Homozygous duplication identified by whole genome sequencing causes LRBA deficiency
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ABSTRACT:
PROVIDER: PRJNA754455 | ENA |
REPOSITORIES: ENA
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Project description:Homozygous duplication identified by whole genome sequencing causes LRBA deficiency
| PRJNA754456 | ENA
Project description:In more than one-third of primary immunodeficiency (PID) patients, extensive genetic analysis including whole-exome sequencing (WES) fails to identify the genetic defect. Whole-genome sequencing (WGS) is able to detect variants missed by other genomics platforms, enabling the molecular diagnosis of otherwise unresolved cases. Here, we report two siblings, offspring of consanguineous parents, who experienced similar severe events encompassing early onset of colitis, lymphoproliferation, and hypogammaglobulinemia, typical of lipopolysaccharide-responsive and beige-like anchor (LRBA) or cytotoxic T lymphocyte antigen 4 (CTLA4) deficiencies. Gene-panel sequencing, comparative genomic hybridization (CGH) array, and WES failed to reveal a genetic aberration in relevant genes. WGS of these patients detected a 12.3 kb homozygous tandem duplication that was absent in control cohorts and is predicted to disrupt the reading frame of the LRBA gene. The variant was validated by PCR and Sanger sequencing, demonstrating the presence of the junction between the reference and the tandem-duplicated sequence. Droplet digital PCR (ddPCR) further confirmed the copy number in the unaffected parents (CN = 3, heterozygous) and affected siblings (CN = 4, homozygous), confirming the expected segregation pattern. In cases of suspected inherited immunodeficiency, WGS may reveal a mutation when other methods such as microarray and WES analysis failed to detect an aberration.
| S-EPMC8602677 | biostudies-literature
Project description:Novel Homozygous FAT1 Mutation Causes glomerulotubular nephropathy in Asian adult
| PRJNA1187624 | ENA
Project description:Linkage analysis and Copy Number Variation were performed on DNA isolated from the peripheral blood of the 2 affected male patients, their unaffected parents, and their unaffected 4 male siblings, according to the manufacturer's description. This allowed to narrow down the region of homozygosity specifice to the patients. This approach, in combination with Whole Exome sequencing performed on DNA isolated from the 2 affected patients and their mother, allowed to identify a homozygous missense mutation in the base excision repair enzyme NEIL3 that reduced its enzymatic activity, and a homozygous duplication of exons 48-53 of the LPS Responsive Beige-Like Anchor Protein LRBA that abolished protein expression.
2016-08-11 | GSE85428 | GEO
Project description:The lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency causes severe autoimmune diseases and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) loss in humans. However, the impact of LRBA on antitumor immunity remains understudied. Here, we identified the role of LRBA in antitumor immunity and developed a novel immunotherapy for cancers. Interestingly, LRBA was negatively associated with antitumor immunity in human patients. Using high-throughput screening and subsequent structure-based hit optimization, we discovered a small molecule LC427 that bound directly to LRBA, and selectively interfered with the LRBA-CTLA4 interaction. This mechanistically unique LC427 facilitated the lysosomal degradation of CTLA4, and bolstered survival and functions of activated T cells. Importantly, orally administrated LC427 increased tumor-infiltrating CD8+ T cells and displayed effective antitumor activity in tumorbearing mouse models. Notably, LC427 did not induce typical irAEs observed with immune checkpoint inhibitors in colitis models. Our study demonstrates that targeting LRBA offers a novel and effective strategy with a favorable safety profile, highlighting the potential of LRBA-based immunomodulatory therapies in the treatment of cancers.
2025-05-23 | GSE297744 | GEO
Project description:Tandem duplication of carbapenemase genes amplifies the gene copy number and enhances carbapenem resistance. These amplifications are often heterogenous, transient, locate in plasmids, which often also contribute to heteroresistance. The duplication is especially important for low-hydrolysis activity enzymes, which is often overlooked or even under controversy. Here we reported an intrinsic oxacillinase duplication mediated by two neighbor ISAba1inserted in the same orientation. The duplication is relatively stable, located in chromosome, and the duplication times is up to twenty-five, much larger than previous reports. We provided genomic, transcriptomic, and proteomic evidence that the duplication resulted oxacillinase overproduction and thus contribute to carbapenem resistance. No other possible carbapenem resistance related changes (point mutations of oxaAb, disturbed expression of porin protein and efflux pump) were found during the duplication process. Furthermore, introducing oxaAb flanked by two ISAba1 to A. baumannii via plasmids, mimicked the in vivo duplication process under carbapenem stress. Taken together, ISAba1 mediated duplication of low activity intrinsic antibiotic hydrolysis enzymes could lead to antibiotic resistance for advanced-generation antibiotics.
2023-01-17 | PXD039528 |
Project description:Linkage analysis and Copy Number Variation were performed on DNA isolated from the peripheral blood of the 2 affected male patients, their unaffected parents, and their unaffected 4 male siblings, according to the manufacturer's description. This allowed to narrow down the region of homozygosity specifice to the patients. This approach, in combination with Whole Exome sequencing performed on DNA isolated from the 2 affected patients and their mother, allowed to identify a homozygous missense mutation in the base excision repair enzyme NEIL3 that reduced its enzymatic activity, and a homozygous duplication of exons 48-53 of the LPS Responsive Beige-Like Anchor Protein LRBA that abolished protein expression. Homozygozity mapping was performed with the Affymetrix genome-wide human single nucleotide polymorphism (SNP) array 6.0, and analyzed with Birdsuite version 1.4 and PLINK version 1.07.
2016-08-11 | E-GEOD-85428 | biostudies-arrayexpress
Project description:Drosophila Duplication 20091218
| PRJNA122357 | ENA
Project description:Introduction: Although sequence variants in FAT1 have been identified in patients with distinct renal disease, definitive proof of causality in human disease is meager. Methods: A 35-year-old Chinese female with microscopic hematuria and proteinuria underwent a renal biopsy to identify the underlying cause. Whole-exome sequencing (WES) with homozygosity mapping revealed genetic factors, and patient-derived primary urinary epithelial cells confirmed the renal agenesis phenotype. RNA sequencing, immunofluorescence staining, and immunoblotting were used to explore the mechanisms involved. Results: The patient, whose parents are cousins, exhibited a syndrome featuring ptosis, corneal dystrophy, macular degeneration and right feet syndactyly, with glomerulotubular nephropathy. A homozygous frameshift mutation in FAT1 (NM_005245: c.7444_7445delGT) was identified. Structural prediction, immunohistochemistry, and Western blot analyses confirmed that the mutation caused translational repression of FAT1. RNA-seq analysis revealed significant dysregulation of cell adhesion and the Rap1 signaling pathway. Immunofluorescence showed a marked loss of intercellular β-catenin junctions and cytoskeletal disruption in patient-derived primary urinary epithelial cells. Pull-down assays demonstrated that these effects were associated with a reduction in activated Rap1 levels. Conclusion: This study presents compelling evidence that the homozygous FAT1 frameshift mutation (c.7444_7445delGT, p.Val2482fs) is causally associated with nephropathy and congenital anomalies. The mutation likely leads to the degradation of transcribed mRNA, which in turn impairs protein expression. These findings underscore the critical role of FAT1 in renal development and offer new insights into the molecular mechanisms underlying these conditions.
2025-11-13 | GSE282237 | GEO