (CSS) (OMIM:614608) is a rare genetic disorder characterized by global developmental delay (GDD), speech impediment, coarse facial features, and hypoplastic or absent fifth fingernails/toenails. Genetic variants in the SMARCB1 gene are associated with CSS, benign tumors (schwannomas), and rhabdoid tumor predisposition syndrome. Genetic variants in the GNE gene are associated with the autosomal dominant sialuria (OMIM#269921), a rare inborn error of metabolism resulting in high levels of free sialic acid. Here we present case reports of two siblings: patient 1 (10 years) and patient 2 (2 years). While both siblings showed GDD and dysmorphic features such as hypotelorism and large ears, patient #1 exhibited additional phenotypes. Whole exome sequencing identified a heterozygous pathogenic variant, NM_003073.5:c.1096C>T (p.Arg366Cys), in the SMARCB1 gene in both siblings. In addition, patient 1 harbored a heterozygous likely pathogenic variant, NM_005476.7:c.2086G>A (p.Val696Met), in the GNE gene, which was absent in patient 2. The co-occurrence of the GNE variant may contribute to the increased severity of the phenotype in patient 1. This study is the first report worldwide of the co-occurrence of two extremely rare disorders. These findings highlight the complexity of genomic contributions while also emphasizing the value of genomic sequencing for congenital problems.

Coffin–Siris syndrome↗

PubMed2025

Glioma mutational signatures associated with haloalkane exposure are enriched in firefighters.

BACKGROUND: Glioma is the most common malignant primary brain tumor and is associated with significant morbidity and mortality. Modifiable risk factors remain unidentified. New advances in exposure assessment, genomic analyses, and statistical techniques permit more accurate evaluation of glioma risk associated with exogenous occupational or environmental exposures. METHODS: By using whole-exome sequencing data from matched germline and glioma tumor samples, the authors compared tumor mutational signatures for 17 persons with glioma and a documented occupational history of firefighting with those of 18 persons with glioma without an occupational history of firefighting. All 35 individuals were participants in the University of California, San Francisco Adult Glioma Study. RESULTS: There was a positive correlation among firefighters between the median number of sample variants attributable to single-base substitution signature 42, a single-base substitution mutational signature associated with haloalkane exposure (from the Catalogue of Somatic Mutational Signatures in Cancer) and firefighting years (p = .04; R2 = 0.29). Among nonfirefighters, the individuals with the highest number of median variants attributable to single-base substitution signature 42 also had occupations that possibly exposed them to haloalkanes, such as painting and being a mechanic. CONCLUSIONS: In summary, the authors identified gliomas that had mutational signatures associated with haloalkane exposure that were enriched in firefighters and other occupations.

Humans↗

PubMed2026

Novel TCOF1 Frameshift Variant and Phenotypic Heterogeneity in a Chinese Family With Treacher Collins Syndrome.

BACKGROUND: Treacher Collins syndrome (TCS) is a congenital craniofacial disorder characterized by malar and mandibular hypoplasia, downward-slanting palpebral fissures, and conductive hearing loss. Pathogenic variants in TCOF1 account for most cases, with POLR1D, POLR1C, and POLR1B also implicated. METHODS: Whole-exome sequencing was performed in a two-generation Chinese family with TCS, followed by Sanger sequencing validation. Clinical features were systematically evaluated, and bioinformatic analyses combined with structural modeling were employed to assess the potential pathogenicity of the identified variant. RESULTS: In this study, a novel heterozygous frameshift variant in TCOF1 (NM_001371623.1:c.1601_1602delCC, p.Pro534Leufs*15) was identified in the proband and his affected father. The proband presented classic TCS features including craniofacial skeletal hypoplasia, downward-slanting palpebral fissures, and conductive hearing loss. He also carried a right-sided preauricular fistula, a nonclassical feature of TCS. The same variant was detected in his affected father with a substantially milder phenotype, indicating marked intrafamilial phenotypic variability. Bioinformatic analysis and structural modeling predicted that this variant produces a severely truncated Treacle protein lacking key functional domains, which is predicted to disrupt nucleolar localization and ribosome biogenesis. CONCLUSION: Our findings expand the variant spectrum of TCOF1, highlight phenotypic heterogeneity in TCS, and reinforce the critical role of molecular diagnosis in distinguishing TCS from phenotypically overlapping craniofacial syndromes.

Humans↗

PubMed2026

Successful Live Birth Following Treatment of Persistent Endometrial Dysbiosis and Recurrent Chronic Endometritis: A Case Report.

CASE: To study the cause of recurrent endometritis, which recurred after standard antibiotic therapy, we report the case of a 40-year-old woman with a history of recurrent pregnancy, preterm birth, and CE. The endometritis recurred following a standard antibiotic regimen. OUTCOME: Microbiome analysis via 16S rRNA gene sequencing revealed persistent dysbiosis in both vaginal and endometrial samples despite antibiotic regimens. Whole-exome sequencing (WES) identified rare variants in TRPV3 and CD36, potentially associated with epithelial barrier dysfunction. Following an extended course of antibiotic therapy, the woman gave birth to a healthy baby at GA 32 weeks. CONCLUSIONS: This case highlights the possibility that barrier gene variants may be associated with persistent endometrial dysbiosis and recurrence of CE. An intensive antibiotic regimen may help achieve a viable pregnancy in patients with recurrent CE following standard antibiotic therapy.

antibiotics↗

PubMed2025

Intratumoral B cell and interferon signatures in newly diagnosed glioblastoma are associated with longer survival in patients treated with SurVaxM.

Glioblastoma (GBM) has proved difficult to treat, and there is dire need for more effective therapies. In a single arm phase IIa trial (NCT02455557), treatment of newly diagnosed GBM patients with the peptide vaccine SurVaxM resulted in promising median progression-free and overall survival. To investigate molecular features that associate with GBM responsiveness to SurVaxM, retrospective whole exome and RNA sequencing was performed on patient tumors (n = 34) collected prior to standard of care treatment plus SurVaxM. Differential gene expression and mutational profiles were characterized between patients with short-term (OS < 18 months) or long-term (OS ≥ 18 months) overall survival. Greater expression of interferon, complement, and humoral immunity signatures were associated with long-term survival. Deconvolution of transcriptomes identified enrichment of intratumoral memory B cell populations in long-term survivors that were validated by CD20 staining in matched samples. A five-gene expression signature and a B cell specific signature predicted survival within the SurVaxM-treated cohort, however, these signatures were not associated with improved outcomes in a similarly treated population obtained from The Cancer Genome Atlas (TCGA) that did not receive immunotherapeutic intervention. Although prospective validation is ongoing, the findings in this discovery cohort specify molecular features of GBM associated with better overall survival and potential responsiveness to immunotherapy with SurVaxM.

Humans↗

PubMed2026

Investigating genetic susceptibility to concussion through rare variants in ion channel and neurotransmission genes.

Some individuals appear more susceptible to concussion or mild traumatic brain injury (mTBI) and the severity, range, and the persistence of post-concussion symptoms vary considerably between affected individuals. Genetic factors are likely to contribute to this variability. Symptomatic overlap of post-concussion syndrome with neurological conditions such as familial hemiplegic migraine (FHM) caused by rare pathogenic variants in ion channel and synapse protein genes, with high sensitivity to head trauma for some patients, suggests that variation in similar pathways may influence concussion susceptibility and recovery. To investigate this hypothesis, we performed whole exome sequencing in 93 unrelated individuals who had sustained a single or multiple concussions and examined rare protein-altering variants in FHM genes, other neuronal ion channel and transporter genes, and genes involved in neurotransmission. We identified 62 different rare missense variants across 24 genes in 59 participants (63%), with 26 individuals carrying 2 or more variants. The prevalence of specific likely damaging rare variants in the 16 ion channel-related genes that were identified was approximately fivefold higher than that observed from gnomAD population controls (Odds Ratio = 5.44, 95% CI [4.13,7.18], P < 0.0001). Notably, voltage-gated calcium and sodium channel genes, including SCN9A, together with neurotransmission-related genes such as SNCAIP, harboured multiple potentially deleterious variants. These findings suggest that rare deleterious variants in genes involved in ion homeostasis and neurotransmission may contribute to an individual's susceptibility to concussion or more severe post-concussion symptoms. This study provides a foundation for future genetic and functional investigations aimed at improving our understanding of concussion susceptibility and outcomes. Further validation in larger cohorts and mechanistic studies is warranted to determine their utility as biomarkers of concussion risk and prognosis.

Humans↗

PubMed2026

MNV-aware molecular characterization of a rare homozygous TTPA complex allele in ataxia with vitamin E deficiency.

Ataxia with vitamin E deficiency (AVED) is a rare autosomal-recessive neurological disorder caused by biallelic pathogenic variants in TTPA. Early vitamin E supplementation may prevent or limit irreversible neurological damage, but diagnosis is often delayed. Multi-nucleotide variants (MNVs) in TTPA have rarely been described and may be misinterpreted when adjacent substitutions are evaluated independently. We investigated a 34-year-old woman with childhood-onset progressive ataxia using clinical, biochemical, neuroimaging, and electrophysiological assessments. Serum vitamin E levels were measured longitudinally during supplementation. Whole-exome sequencing, read-level inspection, and Sanger sequencing were used to identify and confirm a homozygous TTPA complex allele, NM_000370.3:c. 296G > A;299 A > C, predicted to result in NP_000361.1:p. Gly99_Tyr100delinsAspSer, and to assess familial segregation. Population-database review, in silico prediction, and exploratory structure-based analysis were performed to evaluate its potential clinical relevance. The patient had markedly reduced baseline serum vitamin E levels of 0.8 µg/mL, which increased to 7.5 µg/mL after 12 months of supplementation. This biochemical correction was temporally accompanied by qualitatively observed improvements in gait stability, coordination, speech, and fine motor performance. Read-level analysis supported the presence of both substitutions on the same allele, and Sanger sequencing confirmed the homozygous complex allele in the patient and heterozygous carrier status in both parents. The affected residues are conserved and located within the CRAL-TRIO domain of α-tocopherol transfer protein. Exploratory structure-based analysis suggested altered local residue interactions; however, no functional assay was performed, and effects on protein stability, α-tocopherol binding, or transfer could not be established. This report expands the molecular spectrum of AVED by describing a homozygous TTPA complex allele and highlights the importance of MNV-aware interpretation of closely spaced substitutions. Vitamin E supplementation resulted in biochemical correction and was accompanied by possible partial clinical improvement despite initiation in adulthood. Functional studies are required to determine the precise effect of this allele on α-tocopherol transfer protein function.

Humans↗

PubMed2025

Identification of pathogenic variants in six Chinese families with keratoconus of autosomal dominant inheritance: pathogenicity analysis and variable phenotype.

PURPOSE: Keratoconus (KC) is a bilateral, asymmetric disease causing corneal thinning, irregular astigmatism, and vision decline, with unclear etiology. This study aims to investigate pathogenic variants of candidate genes in Chinese KC families via whole exome sequencing (WES). METHODS: The Pentacam 3D anterior segment analysis system was applied for keratectasia detection, and the Corvis ST was used for corneal biomechanics measurement. Probands from KC families were screened via WES and further verified in other family members through Sanger sequencing. Additionally, qPCR was used to validate copy number variants and identify pathogenic gene loci. The identified variants were then classified according to the Standards and Guidelines for the Interpretation of Sequence Variants published by the American College of Medical Genetics and Genomics (ACMG). Finally, STRING protein-protein interaction (PPI) networks analysis was performed to investigate interactions among candidate gene-related proteins. RESULTS: Using WES, four heterozygous missense variants were detected in the ZNF469, KRT12, COL8A2, and COL18A1 genes: c.4384G > A: p.Asp1462Asn, c.1229T > G:p.Val410Gly, c.505A > G:p.Ile169Val, and c.1159G > A:p.Gly387Arg. Additionally, a heterozygous frameshift variant was detected in the PMS2 gene: c.1551_1572del:p.Ser517Argfs*71. The affected parents carried the same variants as the probands verified by Sanger sequencing. A copy number variant was detected in the DPP6 gene: seq[GRCh38] dup(7)(q36.2q36.2) chr7:g.153782360_ 153982491dup. According to ACMG guidelines, ZNF469, KRT12, COL8A2, and COL18A1 gene variants are Likely Pathogenic; PMS2 and DPP6 gene variants are Pathogenic. STRING analysis highlights a tightly interconnected network centered on COL8A2, involving COL18A1, FN1, ZNF469, and KRT12. DPP6 was involved in KC via affecting FN1. In four of six autosomal dominant KC (adKC) families, affected parents had the same variants as probands but milder phenotypes. CONCLUSION: In this study, six novel variants in ZNF469, KRT12, COL8A2, COL18A1, PMS2, and DPP6 were linked to adKC. Family phenotypes showed variable expressivity with irregular dominance inheritance. Abnormal KC-related gene protein expression may contribute to corneal structural instability. This study broadened KC genetic screening candidates and suggested genetic testing could aid early KC diagnosis and intervention.

Adult↗

PubMed2026

Pharmacogenomic diversity in Amazonian Indigenous populations: implications for Berlin-Frankfurt-Münster acute lymphoblastic leukemia therapy.

PURPOSE: This study aimed to characterize pharmacogenomic variation in genes involved in the metabolism and transport of drugs used in Berlin-Frankfurt-Münster-based therapy in Amazonian Indigenous individuals and to compare allele frequencies with major continental populations. METHODS/PATIENTS: Whole-exome sequencing data previously generated from 64 healthy Indigenous individuals from 12 Amazonian ethnic groups were analyzed. A total of 120 genes associated with drugs used in Berlin-Frankfurt-Münster protocols were selected. Variants were annotated and filtered using bioinformatic quality-control criteria, and allele frequencies were compared with African, Admixed American, East Asian, European, and South Asian populations from the 1000 Genomes Project. Multidimensional scaling was used to assess population-level genetic similarity. RESULTS: After quality control, 648 variants were identified. Twenty-eight variants were observed exclusively in the Indigenous study population, including four nonsynonymous coding variants with moderate predicted impact. Significant allele-frequency differences were observed for ADA rs11555566, CBR3 rs881711, and CYP2B6 rs3745274; rs881711 and rs3745274 differed from all five reference populations. Multidimensional scaling showed a distinct Indigenous pharmacogenomic profile, with greater similarity to the Admixed American population. CONCLUSIONS: Amazonian Indigenous populations exhibit substantial pharmacogenomic diversity in genes relevant to Berlin-Frankfurt-Münster-based therapy. These findings identify candidate variants for functional and clinical validation and reinforce the importance of including underrepresented populations in pharmacogenomic research.

Acute lymphoblastic leukemia↗

PubMed2025

High-grade gliomas derived from an ovarian mature teratoma: clonal dynamics and genetic insights.

UNLABELLED: High-grade glioma (HGG) arising from a mature ovarian teratoma is extremely rare and its genetic alterations remain largely unknown. We report a case of WHO Grade 4 HGG (HGG-G4) developing 3 years after cystectomy for ovarian mature teratoma, where a WHO Grade 3 HGG (HGG-G3) was identified upon pathological reevaluation. Whole-exome sequencing confirmed the clonal relationship between HGG-G3 and HGG-G4, revealing genome-wide copy-neutral loss of heterozygosity, copy-number alterations, and whole-genome doubling in both HGGs. Genomic and epigenetic analyses have suggested multistep tumorigenesis and clonal alteration during the clinical course, particularly in response to chemotherapy, in HGGs arising from ovarian teratomas. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13691-025-00790-x.

High-grade glioma↗

PubMed2025

Peripheral Macular Endothelial Dystrophy: Clinical, Histopathologic, Genetic and Functional Characterization.

OBJECTIVE: To report a CHST6-associated corneal endothelial dystrophy. DESIGN: Prospective observational case series. PARTICIPANTS: Thirty-five individuals from seven families, including 13 affected individuals exhibiting corneal epithelial and stromal edema, peripheral posterior corneal macular opacities, and endothelial guttae, as well as 22 unaffected family members. METHODS: Whole-exome sequencing was performed in 3 families and Sanger sequencing of CHST6 was performed in all individuals. Histological examination of Descemet membrane (DM) excised at the time of endothelial keratoplasty was performed for three probands. Serum keratan sulfate (KS) levels were measured in members of six families. Functional analysis of identified mutations was performed using CHST6 promoter containing CHST6 expression vector in human keratocytes (HK) and corneal endothelial cells (HCEnC). MAIN OUTCOME MEASURES: Clinical phenotype; genetic analysis; functional analysis of identified CHST6 mutations; serum KS levels; histologic examinations of DM. RESULTS: All affected individuals demonstrated peripheral macular opacities at the level of DM. Visually significant corneal edema in affected individuals was successfully managed by endothelial keratoplasty. Genetic analysis demonstrated a rare CHST6 promoter mutation (c.-690G>C) in the homozygous state in affected individuals from three families and in the compound heterozygous state with a CHST6 coding mutation (p.R211Q, p.Y268C or p.P280L) in affected individuals from the other four families. In silico analysis predicted c.-690G>C to be a regulatory variant, located at the RNA polymerase II binding site. Functional analysis in vitro demonstrated that c.-690G>C leads to increased KS sulfation in the corneal endothelium and DM, with no change of KS sulfation in keratocytes. Histologic examination of DM from affected individuals revealed elevated levels of sulfated and non-sulfated KS in DM and endothelium, consistent with the functional analysis. Minimum changes in serum sulfated KS levels were observed in affected individuals. CONCLUSIONS: We suggest the name Peripheral macular endothelial dystrophy (PMED) to describe this dystrophy that is characterized by peripheral posterior corneal macular opacities and endothelial dysfunction without stromal haze or opacities. Given that both PMED and macular corneal dystrophy are associated with promoter and coding region mutations in CHST6, we propose that they be categorized as CHST6-associated corneal dystrophies.

Humans↗

PubMed2026

Dental phenotypes associated with novel PHEX variants in X-linked hypophosphatemia.

OBJECTIVES: X-linked hypophosphatemia (XLH) is a genetic disorder related to bone, mainly due to the mutations in PHEX gene. Previous studies have reported that XLH patients had various tooth phenotypes. It is unclear whether there are any rules about these abnormal tooth phenotypes, especially in those XLH cases with PHEX mutations. The objectives of this study were to find the most representative dental characteristics of XLH and the possible phenotype-genotype correlation. DESIGN: Two unrelated patients with XLH underwent clinical, radiographic, biochemical, and genetic evaluation. Whole-exome sequencing and whole-genome sequencing were used to identify pathogenic variants. The ultrastructure of extracted teeth was analyzed using a stereomicroscope, micro-CT, and scanning electron microscopy. In addition, a PubMed search (up to January 2026) identified 22 articles involving 366 patients for descriptive phenotype comparison. RESULTS: Two novel PHEX variants were identified: a novel complex structural variant (NC_000023.11, g.22035649-22041668delins) and a novel heterozygous splice-site variant (NM_000444.6, c.850-1 G>A). Radiographic examination showed enlarged pulp chambers and irregular pulp morphology. Ultrastructural analysis revealed dentin defects, including globular dentin, irregular interglobular dentin, disrupted dentinal tubules, and exposed collagen fibrils. Literature-based analysis indicated prevalent clinical manifestations (pulp necrosis, tooth loss, periodontitis) and radiographic findings (enlarged pulp chamber, and prominent pulp horn). CONCLUSION: In these two patients, novel PHEX variants were associated with a recurrent dentin-pulp phenotype. Integrated clinical, radiographic, ultrastructural, and literature evidence supports dentin defects as a central component of the dental phenotype in XLH and underscores the importance of early dental assessment.

Humans↗

PubMed2026

Clinical and Genomic Characteristics of Mexican Patients with Early Onset Gastric Adenocarcinoma.

BACKGROUND: Gastric cancer is a leading cause of cancer-related deaths in Mexico, with a rising incidence of early onset gastric cancer (EOGC) in young adults. This single-center study aimed to describe the clinical and mutational characteristics associated with EOGC in Mexican patients, based on an age cutoff of 50 years. METHODS: Clinical information was retrieved from electronic records and compared between EOGC and late-onset gastric cancer (LOGC). Whole exome sequencing data from 50 patients were analyzed and compared between both groups to elucidate the genomic overview of EOGC. RESULTS: Clinical data from 2,034 patients were analyzed. Of those, 35.69% had EOGC, with higher proportions of women (52.50%), diffuse histology (74.38%), signet ring cells (79.90%), and advanced stages (IVB: 79.58%; all p <0.001). Multivariate analysis in young patients identified ECOG (hazard ratio [HR]: 1.49) and clinical stage (HR: 1.78) as independent prognostic factors that increased mortality risk. However, the presence of Helicobacter pylori (HR: 0.76) and participation in genetic counseling (HR: 0.61) were independent prognostic factors that decreased the mortality risk. The molecular profile of Mexican patients demonstrated a high prevalence of CDH1 mutations and SBS44 mutational signatures. CONCLUSION: Mexican patients demonstrated higher rates of EOGC compared to other ethnicities. Genetic counseling enhances the overall survival of patients with EOGC; efforts should be made to incorporate it into routine practice. Molecular profiling revealed high CDH1 and SBS44 prevalence; however, sample size limitations warrant caution.

Humans↗

PubMed2026

A recurrent CCDC82 frameshift variant associated with syndromic neurodevelopmental disorder in a consanguineous Pakistani family.

BACKGROUND: Intellectual disabilities (IDs) are part of neurodevelopmental disorders (NDDs) and are genetically heterogeneous conditions characterized by impairments in cognition, learning, and adaptive functioning. Despite advances in gene discovery, many individuals, particularly those from understudied populations, remain without a molecular diagnosis. Recent reports implicate CCDC82 (HGNC: 26282) as an autosomal recessive ID gene, although the phenotypic spectrum and biological context remain incompletely defined. METHODS: Exome sequencing (ES) was performed in a consanguineous Pakistani family (PKMR06A) with four affected individuals presenting with moderate to severe ID. Variant segregation was confirmed by Sanger sequencing. In silico analyses, including pathogenicity prediction, protein structural modeling, and domain intolerance assessment, were used to evaluate the functional consequences of the identified variant. Spatiotemporal gene expression patterns were examined using bulk and single-cell human brain transcriptomic datasets. RESULTS: Clinically, affected individuals of family PKMR06A presented with early childhood global developmental delay, speech delay, hypotonia, gait abnormalities, spasticity, and mild facial dysmorphism. Genetic screening revealed a recurrent rare homozygous frameshift variant in CCDC82 (NM_024725.4): c.373del; p.(Asp125Ilefs*6), segregating with disease in all available affected individuals of the family. The identified c.373del variant was absent from the gnomAD database and was classified as pathogenic (PVS1, PM2, and PP1) based on ACMG/AMP criteria. The c.373del variant is predicted to introduce a premature termination codon, p.(Asp125Ilefs*6), leading to deletion of essential coiled-coil domains from the encoded protein, supporting a loss-of-function mechanism. In silico, transcriptomic analyses demonstrated preferential CCDC82 expression during prenatal human brain development, providing developmental context for the neurodevelopmental phenotype associated with the identified truncating variant. CONCLUSIONS: This study expands the mutational landscape of CCDC82 and provides additional clinical and molecular evidence supporting its role in autosomal recessive NDD. The findings reinforce the importance of CCDC82 in human neurodevelopment and highlight the value of genomic investigation in underrepresented populations.

Autosomal recessive↗

PubMed2026

Novel splice site variants in GBA1 are associated with Gaucher disease and genotype-phenotype correlations.

BACKGROUND: Variants in GBA1 are associated with neurodegenerative disease. This study aimed to explore pathogenic GBA1 variants. METHODS: Four patients with progressive myoclonic epilepsy (PME) and extremely low β-glucosidase levels were recruited. Whole-exome sequencing and long-range PCR were performed to identify GBA1 variants. Bioinformatic analyses were used to predict the impact of the identified variants. A literature review was performed to explore the genotype-phenotype correlations. GBA1 expression data across different brain regions and developmental stages were analyzed using the BrainSpan database. RT-PCR was performed to verify the splicing effects. RESULTS: Compound heterozygous GBA1 variants were identified in four patients. Five distinct variants were detected, including two novel splice site variants (c.308-2A>G and c.762-2A>C) and three previously reported variants. All identified variants were rare or absent in gnomAD. Splice site variants c.308-2A>G and c.762-2A>C were predicted to cause aberrant splicing. Minigene-based splicing assays coupled with RT-PCR and Sanger sequencing confirmed that both variants cause complete exon skipping (exon 4 and exon 7, respectively). All patients presented with PME onset in childhood/adolescence, intellectual regression, low β-glucosidase, and diffuse brain atrophy and were subsequently diagnosed with Gaucher disease type 3. GBA1 expression in the brain showed two distinct peaks: one in infancy and another after five years of age. The onset age of PME aligned with the second GBA1 expression peak (after five years of age). CONCLUSION: This study identified compound heterozygous GBA1 variants, including two novel candidate pathogenic splice site variants, in Gaucher disease type 3 patients, expanding the known mutational spectrum.

Humans↗

PubMed2026

A novel PKHD1 missense variant disrupting splicing in a fetus with Caroli disease.

BACKGROUND: Caroli disease (CD) is a rare inherited disorder characterized by dilatation of intrahepatic bile ducts, and prenatal diagnosis of this disease is extremely rare. PKHD1 is the only known causative gene, yet the pathogenicity of most missense variants remains unclear. METHODS: Exome sequencing (ES) was performed on a fetus with clinical features of CD. Candidate variants were validated by Sanger sequencing in the family. The impact of the novel missense variant on pre-mRNA splicing was assessed using minigene assays, and structural modeling of the PKHD1 protein was conducted with AlphaFold 3. RESULTS: At 23 weeks of gestation, the fetus showed hepatic cysts on ultrasound and a "central dot" sign on MRI, suggesting a diagnosis of CD. The fetus also exhibited features of autosomal recessive polycystic kidney disease and oligohydramnios. ES identified and Sanger sequencing confirmed three PKHD1 variants: a paternal nonsense variant c.5323C>T; p.(Arg1775*), and two maternal missense variants c.6682G>C; p.(Glu2228Gln) and c.8012G>T; p.(Arg2671Leu). The variant c.6682G>C is novel and minigene assays demonstrated that it caused exon 40 skipping, leading to an in‑frame deletion (c.6491_6682del; p.(Gly2164_Arg2227del)). Structural modeling predicts that this deletion lies within a large β‑barrel domain and may compromise its structural stability. Conclusion We characterize a novel missense variant that causes aberrant splicing of PKHD1 in CD. This finding underscores the necessity of functional analysis for evaluating the pathogenicity of missense variants, especially those at the last nucleotide of an exon. Our study expands the mutation spectrum of PKHD1 and provides insights into genotype‑phenotype correlations.

Humans↗

PubMed2024

Critically unwell infants and children with mitochondrial disorders diagnosed by ultrarapid genomic sequencing.

PURPOSE: To characterize the diagnostic and clinical outcomes of a cohort of critically ill infants and children with suspected mitochondrial disorders (MD) undergoing ultrarapid genomic testing as part of a national program. METHODS: Ultrarapid genomic sequencing was performed in 454 families (genome sequencing: n = 290, exome sequencing +/- mitochondrial DNA sequencing: n = 164). In 91 individuals, MD was considered, prompting analysis using an MD virtual gene panel. These individuals were reviewed retrospectively and scored according to modified Nijmegen Mitochondrial Disease Criteria. RESULTS: A diagnosis was achieved in 47% (43/91) of individuals, 40% (17/43) of whom had an MD. Seven additional individuals in whom an MD was not suspected were diagnosed with an MD after broader analysis. Gene-agnostic analysis led to the discovery of 2 novel disease genes, with pathogenicity validated through targeted functional studies (CRLS1 and MRPL39). Functional studies enabled diagnosis in another 4 individuals. Of the 24 individuals ultimately diagnosed with an MD, 79% had a change in management, which included 53% whose care was redirected to palliation. CONCLUSION: Ultrarapid genetic diagnosis of MD in acutely unwell infants and children is critical for guiding decisions about the need for additional investigations and clinical management.

Humans↗