Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Pathogenic variant”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 469 records · Page 26Linked to original sources
PubMed2026

Genomic Sequencing in Neonatal Encephalopathy and Suspected Hypoxic-Ischaemic Encephalopathy: A Systematic Review.

BACKGROUND: Neonatal encephalopathy (NE) is a major cause of neonatal mortality and long-term neurological disability. Although hypoxic-ischaemic encephalopathy (HIE) is the most common cause, several genetic disorders may mimic or coexist with hypoxic-ischaemic injury. Next-generation sequencing has emerged as a promising diagnostic tool in this setting. This systematic review evaluated the current evidence on genomic sequencing in NE. MATERIAL AND METHODS: A systematic review was conducted according to PRISMA 2020 guidelines and prospectively registered in PROSPERO. PubMed/MEDLINE, Embase, and Scopus were searched from inception to June 2026. Eligible studies included neonates (≤28 days) with NE, suspected or confirmed HIE, HIE mimics, or unexplained NE who underwent genomic sequencing. Whole-exome sequencing (WES), whole-genome sequencing (WGS), clinical exome sequencing (CES), rapid genomic sequencing, and targeted next-generation sequencing panels were considered. Study quality was assessed using the Newcastle-Ottawa Scale. RESULTS: Seven studies met the inclusion criteria. Considerable heterogeneity was observed regarding patient selection, sequencing strategies, and reported outcomes. Among diagnostic sequencing studies, diagnostic yield ranged from 23.5% to 53.1%. Pathogenic and likely pathogenic variants were identified in genes associated with developmental and epileptic encephalopathies, metabolic disorders, mitochondrial diseases, and neurodevelopmental syndromes, including SCN2A, KCNQ2, CACNA1A, STXBP1, PTPN11, BCOR, MMUT, COQ2, and GBE1. Genomic sequencing frequently refined or changed the initial diagnosis, improved prognostic assessment and genetic counselling, and, in selected cases, guided disease-specific treatment. One study investigated genetic susceptibility to hypoxic-ischaemic injury rather than diagnostic sequencing. CONCLUSIONS: Genomic sequencing provides clinically meaningful diagnoses in a substantial proportion of neonates with unexplained NE or atypical HIE presentations. Current evidence supports integrating genomic sequencing into the diagnostic evaluation of selected infants, although larger prospective studies are needed to define its optimal timing, clinical utility, and cost-effectiveness.

Humans↗
PubMed2026

Novel Co-Occurrence of Germline EGFR p.V843I and Somatic EGFR Exon 19 Deletion in NSCLC: Insights into Reduced Sensitivity to EGFR-TKIs.

Germline EGFR pathogenic variants (PVs) are rare and define a distinct hereditary subset of NSCLC with unique clinical characteristics. Germline EGFR p.T790M is the most frequent and best characterized, with reported sensitivity to first- and second-generation EGFR-TKIs. Yet, the response of germline EGFR variants, especially the rarer ones such as p.V843I, to osimertinib remains poorly characterized. Given the very low frequency of germline non-p.T790M variants, their clinical relevance can only be investigated via case reports. Herein, we report what is, to the best of our knowledge, the first case of advanced lung adenocarcinoma harboring a germline EGFR p.V843I variant coexisting in cis with the unusual somatic EGFR exon 19 C-helix deletion, p.S752_I759del. Additionally, a somatic TP53 variant was detected. Treatment with afatinib induced a partial response lasting only six months, as rapid disease progression occurred without identifiable acquired resistance mechanisms. Subsequently, no objective response to osimertinib or afatinib rechallenge was observed. Acquired EGFR and MET amplification were detected in corresponding rebiopsies. Overall survival was 29 months. Our findings suggest that, despite the presence of the previously reported EGFR-TKI-sensitive, EGFR p.S752_I759del, the co-occurrence of germline p.V843I may have contributed to reduced sensitivity to afatinib and osimertinib. This case expands the molecular spectrum of hereditary EGFR-mutated NSCLC and, together with our narrative review of the literature, supports an emerging model in which germline EGFR PVs may act both as tumor-predisposing events and as potential mechanisms of early resistance to EGFR-TKIs.

Humans↗
PubMed2026

From the Microscope to the Genome: A New Era in the Molecular Genetics of Epidermolysis Bullosa.

Epidermolysis bullosa (EB) is a heterogeneous group of inherited disorders characterised by skin fragility, caused by pathogenic variants in genes encoding structural components of the dermo-epidermal junction. With the advent of next-generation sequencing (NGS), the diagnostic paradigm has shifted from a morphological to a genotype-oriented approach. This review summarises the genetic architecture of EB, the types of mutations and genotype-phenotype relationships, the challenges in interpreting variants of unknown significance (VUS), and therapeutic strategies targeting specific mutational mechanisms, including read-through approaches, exon skipping and genome editing. The role of modifier genes and epigenetic factors in clinical variability is also discussed. The focus is on the translational potential of genomics for personalized therapy in EB. Overall, this review synthesizes the molecular basis of all four major EB types across 16+ classical genes, highlights the paradigm shift where NGS achieves a diagnostic yield exceeding 90%, and critically assesses recent therapeutic milestones-ranging from the first FDA-approved topical gene therapy to precision RNA and genome-editing modalities.

Humans↗
PubMed2026

Genetic Heterogeneity of Inborn Errors of Immunity Revealed by Whole-Genome Sequencing: Insights from a Russian Patient Cohort.

Identifying genetic cause(s) is a key step for management and treatment of patients with inborn errors of immunity (IEI). Here, in an observational cross-sectional genomic study, we analyzed whole-genome sequencing (WGS) data of 72 IEI patients from Saint Petersburg and Northwestern Russia: 42 patients with common variable immunodeficiency (CVID)-like phenotypes, 6 patients with clinically diagnosed X-linked agammaglobulinemia (XLA or Bruton's disease), and 24 patients with other forms of IEI. Causative pathogenic and likely pathogenic variants in BTK, CYBB, CHD7, AIRE, ATM, SBDS, NFKB1, and CTLA4 genes were identified in 14 (19%) patients. Variants of uncertain significance that could be linked to observed clinical phenotypes were detected in 6 patients. These included a BTK variant in a patient with Bruton's disease, variants in SH2D1A, SOCS1, and IKBKB in patients with CVID, and variants in CARD11 and CD40LG in patients with other forms of IEI. Additional rare variants that were mostly unique to individual patients were found in multiple IEI genes from the International Union of Immunological Societies (IUIS) Expert Committee 2024 list. In the CVID-like subcohort, pathway-level analysis of these rare variants revealed patterns associated with clinical manifestations. Taken together, our results expand the genetic characterization of an understudied regional IEI cohort, particularly of patients with CVID-like phenotypes, and identify genetic factors that are implicated in or may contribute to the disease.

Humans↗
PubMed2026

Hyper-IgE syndromes in pediatrics: clinical spectrum, differential diagnosis, and management.

Hyper-IgE syndromes (HIES) are rare inborn errors of immunity (≈1 per million) caused by pathogenic variants in STAT3, DOCK8 or IL6ST. They present with very high serum immunoglobulin E (IgE), recurrent bacterial or fungal infections, eczema and characteristic organ involvement. The autosomal dominant STAT3-deficient form features early-onset eczema, “cold” abscesses, recurrent pneumonias with pneumatoceles and skeletal or dental anomalies. Autosomal recessive forms such as DOCK8 or PGM3 deficiency show a more severe phenotype with viral skin infections, allergy, asthma and increased malignancy risk. HIES should be suspected in children with IgE >2000 IU/mL plus recurrent sinopulmonary or skin infections, severe eczema, atypical viral infections or a National Institutes of Health Hyper-IgE Syndrome (NIH HIES) score >40. Differentiation from severe atopic dermatitis, asthma, eosinophilic disorders and parasitic infections is essential. Evaluation includes eosinophils, lymphocyte subsets, T-helper 17 (Th17) cell analysis and targeted genetic testing. Management involves antimicrobial prophylaxis, treatment of complications, dermatologic care and genotype-based hematopoietic stem cell transplantation (HSCT), which is curative in DOCK8 but less effective in STAT3 deficiency. Early genomic confirmation enables timely recognition, identification of red flags, and genotype-specific therapy to improve long-term outcomes.

Humans↗
PubMed2025

[Achievements and Expectations of the Rare Disease Diagnostic Support Program in the Republic of Korea].

OBJECTIVES: The Rare Disease Diagnostic Support Program in the Republic of Korea aims to improve early diagnosis and diagnostic yield for patients with rare diseases, particularly for those residing in non-metropolitan areas, by providing whole genome sequencing (WGS) services through regional medical institutions. This study evaluated the performance of the program, focusing on its clinical utility, including early diagnosis and treatment linkage, and its policy impact related to patient benefits. METHODS: From August 2024, WGS was performed on 410 patients with suspected rare diseases at 23 institutions outside the metropolitan area. A one-stop diagnostic pathway was established to perform sample collection, test referral, report delivery, and genetic counseling within a single clinical flow based on the patient’s location of residence. Sequencing was performed by external laboratories. RESULTS: Among the 410 patients, pathogenic variants were identified in 129 (31.5%), with a turnaround time of 28 days. Of those diagnosed, 78.2% received treatment benefits via national programs such as co-payment exemption and medical expense support programs. Approximately 30% of the patients were eligible for therapeutic intervention, particularly medication or dietary therapy. Family genetic testing of three members identified potential carriers or high-risk groups in 28 households (65.1%). Consent for secondary findings was 99.0%, with clinically significant variants found in 3.9% of cases. CONCLUSIONS: The program demonstrated clinical value by improving diagnostic accessibility, reducing regional disparities, facilitating timely treatment, and supporting preventive care through family risk identification. These findings support the need for sustainable expansion of genome-based diagnostic services in the national health policy.

Diagnosis↗
PubMed2026

Combinatorial base editing couples disease correction with lineage amplification in hematopoietic stem and progenitor cells.

First-generation genome editing therapies have largely focused on correcting or compensating for pathogenic variants. However, as these approaches enter the clinic, emerging biological constraints limit maximal therapeutic impact. Because globin genes are activated late during erythroid differentiation, genome-corrected hematopoietic stem and progenitor cells (HSPCs) gain little selective advantage in the bone marrow. Here, we establish a strategy that links therapeutic genome edits to an erythroid fitness-enhancing allele to amplify the output of clinically relevant cells. We develop a multiplex base editing strategy that couples fetal hemoglobin (HbF) reactivation with erythroid lineage expansion. Introduction of a naturally occurring erythropoietin receptor truncation (tEPOR) associated with benign erythrocytosis increased erythroid cell production without impairing viability or differentiation. Combinatorial editing of tEPOR together with the BCL11A erythroid enhancer and HBG1/2 promoters in healthy donor, sickle cell disease, and β-thalassemia HSPCs synergistically increased erythroid proliferation and HbF expression beyond single base-edited or Casgevy-treated controls. Multiplex base-edited HSPCs retained long-term lineage repopulation and engraftment capacity in vivo, establishing a modular strategy that pairs disease correction with lineage amplification to improve therapeutic potency.

Journal Article↗
PubMed2026

Complementary vertebrate Wac models exhibit phenotypes relevant to DeSanto-Shinawi Syndrome.

Monogenic syndromes are associated with neurodevelopmental changes that result in cognitive impairments and neurobehavioral phenotypes, including autism and seizures. Limited studies and resources are available to make meaningful headway into the underlying molecular mechanisms that result in these symptoms. One such example is DeSanto-Shinawi Syndrome (DESSH), a rare disorder caused by pathogenic variants in the WAC gene. Individuals with DESSH syndrome exhibit a recognizable craniofacial gestalt, developmental delay/intellectual disability, neurobehavioral symptoms that include autism, ADHD, behavioral difficulties, and seizures. However, no thorough studies from a vertebrate model exist to understand how these changes occur. To overcome this, we developed both murine and zebrafish Wac/wac deletion mutants and studied whether their phenotypes recapitulate those described in individuals with DESSH syndrome. We first show that the two Wac models exhibit craniofacial and behavioral changes, reminiscent of abnormalities found in DESSH syndrome. In addition, each model revealed impacts on GABAergic neurons and further studies showed that the mouse mutants are susceptible to seizures, changes in brain volumes that are different between sexes and relevant behaviors. Finally, we uncovered transcriptional impacts of Wac loss-of-function in mice that will pave the way for future molecular studies into DESSH. These studies present two new vertebrate models that begin to uncover biological underpinnings of DESSH syndrome and elucidate the biology of Wac.

Animals↗
PubMed1999

Pronounced intraspecific haplotype divergence at the RPP5 complex disease resistance locus of Arabidopsis.

In Arabidopsis ecotype Landsberg erecta (Ler), RPP5 confers resistance to the pathogen Peronospora parasitica. RPP5 is part of a clustered multigene family encoding nucleotide binding-leucine-rich repeat (LRR) proteins. We compared 95 kb of DNA sequence carrying the Ler RPP5 haplotype with the corresponding 90 kb of Arabidopsis ecotype Columbia (Col-0). Relative to the remainder of the genome, the Ler and Col-0 RPP5 haplotypes exhibit remarkable intraspecific polymorphism. The RPP5 gene family probably evolved by extensive recombination between LRRs from an RPP5-like progenitor that carried only eight LRRs. Most members have variable LRR configurations and encode different numbers of LRRs. Although many members carry retroelement insertions or frameshift mutations, codon usage analysis suggests that regions of the genes have been subject to purifying or diversifying selection, indicating that these genes were, or are, functional. The RPP5 haplotypes thus carry dynamic gene clusters with the potential to adapt rapidly to novel pathogen variants by gene duplication and modification of recognition capacity. We propose that the extremely high level of polymorphism at this complex resistance locus is maintained by frequency-dependent selection.

Amino Acid Sequence↗
PubMed2001

[Determination of the type and subtype of the hepatitis C virus in chronic viral hepatitis patients in Hungary].

The huge variability of hepatitis virus C is well-established. The geographical differences in its nucleotide sequence have important clinical significance by causing variant pathogenicities and affecting sensitivity to therapy. The authors pioneered the determination of the viral type and subtype in patients suffering from chronic viral hepatitis in Hungary. In this present work they report the applied methods and the results. In their virus serological laboratory was introduced the test "HCV Serotyping 1-6 Assay", which is based on the analysis of antibodies, in 1996. By this method they examined the samples of 127 patients and they found type 1 in 75.5%, type 4 in 25%, mixed types (type 1 + 2, 3, 4, 5, 6) in 9% and non-classifiable, non-reacting antibodies in 13% of the cases. Since 1999 they have used the combination of direct reverse-PCR of the viral antigen and reverse hybridization to type-specific specimens. These results, from 211 patients show that 6% belong to 1a, 85.5% to 1b, 3% to 1a + 1b, 1% to 1b + 2, 0.5% to 3 and 4% to mixed subtypes. Genotype 1b was associated with higher viremia. On the basis of the above they can conclude that 90% of the Hungarian population are infected by the most resistant 1b subtype of hepatitis virus C. It could explain the fact that only 20% of their patients with interferon monotherapy have become permanently virus-free. In view of these results they recommend combined, higher dose, long-lasting treatment in therapeutic protocols.

Adult↗
PubMed2004

Evidence of rickettsial and leptospira infections in Andean northern Peru.

Between May and October 2002, a cluster of acute febrile illnesses occurred in the subtropical Andean foothills of Peru. Serologic evidence in villages where disease had been documented showed that the prevalence of IgM antibody to Leptospira ranged from 6% to 52%, that of IgM antibody to spotted fever group (SFG) rickettsia ranged from 10% to 19%, and that of IgM antibody to Coxiella burnetii from 1% to 15%. Measurement of IgG antibodies for SFG rickettsiae suggested that this disease was endemic. In contrast, IgG antibodies against C. burnetii were largely absent. In humans, microagglutination tests identified pathogenic variants of Leptospira. The presence of an SFG rickettsial infection was confirmed in four febrile patients following polymerase chain reaction and sequencing of the conserved 17-kD common antigen gene (htrA). Collectively, these analyses indicated that Rickettsia sp., C. burnetii, and Leptospira sp. were circulating in the region during the time of disease outbreak and implicate the involvement of an as yet undetermined SFG rickettsia in northwestern Peru.

Adolescent↗
PubMed1990

Spread of herpes simplex virus (HSV) strains SC16, ANG, ANGpath and its glyC minus and GlyE minus mutants in DBA-2 mice.

Herpes simplex virus type 1 (HSV-1) strains SC16, ANG, its pathogenic variant ANGpath and the mutants ANG-pathgC18 glycoprotein C (glyC) negative and ANGpathI2-4 (glyE negative) were compared for their ability to spread in DBA-2 mice after peripheral inoculation. Virus infectivity assay in 9 organs at days 2, 3, 4, 5, 6, and 10 post-infection (p.i.) and morphologic examinations (immunofluorescence, PAP staining) showed the following: SC16, ANG, and ANGpath spread first (days 2-3 p.i.) by haematogenic route to spleen, liver, and adrenal gland. Since day 4 the invasion of the vegetative and peripheral nervous system took place in SC16 and ANGpath-infected mice, followed by virus spread to the spinal cord and brain stem. In ANG-infected mice the invasion of peripheral nervous system was minimal although both ANG as well as ANGpath spread along the axons. In ANG pathC18-infected mice a relatively prolonged viraemic phase (days 2-4 p.i.) represented with foci of virus antigen-containing cells in spleen, liver, and mesenterial connective tissue was accompanied with a low grade invasion of the peripheral nervous system (days 3-4 p.i.). No spread by any route of ANGpathI2-4 was observed after intraperitoneal inoculation. When comparing ANGpath and SC16, the latter seemed slightly more lethal, since ANGpath killed 67.2% of DBA-2 mice which were given 2 X 10(6) PFU/0.1 ml by i.p. route as compared to the 100% lethality of SC16-infected animals.

Animals↗
PubMed1978

[Characterization of plasmid DNA in a lecithinase-positive and in a lecithinase-negative strain of Clostridium perfringens (author's transl)].

A non pathogenic variant of Clostridium perfringens and the wild type strain were characterized. The strains agreed in most of the biochemical properties, in susceptibility against antibiotics and in bacteriocin production. Contrary to the wild type the variant did not produce lecithinase and gelatinase. In deoxyribonucleic acid (DNA) of both strains centrifuged in cesiumchlorid-ethidiumbromide equilibrium there was found a satellite peak containing three distinct, covalently closed circular (CCC) DNA elements. The sum of the average molecular weight or contour length of the two small circular molecules was equal to the average molecular weight or contour length of the third. The presence of the plasmids in the variant indicated that the synthesis of lecithinase might not be coded by a plasmid.

Bacteriocins↗
PubMed1979

[Plexus paresis and smallpox vaccination (author's transl)].

Paresis of the left side upper plexus brachialis is diagnosed to a boy of 2;8 years. The trouble appeared after a smallpox vaccination, which had been carried out successfully. There are no symptoms of CNS-disturbance. serumneuritis and virogenic radiculatis are discussed as pathogenic variants. Although postvaccinal peripheral nervous lesions very seldom occur, it does seem possible that the ailment in question could be a consequence of the smallpox vaccination.

Brachial Plexus↗
PubMedDate not supplied

[Influenza virus variability and human sensitivity].

The data from the literature concerning the limited number of influenza A virus variants pathogenic for man are analysed. The possibilities of employing these theoretical concepts for improvement of the methods for virus investigations and epidemiological prognosing of epidemics, as well as the possibilities of creating a species-specific preparation for influenza A prevention are discussed.

Adult↗
PubMedDate not supplied

[Porcine reproductive and respiratory syndrome: ten years of experience (1986-1996) with this undesirable viral infection].

Porcine reproductive and respiratory syndrome (PRRS) is an infectious disease in swine that emerged 10 years ago. Today, PRRS is endemic in many if not all the pig-producing countries. The syndrome is due to a small enveloped RNA virus which belongs to the new Arteriviridae group. This group also includes the equine arterivirus and the simian hemorrhagic fever virus. The disease produces many clinical symptoms in pigs of any age but the two major features of the syndrome are respiratory and reproductive failure. An influenza-like illness is often observed consisting of a transient loss of appetite, slight hyperthermia and respiratory distress. The reproductive problems include late-term abortion, stillbirth and young piglet mortality. The virus is remarkably well adapted to its natural host. It infects almost exclusively pig monocytes or macrophages. For unexplained reasons, the virus may persist in the body for extended periods (several weeks) after an antibody immune response has been mounted. Within herds, the virus may persist for several years. In the acute phase of the infection, the immune functions of the pig may be impaired, however, a chronic immunosuppressive effect does not seem to occur thereafter. Several vaccines are available, which all have protective value against PRRS clinical disorders. None of them, however, has been tested for its ability to prevent or shorten the persistent infection in individual pigs or the long-term effect of virus circulation within herds. In the future, PRRS virus may be only an additional contaminant of farms with limited effects on profitability; however the possibility for this persistent infection to supply swine or eventually other species with new pathogenic variants must be also considered. This review provides a detailed description of the aetiology, pathology, immunology, diagnostic methods and epidemiology of PRRS.

Abortion, Veterinary↗
PubMedDate not supplied

Genetic heterogeneity and properties of hepatitis C virus.

Hepatitis C virus (HCV) is a member of the Flaviviridae family. Its genome is a positive single-stranded RNA molecule which comprises three distinct regions: a 5' non coding region, a long open reading frame encoding both the structural and non structural viral proteins, and a 3' non coding region. HCV circulates in infected individuals as complex mixtures of genetically distinct but closely related variants referred to as "quasispecies". The quasispecies nature of HCV genomes appears to play a major role in viral persistence, cell tropism of viral variants, pathogenicity and resistance to antiviral therapy.

Genetic Heterogeneity↗