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PubMed2025

Hypercalcemia and co-occurring TBX1 mutation in Glycogen Storage Disease Type Ib: case report.

Glycogen Storage Disease Type Ib (GSD-Ib) is a rare autosomal recessive metabolic disorder caused by mutations in SLC37A4, leading to a deficiency in glucose-6-phosphate translocase. This disorder is characterized by impaired glycogenolysis and gluconeogenesis, resulting in clinical and metabolic manifestations. We report a three-month-old Moroccan female patient presenting with doll-like facies, hepatomegaly, dysmorphic features, and developmental delays. Laboratory analysis revealed hypoglycemia, elevated triglyceride levels, hypercalcemia, and neutropenia. Genetic testing confirmed a homozygous pathogenic variant in SLC37A4 and a heterozygous variant of uncertain significance in TBX1. Initial management included a lactose-free and galactose-free diet, multivitamin supplementation, and granulocyte colony-stimulating factor (G-CSF) therapy to address neutropenia. A novel aspect of this case involves hypercalcemia as an unusual finding in GSD-Ib and the co-occurrence of a variant in the TBX1 gene, which is not typically associated with the disease but may contribute to the patient's clinical presentation. These findings add a new dimension to our understanding of GSD-Ib and suggest potential avenues for future research to elucidate these genetic interactions and their impact on clinical outcomes.

Humans↗
PubMed2025

Identification of a novel non-coding deletion in Allan-Herndon-Dudley syndrome by long-read HiFi genome sequencing.

BACKGROUND: Allan-Herndon-Dudley syndrome (AHDS) is an X-linked disorder caused by pathogenic variants in the SLC16A2 gene. Although most reported variants are found in protein-coding regions or adjacent junctions, structural variations (SVs) within non-coding regions have not been previously reported. METHODS: We investigated two male siblings with severe neurodevelopmental disorders and spasticity, who had remained undiagnosed for over a decade and were negative from exome sequencing, utilizing long-read HiFi genome sequencing. We conducted a comprehensive analysis including short-tandem repeats (STRs) and SVs to identify the genetic cause in this familial case. RESULTS: While coding variant and STR analyses yielded negative results, SV analysis revealed a novel hemizygous deletion in intron 1 of the SLC16A2 gene (chrX:74,460,691 - 74,463,566; 2,876 bp), inherited from their carrier mother and shared by the siblings. Determination of the breakpoints indicates that the deletion probably resulted from Alu/Alu-mediated rearrangements between homologous AluY pairs. The deleted region is predicted to include multiple transcription factor binding sites, such as Stat2, Zic1, Zic2, and FOXD3, which are crucial for the neurodevelopmental process, as well as a regulatory element including an eQTL (rs1263181) that is implicated in the tissue-specific regulation of SLC16A2 expression, notably in skeletal muscle and thyroid tissues. CONCLUSIONS: This report, to our knowledge, is the first to describe a non-coding deletion associated with AHDS, demonstrating the potential utility of long-read sequencing for undiagnosed patients. Although interpreting variants in non-coding regions remains challenging, our study highlights this region as a high priority for future investigation and functional studies.

Humans↗
PubMed2026

Neonatal Aicardi-Goutières syndrome presenting with macrophage activation syndrome-like hyperinflammation and severe congenital glaucoma: a case report.

BACKGROUND: Neonatal-onset Aicardi-Goutières syndrome (AGS) is a rare monogenic type I interferonopathy that may mimic congenital infection and can present with severe multisystem inflammation. The distinction between primary hemophagocytic lymphohistiocytosis (HLH) and AGS-associated macrophage activation syndrome (MAS)-like hyperinflammation can be challenging in neonates. CASE PRESENTATION: We report a term neonate presenting with cholestatic jaundice, a generalized blueberry muffin-like ecchymotic-purpuric rash, cytopenias, hyperferritinemia, hepatosplenomegaly, intracranial calcifications, and severe bilateral congenital glaucoma. Extensive infectious evaluation was negative. The patient fulfilled five of eight HLH-2004 criteria, consistent with a severe MAS-like hyperinflammatory phenotype. Dexamethasone and intravenous immunoglobulin had been initiated at the referring center for presumed virus-associated HLH but were not continued after transfer to our unit. With persistent disease activity, negative microbiological studies, and neuroimaging strongly suggestive of a type I interferonopathy, ruxolitinib was initiated on day of life (DOL) 34 before molecular confirmation. Exome sequencing subsequently identified homozygous pathogenic variants in RNASEH2B and CYP1B1, supporting AGS type 2 and primary congenital glaucoma (glaucoma 3 A), respectively. Serial laboratory data showed sustained improvement after initiation of JAK1/2 inhibition, although the observational nature of a single case and other immunomodulatory exposures limit causal attribution. CONCLUSIONS: This case illustrates the clinical overlap between neonatal AGS and MAS-like hyperinflammation, underscores the potential role of early mechanism-based therapy in selected critically ill neonates with suspected interferonopathy, and emphasizes the importance of comprehensive genomic evaluation when severe ocular disease accompanies AGS. The identified CYP1B1 variant provides a strong molecular explanation for the patient's congenital glaucoma.

Humans↗
PubMed2025

Significance of GNAS mutations for morbid obesity in children.

BACKGROUND: Hereditary forms of obesity are characterized by early severe heterogeneous manifestations of the phenotype along with a rapid progression to morbid obesity, primary due to pathogenic variants of certain genes. Most forms are characterized by moderate to severe neuropsychic developmental delays, dysmorphic features and organ-specific developmental anomalies. RESULT: We searched for hereditary causes of morbid obesity in children by exome sequencing. As a result, we have identified 5 variants in the GNAS locus, two of which were identified for the first time: NM_000516.7(GNAS):c.201del, (p.Phe68Leufs*32) and NM_000516.7(GNAS):c.586 - 18_591del. Children showed tolerance to parathyroid hormone and thyroid-stimulating hormone. It has been observed that almost all the children with frameshift variants or nonsense mutations presented with subcutaneous ossifications. CONCLUSIONS: The search for variants in a group of patients with morbid obesity, as conducted in our research, reaffirms the need for use molecular genetic testing to determine the main diagnosis and facilitate early detection of the disease. This is particularly relevant given the wide clinical variability of monogenic forms of obesity.

Humans↗
PubMed2005

A clinic-based study of the LRRK2 gene in Parkinson disease yields new mutations.

Referral-based studies indicate that a mutation (G2019S) in exon 41 of the LRRK2 gene might be a common cause of Parkinson disease (PD). The authors sequenced leucine-rich repeat kinase 2 (LRRK2) exons 31, 35, and 41 in 371 consecutively recruited patients with PD and found mutations in six (1.6%) subjects, including two heterozygous for new putative pathogenic variants (R1441H, IVS31 + 3A-->G). These data confirm the important contribution of LRRK2 to PD susceptibility in a clinic-based population.

Aged↗
PubMed2006

Idiopathic generalized epilepsy phenotypes associated with different EFHC1 mutations.

We sequenced 61 patients with various idiopathic generalized epilepsy (IGE) syndromes for mutations in the EFHC1 gene. We detected three novel heterozygous missense mutations (I174V, C259Y, A394S) and one possibly pathogenic variant in the 3' UTR (2014t>c). The mutation I174V was also detected in 1 of 372 screened patients with temporal lobe epilepsy. We conclude that mutations in the EFHC1 gene may underlie different types of epilepsy syndromes.

3' Untranslated Regions↗
PubMed2026

ACG Clinical Guideline: Diagnosis and Management of Adenomatous Colorectal Polyposis Syndromes.

The hereditary adenomatous colorectal polyposis syndromes are incurable, systemic, cancer risk predisposition syndromes with substantial morbidity and mortality. They differ in their mode of inheritance, age at disease onset, phenotypic expression, and cancer risk. The most common cancer risks involve the gastrointestinal tract including the colon, rectum, duodenum, ampulla, and stomach. Identifying these syndromes through personal and family history risk assessment and germline genetic testing, along with timely surgical and endoscopic management, can reduce cancer incidence and mortality. These guidelines use the Grading of Recommendations, Assessment, Development, and Evaluation methodology to provide clinical guidance on the selection of individuals who should undergo a risk assessment for a hereditary adenomatous colorectal polyposis syndrome, modality and timing of germline genetic testing, cancer risk mitigation through endoscopic and surgical interventions, and the role of chemoprevention. This document reviews the approach to genetic testing in patients with phenotypic colorectal polyposis and the impact of presymptomatic diagnosis in families with a known familial germline pathogenic variant or clinical features suggestive of a hereditary adenomatous polyposis syndrome. Management strategies for patients based on genetic test results or without genetic testing are provided. We also review colorectal and extracolonic phenotypic benign and malignant manifestations of the known hereditary syndromes with a focus on the 2 most common hereditary colorectal polyposis syndromes: familial adenomatous polyposis and MUTYH-associated polyposis. The document concludes with recommendations on polyposis and cancer risk mitigation strategies and highlights updates to management since the previous guideline was published.

Humans↗
PubMed2005

Initial conformational changes of human transthyretin under partially denaturing conditions.

Human transthyretin (TTR) is an amyloidogenic protein. The pathway of TTR amyloid formation has been proposed based on lines of evidence: TTR tetramer first dissociates into native monomers, which is shown to be a rate-limiting step in the formation of fibrils. Subsequently, the monomeric species partially unfold to form the aggregation intermediates. Once such intermediates are formed, the following self-assembly process is a downhill polymerization. Hence, tertiary structural changes within the monomers after the dissociation are essential for the amyloid formation. These tertiary structural changes can be facilitated by partial denaturation. To probe the conformational changes under the partially denaturing conditions, five independent trajectories were collected for the wild-type (WT) and its pathogenic variants at 300 and 350 K, resulting in simulations that totaled 59 ns. Under these conditions, L55P variant is more labile than the wild-type and V30M variant. We have observed that the D strand of WT-TTR is trapped in two local minima: the native conformation and the amyloidogenic fold that resembles the surface loop of residues 54-55 of L55P variant. In the tetrameric state, the F strand is bent with large separations at the F-F' interface. This strand becomes flatter in the monomeric state, which may facilitate the formation of new F-F' interface with possible prolonged hydrogen bonds and/or shift in beta-strand register in the fibril state. During the unfolding process, the anticorrelated motion between the strands H and G as well as the strands H and A pulls the H strand out of the inner sheet plane, leading to a more twisted inner sheet. Our simulation has provided important detailed structural information about the partially unfolded state of TTR that may be related to the amyloidogenic intermediates.

Amyloid↗
PubMed2026

Molecular clusters and precision medicine in pheochromocytomas and paragangliomas.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from chromaffin cells of the adrenal medulla and extra-adrenal paraganglia. Over the past two decades, the genomic characterization of PPGLs has profoundly transformed their diagnosis, classification, risk stratification, and therapeutic management. Up to 40% of PPGLs harbor germline pathogenic variants, the highest proportion among human neoplasms, and somatic driver events are identified in a substantial fraction of the remaining cases. Integrative multi-omic studies have established three main molecular clusters: a pseudohypoxic cluster driven by Krebs-cycle alterations (SDHx, FH, MDH2, DLST) and HIF-2α pathway alterations (VHL, EPAS1, EGLN1/2); a kinase-signaling cluster driven by activation of RAS/MAPK and PI3K/AKT pathways (RET, NF1, HRAS, TMEM127, MAX); and a Wnt-signaling cluster characterized primarily by MAML3 fusions. This review summarizes progress in PPGL genomics, highlighting geographic and sex-related particularities. Using EPAS1/HIF-2α and RET as paradigmatic examples, we illustrate how diverse germline, somatic, mosaic, and fusion events converge on common core signaling hubs that can be therapeutically exploited with FDA-approved selective inhibitors for relevant targets (e.g. belzutifan for HIF-2α; selpercatinib and pralsetinib for RET). We further review the genomic determinants of metastatic risk (SDHB, ATRX, TERT, and MAML3 fusions), the immune microenvironment of metastatic disease, and emerging radionuclide theranostics, liquid biopsy biomarkers, and integrative multi-omic approaches that are reshaping precision medicine for PPGLs.

Humans↗
PubMed2025

Is there are relationship between polymorphisms TSHR gene frequencies and genetic ancestry markers in patients with Primary Congenital Hypothyroidism?

The literature shows a correlation between ethnicity and pathogenic variants of the thyroid stimulating hormone receptor (TSHR) gene. Some of these polymorphisms may be risk factors for the development of primary congenital hypothyroidism (PCH). In this study, we investigated the relationship between the frequency of TSHR gene polymorphisms and the genetic influence of African, Amerindian, and European ancestry-informative markers in patients from an Amazonian population in Brazil who were diagnosed with PCH. The study was conducted on samples from 106 patients who were diagnosed with PCH. Genomic DNA was isolated from peripheral blood samples, and 10 exons from the TSHR gene were automatically sequenced. Ancestry-informative marker identification was performed using a panel of 48 markers, and the results were compared with parental Amerindian, Western European, and Sub-Saharan African populations using Structure v2.3.4 software. Four nucleotide alterations were identified among 49 patients. The distribution of tested ancestry markers among the 106 patients indicated a significant difference in the percentages of Amerindian (25.90 %), European (41.80 %), and African (32.20 %) ancestry. Logistic regression analysis revealed no significant association between the rs2075179 and rs1991517 polymorphisms and genetic ancestry. This study revealed no evidence of a relationship between polymorphic TSHR gene variants and genetic ancestry markers in patients with PCH.

Journal Article↗
PubMed2005

Molecular epidemiology of infectious bursal disease viruses: distribution and genetic analysis of newly emerging viruses in the United States.

Genetic mutations in the genome of infectious bursal disease virus (IBDV) have resulted in antigenic and pathogenic variants that continue to cause disease in commercially reared chickens. The extent of the genetic diversity among IBDV strains circulating in the United States is unknown. This study was designed to identify newly emerging viruses infecting chickens on poultry farms experiencing immune suppression-related problems. Fifty IBDV-positive samples were identified from 273 bursa samples using a real-time reverse transcription-polymerase chain reaction (RT-PCR) assay. Mutation probes were designed to the hydrophilic B coding region of the VP2 gene. Six mutation probes used in this study were based on the nucleotide sequences of the Del-E, Bursine 2, D-78, STC, G6, and T1 IBDV strains. Following real-time RT-PCR, these mutation probes identified 11 of the 50 viruses in the melting temperature (Tm) analysis. The results indicated that the remaining 39 viruses had one or more nucleotide mutations compared with the six mutation probes in this region of the VP2 gene. Thirty-eight viruses were chosen for nucleotide sequence analysis across the hypervariable region of the VP2 gene. Within this group of 38 viruses, four were identified by the mutation probes and their nucleotide sequences confirmed that real-time RT-PCR data. In the remaining 34 viruses, nucleotide mutations were observed in as many as 8 of 23 nucleotides across the hydrophilic B epitope coding region. Furthermore, every amino acid position except one between 316 and 324 had at least one substitution mutation. Phylogenic analysis placed two of the 38 viruses sequenced on branches with classic viruses and the remaining 36 viruses were placed on four distinct branches. Branches 1 and 2 contained a majority of the viruses, which were distributed across most of the major poultry-producing states in the United States. These branches contained previously characterized variant IBDV strains. Viruses in branches 3 and 4 were confined to three states and did not contain any previously characterized IBDV strains.

Animals↗
PubMed2026

A Case Report of Infantile Dopa-Responsive Dystonia Onset With Sleep Disorder Complicated With Autism Spectrum Disorder.

AIMS/BACKGROUND: Dopa-responsive dystonia (DRD) is a rare genetic disorder with complex and diverse clinical manifestations, resulting in a high rate of misdiagnosis. This case report describes an infantile case of DRD complicated by autism spectrum disorder (ASD), initially presenting with a sleep disorder. We aim to summarize its clinical manifestations, diagnostic process, treatment, and follow-up outcomes in order to improve clinical understanding of this disease. CASE PRESENTATION: A retrospective analysis was performed on a male infant who was treated at Jinhua Maternal and Child Health Care Hospital in 2020. The patient presented at one month of age with sleep disturbances, delayed motor development, and intermittent upward deviation of the eyes. Genetic testing identified two heterozygous pathogenic variants in the tyrosine hydroxylase (TH) gene. Among them, the c.738-2A>G variant was not recorded in the Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD), or 1000 Genomes Asian population databases. During follow-up, the patient was also found to have comorbid ASD. RESULTS: Genetic testing confirmed biallelic TH mutations, establishing the diagnosis of infantile DRD. The patient exhibited marked clinical response to levodopa/benserazide, though dose titration was required with growth. CONCLUSION: For infants with unexplained sleep disorder accompanied by delayed motor development, genetic testing should be performed as early as possible to facilitate the identification of the root cause and implement timely treatment. In addition, close follow-up should be conducted to detect comorbid neurodevelopmental disorders.

Humans↗
PubMed1996

Increased susceptibility to the pathogenic effects of wild-type and recombinant herpesviruses in MPS VII mice compared to normal siblings.

In previous studies, we have shown that a herpesvirus vector can transfer a therapeutic cellular gene (beta-glucuronidase) from peripheral sites of inoculation into the central nervous system in mice with a model neurodegenerative disease caused by a deficiency of this enzyme (mucopolysaccharidosis type VII, Sly disease). The vector corrects the enzymatic deficiency in transduced cells but the number of cells corrected is too low to alter the pathology of the disease. The recombinant vector virus, which has the foreign gene substituted into the viral LAT locus, had reduced pathogenicity after corneal inoculation compared to the wild-type virus from which it was derived (HSV-1 strain 17+). We therefore attempted to increase the number of corrected cells in the MPS VII brain by increasing the inoculating dose of the vector. However, the vector was acutely pathogenic in the diseased mice at doses that were non-pathogenic in normal littermates. The pathogenic effect of the vector virus in the mutants could be blocked by passive immunization with human gamma-globulin containing anti-HSV-1 antibodies on the day of infection but not when given at the peak of viral replication (day 4). However, effective protection also blocked transduction by the vector, thereby abrogating the effects of increased vector dosage. The effect was virus specific because inoculation of a high dose of a non-pathogenic variant of strain 17+ virus (1716) directly into the brains of MPS VII mice was not lethal. We found no apparent differences in the acute inflammatory response in mutant versus normal animals. These data suggest that the increased susceptibility to vector virulence was related to the overall compromised state of health of the diseased animals, which is further supported by the observations that the mutant mice are more sensitive to stress and to anesthetics than normal littermates. These findings indicate that adverse effects of gene transfer vectors for genetic diseases may not be fully apparent when tested in normal animals.

Anesthesia↗
PubMed2005

Hybrid Vibrio vulnificus.

The recent emergence of the human-pathogenic Vibrio vulnificus in Israel was investigated by using multilocus genotype data and modern molecular evolutionary analysis tools. We show that this pathogen is a hybrid organism that evolved by the hybridization of the genomes from 2 distinct and independent populations. These findings provide clear evidence of how hybridization between 2 existing and nonpathogenic forms has apparently led to the emergence of an epidemic infectious disease caused by this pathogenic variant. This novel observation shows yet another way in which epidemic organisms arise.

Animals↗
PubMed2006

Canine coronavirus highly pathogenic for dogs.

Canine coronavirus (CCoV) is usually responsible for mild, self-limiting infections restricted to the enteric tract. We report an outbreak of fatal disease in puppies caused by a pathogenic variant of CCoV that was isolated from organs with severe lesions.

Animals↗
PubMed2026

An isogenic hiPSC-derived keratinocyte model reveals CXCL10/CXCL11 inflammatory dysregulation in epidermolysis bullosa simplex.

Epidermolysis bullosa simplex (EBS) is a genetic skin disorder driven by dominant pathogenic variants in KRT5 or KRT14 genes, leading to cytoskeletal fragility in basal keratinocytes and intraepidermal blistering. No curative therapies are currently available, and the link between keratin mutations and disease mechanisms remains incompletely understood. To further investigate the inflammatory component of EBS, we used a model of hiPSC-derived keratinocytes carrying dominant KRT5 variants, alongside a genetically corrected isogenic counterpart. This approach established a direct link between the KRT5 variants and keratin aggregation, impaired proliferation, and an inflammatory phenotype. The inflammatory signature was confirmed by increased expression of IL1A and IL1B, consistent with previous observations in EBS, while CXCL10 and CXCL11 emerged as newly identified dysregulated chemokines. Their consistent increase across independent cell lines, elevated secretion, and normalization in the CRISPR-corrected isogenic cells indicate that KRT5 variants trigger a keratinocyte-intrinsic CXCL10/CXCL11 inflammatory response. Pharmacological inhibition of the IFN-γ-JAK1/2-STAT1 pathway suppressed their secretion, supporting JAK inhibition as a potential therapeutic strategy to modulate EBS-associated inflammatory dysregulation. In conclusion, this study shows that beyond structural defects, KRT5 variants establish a keratinocyte-intrinsic inflammatory phenotype in which the CXCL10 and CXCL11 axis emerges as a key disease-associated signature and a promising therapeutic target.

CXCL10/CXCL11↗
PubMed2026

Genomic and epigenomic diversity of breast cancer across Western and MENA populations: implications for precision oncology.

Breast cancer is the most common malignancy in women worldwide and is increasingly recognized as a biologically diverse disease shaped by both molecular and ancestral context. Women from the Middle East and North Africa (MENA) populations, including Saudi Arabia, often present at a younger age and with more aggressive subtypes such as HER2-positive and triple-negative breast cancer (TNBC) compared with Western cohorts. These clinical patterns reflect a distinctive genomic background marked by high consanguinity, founder mutations in key susceptibility genes, and population-specific somatic alterations that are not fully captured in global reference datasets. This review brings together current evidence on somatic, germline, transcriptomic, and epigenomic diversity in breast cancer across Western and MENA populations, with a focus on Saudi cohorts. Drawing on a previously published systematic review of more than 2,500 MENA breast cancer cases, TP53 accounted for approximately 24% and PIK3CA for roughly 10% of curated somatic mutation records pooled across 44 studies (proportions of mutation calls, not per-patient prevalence); in a separate single-center Saudi cohort, only 3.7% of patients underwent BRCA testing, and 37.5% of this clinically selected, testing-referred subgroup carried a pathogenic variant, a figure that should not be read as general-population BRCA prevalence. Variants of uncertain significance exceeded 20% across several regional genomic studies. We summarize conserved driver events, such as recurrent TP53 and PIK3CA mutations, while highlighting regional features, including unique stop-gain and loss-of-function variants, a high copy-number burden, and early-onset disease linked to ancestral architecture. We also discuss emerging data on MENA-specific regulatory signatures, including immune-enriched and basal-myo transcriptomic clusters, CIMP-like methylation patterns, and non-coding RNA networks; these associations are numerically suggestive in available cohorts but have not reached statistical significance in existing studies and warrant validation in larger, dedicated MENA/Saudi cohorts before being considered established determinants of treatment response and resistance. Finally, we examine the clinical implications of this diversity for biomarker development, pharmacogenomics, and access to targeted therapies, and outline practical steps toward ancestry-aware precision oncology in the region.

BRCA↗
PubMed2023

Retinal Phenotyping of a Murine Model of Lafora Disease.

Lafora disease (LD) is a progressive neurologic disorder caused by biallelic pathogenic variants in EPM2A or EPM2B, leading to tissue accumulation of polyglucosan aggregates termed Lafora bodies (LBs). This study aimed to characterize the retinal phenotype in Epm2a-/- mice by examining knockout (KO; Epm2a-/-) and control (WT) littermates at two time points (10 and 14 months, respectively). In vivo exams included electroretinogram (ERG) testing, optical coherence tomography (OCT) and retinal photography. Ex vivo retinal testing included Periodic acid Schiff Diastase (PASD) staining, followed by imaging to assess and quantify LB deposition. There was no significant difference in any dark-adapted or light-adapted ERG parameters between KO and WT mice. The total retinal thickness was comparable between the groups and the retinal appearance was normal in both groups. On PASD staining, LBs were observed in KO mice within the inner and outer plexiform layers and in the inner nuclear layer. The average number of LBs within the inner plexiform layer in KO mice were 1743 ± 533 and 2615 ± 915 per mm2, at 10 and 14 months, respectively. This is the first study to characterize the retinal phenotype in an Epm2a-/- mouse model, demonstrating significant LB deposition in the bipolar cell nuclear layer and its synapses. This finding may be used to monitor the efficacy of experimental treatments in mouse models.

Mice↗