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PubMed1973

Comparison of the rhamnomannans from the human pathogen Sporothrix schenckii with those from the Ceratocystis species.

Rhamnomannans from several isolates of Sporothrix schenckii and Ceratocystis species were compared. No major differences emerged in the analysis of the carbohydrate composition of polysaccharides from either species. Methylation analysis for the identification of the glycosidic linkages present in the polysaccharides showed that they all were very similar with minor differences being observed among strains and between polysaccharides obtained at 25 and 37 C. Partially methylated derivatives were identified by gas-liquid chromatography and mass spectrometry. Their proportions suggest that polysaccharides from S. schenckii and C. stenoceras have a general structure similar to that of C. ulmi: a (1 --> 6)-linked alpha-d-mannopyranosyl main chain substituted in the 3-positions by alpha-l-rhamnopyranosyl and in many cases by alpha-l-rhamnopyranosyl (1-->2)-l-rhamnopyranosyl side chains. Differences among polysaccharides resided in the proportions of the dirhamnosyl side chains and of 4-O-substituted and 2, 4-di-O-substituted mannose units. Increased proportions of dirhamnosyl side chains were observed in the polysaccharides from S. schenckii strains and from a pathogenic variant of C. stenoceras grown at 25 C. Proton magnetic resonance spectra (H-1 region) of the rhamnomannans showed that S. schenckii strains could be placed in two different groups similar but not identical to any Ceratocystis species. These spectra were very close to those of the polysaccharides from the C. clavata and C. ambrosia groups of Ceratocystis species.

Ascomycota↗
PubMed1989

Requirement of the single base insertion at the 3' end of the env-related gene of Friend spleen focus-forming virus for pathogenic activity and its effect on localization of the glycoprotein product (gp55).

In order to obtain evidence for the essential role of the single base insertion occurring at the 3' end of the env-related gene of Friend spleen focus-forming virus (SFFV) encoding the leukemogenic glycoprotein (gp55) a mutant SFFV genome was constructed in which the segment of the gp55 gene of the polycythemia-inducing strain of SFFV containing the single base insertion and the 6-base-pair duplication was replaced by the corresponding sequence of the Friend murine leukemia virus env gene. The mutant SFFV-Friend murine leukemia virus complex did not induce symptoms of the erythroproliferative disease in adult DBA/2 mice. During passage through newborn DBA/2 mice, the mutant virus complex invariably gave rise to weakly pathogenic variant SFFVs. All of the variant SFFVs induced in adult DBA/2 mice a transient mild splenomegaly associated with normal or slightly low hematocrit value, and they produced gp55 with a molecular weight similar to that of gp55 of the wild-type SFFV. For the two isolates of variant SFFV, the 3' portion of the viral DNA intermediate containing the 3' portion of the gp55 gene was molecularly cloned. Nucleotide sequences of these biologically active cloned DNAs were determined and showed that the variant SFFV genomes arose from the mutant SFFV genome by regaining the single base insertion, indicating that the single base insertion is essential for the biological activity of gp55. Evidence is presented indicating that the single base insertion which causes a loss of the cytoplasmic domain of the env-related protein is not related to the localization of the further-glycosylated form of gp55 in the plasma membrane but is involved with the release of gp55 from cells.

Amino Acid Sequence↗
PubMed1995

Long terminal repeat enhancer core sequences in proviruses adjacent to c-myc in T-cell lymphomas induced by a murine retrovirus.

The transcriptional enhancer in the long terminal repeat (LTR) of the T-lymphomagenic retrovirus SL3-3 differs from that of the nonleukemogenic virus Akv at several sites, including a single base pair difference in an element termed the enhancer core. Mutation of this T-A base pair to the C-G C-G sequence found in Akv significantly attenuated the leukemogenicity of SL3-3. Thus, this difference is important for viral leukemogenicity. Since Akv is an endogenous virus, this suggests that the C-G in its core is an adaptation to being minimally pathogenic. Most tumors that occurred in mice inoculated with the mutant virus, called SAA, contained proviruses with reversion or potential suppressor mutations in the enhancer core. We also found that the 72-bp tandem repeats constituting the viral enhancer could vary in number. Most tumors contained mixtures of proviruses with various numbers of 72-bp units, usually between one and four. Variation in repeat number was most likely due to recombination events involving template misalignment during viral replication. Thus, two processes during viral replication, misincorporation and recombination, combined to alter LTR enhancer structure and generate more pathogenic variants from the mutant virus. In SAA-induced tumors, enhancers of proviruses adjacent to c-myc had the largest number of core reversion or suppressor mutations of all of the viral enhancers in those tumors. This observation was consistent with the hypothesis that one function of the LTR enhancers in leukemogenesis is to activate proto-oncogenes such as c-myc.

3T3 Cells↗
PubMed2001

Vaccine-elicited V3 loop-specific antibodies in rhesus monkeys and control of a simian-human immunodeficiency virus expressing a primary patient human immunodeficiency virus type 1 isolate envelope.

Vaccine-elicited antibodies specific for the third hypervariable domain of the surface gp120 of human immunodeficiency virus type 1 (HIV-1) (V3 loop) were assessed for their contribution to protection against infection in the simian-human immunodeficiency virus (SHIV)/rhesus monkey model. Peptide vaccine-elicited anti-V3 loop antibody responses were examined for their ability to contain replication of SHIV-89.6, a nonpathogenic SHIV expressing a primary patient isolate HIV-1 envelope, as well as SHIV-89.6P, a pathogenic variant of that virus. Low-titer neutralizing antibodies to SHIV-89.6 that provided partial protection against viremia following SHIV-89.6 infection were generated. A similarly low-titer neutralizing antibody response to SHIV-89.6P that did not contain viremia after infection with SHIV-89.6P was generated, but a trend toward protection against CD4+ T-lymphocyte loss was seen in these infected monkeys. These observations suggest that the V3 loop on some primary patient HIV-1 isolates may be a partially effective target for neutralizing antibodies induced by peptide immunogens.

AIDS Vaccines↗
PubMed2026

Exome sequencing and large-scale analysis of electronic medical record-linked biobank data identify candidate deafness genes.

INTRODUCTION: Rapid advances in whole-exome sequencing (WES) have enabled large-scale detection of pathogenic variants. Although hundreds of genes are implicated in hearing loss, up to half of inherited cases remain unsolved, limiting eligibility for gene therapy trials that require genetic diagnosis. Biobanks and electronic medical records (EMRs) offer opportunities to integrate genomic and clinical data at scale and expand the spectrum of hearing loss genes. Despite clinical value, EMRs often lack key information such as inheritance patterns, posing challenges for accurate interpretation. METHODS: WES was performed on DNA samples from 1038 hearing-impaired patients enrolled in the Maccabi Research and Innovation Center Tipa Biobank. Clinical data were extracted from EMRs. Audiograms were available for all cases, although data on age of onset, family history and mode of inheritance were mostly unavailable. We applied a scalable bioinformatics analysis strategy for high-throughput annotation, filtering and prioritisation of WES variants across more than 1000 patients, designed to accommodate incomplete and heterogeneous clinical records. RESULTS: Using this approach, 15% of cases were solved or potentially solved through known or novel variants in established deafness genes. Homozygous variants in novel candidate genes were identified in 3% of cases. Functional characterisation was performed for promising candidate genes to validate their role in the ear. CONCLUSION: These findings demonstrate that WES can determine disease aetiology in large, genetically heterogeneous populations, even in the context of incomplete clinical data. This approach supports large-scale genetic screening and provides a framework for identifying patients who may benefit from emerging gene-based therapies.

Genetic Testing↗
PubMed2026

An Update on Inborn Errors of V(D)J Recombination.

V(D)J recombination is the fundamental process by which developing T and B lymphocytes generate diverse antigen receptors, enabling adaptive immunity. This tightly regulated program operates exclusively in lymphoid precursors during G1 phase and depends on the lymphocyte-specific RAG1-RAG2 recombinase to introduce programmed DNA double-strand breaks at recombination signal sequences, followed by repair through the classical nonhomologous end joining (c-NHEJ) pathway. Disruption of any step in this molecular choreography compromises antigen receptor diversity and underlies a spectrum of inborn errors of immunity (IEIs), ranging from severe combined immunodeficiency (SCID) to immune dysregulation with autoimmunity and granulomatous disease. In this review, we place disorders of V(D)J recombination within the broader framework of T-cell development, detailing the temporal waves of recombinase activity, chromatin accessibility, and DNA damage responses that guide thymocyte differentiation. We discuss pathogenic variants affecting the cleavage phase [RAG1, RAG2, and the recently identified RAG cochaperone NudC domain-containing 3 (NUDCD3)], end processing (ARTEMIS), ligation and repair (LIG4, XLF, XRCC4, PRKDC), and genome surveillance pathways (ATM, MRN complex, RNF168), highlighting genotype-phenotype correlations and mechanisms driving immune deficiency and dysregulation. We briefly review recent diagnostic advances, including newborn screening using T-cell receptor excision circles, repertoire sequencing, and functional assays, alongside current therapeutic strategies. Finally, we outline key unanswered questions and argue that continued integration of clinical observation with molecular discovery is essential to improve outcomes and deepen understanding of adaptive immune development.

Humans↗
PubMed2024

Adult-Onset Cancer Predisposition Syndromes in Children and Adolescents-To Test or not to Test?

With the increasing use of comprehensive germline genetic testing of children and adolescents with cancer, it has become evident that pathogenic variants (PV) in adult-onset cancer predisposition genes (aoCPG) underlying adult-onset cancer predisposition syndromes, such as Lynch syndrome or hereditary breast and ovarian cancer, are enriched and reported in 1% to 2% of children and adolescents with cancer. However, the causal relationship between PVs in aoCPGs and childhood cancer is still under investigation. The best-studied examples include heterozygous PVs in mismatch repair genes associated with Lynch syndrome in children with mismatch repair deficient high-grade glioma, heterozygous PVs in BARD1 in childhood neuroblastoma, and heterozygous PVs in BRCA2 in children with rhabdomyosarcoma. The low penetrance for pediatric cancers is considered to result from a combination of the low baseline risk of cancer in childhood and the report of only a modest relative risk of disease in childhood. Therefore, we do not advise that healthy children empirically be tested for PVs in an aoCPG before adulthood outside a research study. However, germline panel testing is increasingly being performed in children and adolescents with cancer, and exome and genome sequencing may be offered more commonly in this population in the future. The precise pediatric cancer risks and spectra associated with PVs in aoCPGs, underlying cellular mechanisms and somatic mutational signatures, as well as treatment response, second neoplasm risks, and psycho-oncological aspects require further research.

Adolescent↗
PubMed2025

Double Genetic Diagnosis Involving MECP2 and EPHB4 in a Child with Neurodevelopmental Delay and Vascular Anomalies: A Case Report.

BACKGROUND: Double genetic diagnoses are increasingly identified with the advent of genome-wide sequencing techniques. While MECP2 mutations are associated with Rett syndrome and EPHB4 mutations with vascular malformation syndromes, their co-occurrence has not been previously described. CASE PRESENTATION: We describe an 8-year-and-2-month-old girl presenting with global developmental delay, autism spectrum disorder, and stereotypic behaviors, along with multiple well-demarcated cutaneous vascular lesions. Although she had no clinical seizures, electroencephalogram revealed epileptiform discharges. Physical examination showed dysmorphic features and vascular anomalies, including telangiectatic pink-to-red macular vascular lesions. Whole exome sequencing (WES) identified two de novo heterozygous pathogenic variants: a missense mutation in MECP2 (c.433C>T; p.Arg145Cys), a gene classically implicated in Rett syndrome, and a nonsense mutation in EPHB4 (c.1093C>T; p.Arg365Ter), which has been previously associated with capillary malformation-arteriovenous malformation syndrome type 2. The neurodevelopmental findings, while consistent with the broader spectrum of MECP2-related disorders, along with coexisting vascular anomalies, were best accounted for by a dual genetic diagnosis involving both MECP2 and EPHB4. CONCLUSION: This case underscores the diagnostic value of considering dual genetic diagnoses in patients with complex phenotypes and highlights the role of WES in uncovering multilocus variation, thereby expanding the known phenotypic spectrum associated with MECP2 and EPHB4 mutations.

Double genetic diagnosis↗
PubMed2026

Dysregulated Ribonucleoprotein Granules Impair Mitochondrial Function in RBM20-Related Dilated Cardiomyopathy.

BACKGROUND: Pathogenic variants in RBM20 cause severe dilated cardiomyopathy. Loss-of-function variants disrupt splicing; neomorphic gain-of-function (GoF) variants also mislocalize RBM20 to cytoplasmic ribonucleoprotein granules and are associated with more aggressive disease. The mechanism by which RBM20 mislocalization drives cardiac dysfunction remains unknown. METHODS: We investigated the effects of Rbm20 GoF and loss-of-function (LoF) variants using proteomic profiling, protein solubility assays, mitochondrial respiration and calcium flux analyses, and ultrastructural imaging in mouse models. Human induced pluripotent stem cell-derived cardioids were used to validate variant-specific phenotypes. RESULTS: Rbm20 GoF, but not LoF, variants caused posttranscriptional downregulation of soluble mitochondrial proteins, including the calcium efflux regulator TMEM65 (transmembrane protein 65), and reduced solubility of mitochondrial membrane proteins. Electron microscopy revealed enlarged mitochondria with cristae disorganization. Functional assays confirmed impaired oxidative phosphorylation, reduced mitochondrial membrane potential, and abnormal calcium handling in Rbm20 GoF models. Human cardioids reproduced these findings, demonstrating that cytoplasmic mislocalization, rather than splicing deficiency, drives mitochondrial dysfunction. CONCLUSIONS: Cytoplasmic mislocalization of RBM20 disrupts mitochondrial function by reducing mitochondrial protein abundance, leading to oxidative phosphorylation failure and abnormal mitochondrial calcium handling. This mechanism distinguishes RBM20 GoF from LoF variants and may explain the more severe heart failure phenotype observed in patients with RBM20 GoF variants. These insights advance the mechanistic understanding of RBM20-related cardiomyopathy and identify mitochondrial mRNA/protein regulation as a key node in cardiac energetics.

cardiomyopathy, dilated↗
PubMed2026

Cardiomyocyte-Specific Plakophilin-2 Loss Is Sufficient to Induce Aging and Senescence of Nonmyocytes: Relevance to Arrhythmogenic Cardiomyopathy.

BACKGROUND: Pathogenic variants in PKP2 are the most common cause of familial arrhythmogenic right ventricular cardiomyopathy. This study tests whether plakophilin-2 (PKP2) deficiency only in cardiomyocytes is sufficient to provoke premature aging and proinflammatory senescence in nonmyocyte, cardiac resident cells. METHODS: We studied mice with cardiomyocyte-specific, tamoxifen-activated loss of PKP2 (cardiomyocyte-specific conditional knockout of plakophilin-2) using conventional and multiplex imaging, cytokine arrays, epigenetic clocks, spatial transcriptomics, expansion and structured illumination microscopy, and correlative data analysis. We examined nonmyocytes and cardiomyocytes for premature aging and senescence. RESULTS: We observed senescence-associated heterochromatin foci in nonmyocytes, predominantly in cells positive for α-smooth muscle actin staining. Cytokines in media of nonmyocyte cells were consistent with senescence-associated secretory phenotype. Epigenetic clocks identified premature aging. Multiplex immunohistochemistry showed nonmyocyte cells in niches, intermingled with cardiomyocytes. Spatial transcriptomics showed overrepresentation of senescence-associated secretory phenotype-related transcripts, predominantly in myocyte-rich areas of the left ventricle. Senescence-associated heterochromatin foci and increased epigenetic age were not found in cardiomyocytes from cardiomyocyte-specific conditional knockout of plakophilin-2 hearts, although we observed structural features associated with premature aging. Cross-reference analysis showed correlation between the cardiomyocyte-specific conditional knockout of plakophilin-2 cardiac proteome and that of mice 5 or 6 times their chronological age, as well as transcriptional signatures of neurodegenerative diseases. CONCLUSIONS: Loss of PKP2 expression only in adult cardiac myocytes is sufficient to induce proinflammatory senescence in nonmyocytes, and overall premature cardiac aging. This is the first study to intersect cellular senescence and premature aging with desmosomal arrhythmogenic cardiomyopathies. We speculate that cell-agnostic molecular signatures, biomarkers, and pharmacology of senescence and of neurodegenerative diseases may be relevant to diagnose or treat PKP2 arrhythmogenic right ventricular cardiomyopathy.

Animals↗
PubMed2003

NYX (nyctalopin on chromosome X), the gene mutated in congenital stationary night blindness, encodes a cell surface protein.

PURPOSE: The complete type of X-linked congenital stationary night blindness (CSNB1) in human and mouse is caused by mutations in the NYX gene. The human NYX protein has been predicted to contain an N-terminal endoplasmic reticulum (ER) signaling sequence and a C-terminal glycosylphosphatidylinositol (GPI) anchor. In the current study, these computer predictions were verified experimentally by expression of domain-specific cDNA constructs in COS-7 and HeLa cells. Moreover, computer-based analysis of the orthologue mouse amino acid sequence did not reveal a GPI anchor, which may result in a different protein localization compared with human NYX. Therefore, the cellular localization for the mouse Nyx protein was also examined. METHODS: A new method was established that differentially visualizes both the protein at the surface of the living cell and subsequently in intracellular compartments. The localization of the human and mouse V5-tagged wild-type and mutant NYX protein were studied. RESULTS: Human and mouse V5-NYX proteins were dispersed in the form of speckles over the entire cell surface. Subsequent staining of the same cells after detergent extraction revealed that V5-NYX located to the ER and Golgi apparatus. Deletion of the GPI anchor domain of NYX resulted in a time-dependent loss of V5-NYX from the surface of living cells and accumulation of this truncated protein in the ER and Golgi apparatus. Deletion of the ER signal sequence in Nyx delocalized the intracellular V5-Nyx protein and caused its dispersion in the cytosol. Furthermore, mutations introduced in the leucine-rich repeat (LRR)-region, which has been described as a pathogenic variant of NYX, had no effect on subcellular localization of the protein. CONCLUSIONS: These data provide evidence that human and mouse nyctalopin are membrane-bound extracellular proteins and are functionally conserved.

Animals↗
PubMed2026

Comparative analysis of distinct genomic landscapes in young-onset gBRCA1/2 breast cancer.

Carriers of germline BRCA1/2 pathogenic variants (gBRCA1/2 PVs) have elevated young-onset breast cancer risk. To define the pretreatment genomic landscapes of young-onset gBRCA-associated breast cancer, we evaluated 136 treatment-naive tumors diagnosed before age 50 in the prospective POSH study and 66 noncarriers from The Cancer Genome Atlas. Using whole-exome sequencing, we analyzed somatic variation, allele-specific loss of heterozygosity (asLOH), homologous recombination deficiency (HRD), and single-base substitution (SBS) signatures. gBRCA1 and gBRCA2 breast cancers had high rates of asLOH but differed significantly in average HRD scores and median SBS composition of signatures SBS1 (aging-associated), SBS18 (ROS-associated), and SBS3 (HRD-associated). Compared with gBRCA2 tumors, gBRCA1 tumors with asLOH were significantly enriched for alterations in hallmark ROS, DNA repair, and epithelial-mesenchymal transition pathways. In ER-positive, HER2-negative tumors from gBRCA1/2 carriers compared with noncarriers, we found significant enrichment of RB1, TP53, FAT1, and MYC single-nucleotide variants, indels, and copy number variants associated with CDK4/6 inhibitor (CDK4/6i) resistance. Together, these findings demonstrate significant differences between gBRCA1- and gBRCA2-associated breast cancers, and preexisting CDK4/6i resistance mechanisms, supporting prospective trials comparing individualized therapy for gBRCA1 versus gBRCA2 carriers and comparing poly(ADP-ribose) polymerase inhibitors versus CDK4/6i for ER-positive gBRCA1/2-associated breast cancer.

Humans↗
PubMed2026

Congenital core myopathy linked to SOX5: Expanding the phenotypical spectrum of Lamb-Shaffer syndrome.

Haploinsufficiency of SOX5 causes Lamb-Shaffer syndrome, a rare condition with developmental delay, impaired language and intellectual disability and optic nerve abnormalities. Muscle involvement is poorly characterized. We report a 20-year-old woman with neonatal hypotonia, delayed motor milestones, proximal weakness and learning difficulties. Serum creatine kinase was normal. Electroneuromyography revealed a mild myogenic pattern. Muscle biopsy revealed myopathic changes, with cores and protein aggregates. Whole genome sequencing disclosed a heterozygous pathogenic variant in the SOX5 gene. This case expands the phenotypic spectrum of Lamb-Shaffer syndrome, confirming primary muscle involvement with core myopathy.

Female↗
PubMed2005

Role of viral evolutionary rate in HIV-1 disease progression in a linked cohort.

BACKGROUND: The actual relationship between viral variability and HIV disease progression and/or non-progression can only be extrapolated through epidemiologically-linked HIV-infected cohorts. The rarity of such cohorts accents their existence as invaluable human models for a clear understanding of molecular factors that may contribute to the various rates of HIV disease. We present here a cohort of three patients with the source termed donor A--a non-progressor and two recipients called B and C. Both recipients gradually progressed to HIV disease and patient C has died of AIDS recently. By conducting 15 near full-length genome (8.7 kb) analysis from longitudinally derived patient PBMC samples enabled us to investigate the extent of molecular factors, which govern HIV disease progression. RESULTS: Four time points were successfully amplified for patient A, 4 for patient B and 7 from patient C. Using phylogenetic analysis our data confirms the epidemiological-linkage and transmission of HIV-1 from a non-progressor to two recipients. Following transmission the two recipients gradually progressed to AIDS and one died of AIDS. Viral divergence, selective pressures, recombination, and evolutionary rates of HIV-1 in each member of the cohort were investigated over time. Genetic recombination and selective pressure was evident in the entire cohort. However, there was a striking correlation between evolutionary rate and disease progression. CONCLUSION: Non-progressing individuals have the potential to transmit pathogenic variants, which in other host can lead to faster HIV disease progression. This was evident from our study and the accelerated disease progression in the recipient members of he cohort correlated with faster evolutionary rate of HIV-1, which is a unique aspect of this study.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Evolution of the uniquely adaptable lentiviral envelope in a natural reservoir host.

BACKGROUND: The ability of emerging pathogens to infect new species is likely related to the diversity of pathogen variants present in existing reservoirs and their degree of genomic plasticity, which determines their ability to adapt to new environments. Certain simian immunodeficiency viruses (SIVcpz, SIVsm) have demonstrated tremendous success in infecting new species, including humans, resulting in the HIV-1 and HIV-2 epidemics. Although SIV diversification has been studied on a population level, the essential substrates for cross-species transmission, namely SIV sequence diversity and the types and extent of viral diversification present in individual reservoir animals have not been elucidated. To characterize this intra-host SIV diversity, we performed sequence analyses of clonal viral envelope (env) V1V2 and gag p27 variants present in individual SIVsm-infected sooty mangabeys over time. RESULTS: SIVsm demonstrated extensive intra-animal V1V2 length variation and amino acid diversity (le38%), and continual variation in V1V2 N-linked glycosylation consensus sequence frequency and location. Positive selection was the predominant evolutionary force. Temporal sequence shifts suggested continual selection, likely due to evolving antibody responses. In contrast, gag p27 was predominantly under purifying selection. SIVsm V1V2 sequence diversification is at least as great as that in HIV-1 infected humans, indicating that extensive viral diversification in and of itself does not inevitably lead to AIDS. CONCLUSION: Positive diversifying selection in this natural reservoir host is the engine that has driven the evolution of the uniquely adaptable SIV/HIV envelope protein. These studies emphasize the importance of retroviral diversification within individual host reservoir animals as a critical substrate in facilitating cross-species transmission.

Animals↗
PubMed2026

Recurrent and unusual infections unmasking a rare inborn error of immunity: a case report RAS-associated Autoimmune Lymphoproliferative Disease (RALD).

BACKGROUND: RAS-associated Autoimmune Lymphoproliferative Disease (RALD) is a rare, non-malignant lymphoproliferative disorder caused by somatic mutations in RAS genes that impair lymphocyte apoptosis. Patients often present with features of lymphoproliferation, autoimmune manifestations, and an increased risk of malignant transformation. CASE PRESENTATION: We report the case of a 3-year-old boy with splenic microabscesses and Burkholderia pseudomallei IgM serology positivity, who was treated as melioidosis. He had recurrent respiratory infections and chronic rhinorrhoea since the age of one year. Clinical examination revealed persistent lymphadenopathy and hepatosplenomegaly. Laboratory investigations demonstrated persistent absolute monocytosis and thrombocytopenia, while immunological evaluation showed elevated IgM levels and B-cell lymphocytosis. Whole exome sequencing identified a heterozygous pathogenic variant in NRAS, NM_002524.5:c.35G > C, NP_002515.1:p.Gly12Ala, establishing the diagnosis of RALD. The patient was subsequently started on antibiotic prophylaxis and immunoglobulin replacement therapy, and his family was counseled regarding the potential role of immunosuppressive therapy and hematopoietic stem cell transplantation (HSCT) in future management. CONCLUSIONS: This case highlights the coexistence of an unusual infection with a rare inborn error of immunity, expanding the recognized infectious spectrum of RALD. It underscores the importance of considering RALD in patients presenting with recurrent or atypical infections and persistent lymphoproliferative features. Early recognition and molecular genetic testing are essential for confirming the diagnosis and guiding individualized management.

Humans↗
PubMed2026

Systemic immune activation in hereditary cancer predisposition syndromes: a cross-sectional study.

BACKGROUND: Immune surveillance mechanisms contribute to the elimination of precancerous lesions in hereditary cancer predisposition syndromes (HCPSs). METHODS: By combining single-cell transcriptomics, multiparametric mass cytometry and cytokine profiling of the systemic immune environment in 391 individuals among whom 227 are living with HCPSs we investigated phenotypic alterations in cancer-free individuals with HCPS. RESULTS: A decrease in peripheral B cell abundance and their more differentiated phenotype have been confirmed both in breast cancer patients with germline pathogenic variants in BRCA1 (gpath(BRCA1)) and in patients living with Lynch syndrome (LS). Pre-cancer women with gpath(BRCA1) exhibited an activated phenotype of multiple immune cell lineages, similar to those with manifest disease. In LS, B cell phenotypes exhibited the largest changes in response to cancer eradication, while increased peripheral IL-6 levels was detected even in presymptomatic individuals with LS. CONCLUSIONS: HCPS-specific differences in the phenotype of the systemic immune system might be leveraged in future risk-reducing strategies.

Humans↗
PubMed2024

A healthy live birth after mosaic blastocyst transfer in preimplantation genetic testing for GATA1-related cytopenia combined with HLA matching.

BACKGROUND: GATA1-related cytopenia (GRC) is characterized by thrombocytopaenia and/or anaemia ranging from mild to severe. Haematopoietic stem cell transplantation (HSCT) is a healing therapeutic choice for GRC patients. We identified a novel pathogenic variant (GATA1: c.1019delG) in a boy with GATA1-related cytopenia. Then we performed preimplantation genetic testing (PGT) in this GRC family. After a mosaic embryo transfered, a healthy and HLA-compatible with the proband baby was delivered. CASE PRESENTATION: The proband is a 6-year-old boy who was diagnosed to have transfusion-dependent anaemia since 3 year old. Whole-exome sequencing (WES) showed that the proband has a hemizygous variant c.1019delG in GATA1, which is inherited from his mother. His parents decided to undergo PGT to have a health and HLA-compatible offspring. After whole genome amplification (WGA) of biopsied trophectoderm (TE) cells, next generation sequencing (NGS)-based PGT was preformed to analyse embryos on chromosomal aneuploidy, target mutation and HLA typing. There were 3 embryos HLA-matched to the proband. The genotypes of the 3 embryos were heterozygous variant, hemizygous variant, normal respectively. After a heterozygous, mosaic partial trisomy (chr)16, and HLA-matched embryo transfer, a healthy baby was delivered and whose HSCT is compatible with the proband. CONCLUSIONS: NGS-based PGT-HLA is a valuable procedure for the treatment of GATA1-related cytopenia caused by GATA1 variants, or other haematological disorders, oncological and immunological diseases. Furthermore, our study reconfirms that mosaic embryos transfer would bring healthy offspring.

Child↗