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| [Paper Type: Novel mutation and VUS] AND [Author: Abrego Fuentes, Laura] (4) | 26 Mar 2025 |
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- FREE ACCESSBackground: Dominant negative STAT3 loss-of-function is the most common genetic cause of hyper-IgE syndrome (HIES). Patients may present with a host of both immune and non-immune manifestations, including connective tissue abnormalities, recurrent infections, malignant predisposition, and biochemical evidence of elevated serum IgE or eosinophilia.Aim: To describe a novel splice-site variant in STAT3 resulting in HIES.Methods: Case report of two family members with HIES.Results: A proband and his son presented with neonatal-onset pustular rash, recurrent skin and sinopulmonary infections and elevated serum IgE and were diagnosed with AD-HIES. They were identified to harbor a novel splice-site variant in the DNA-binding domain (DBD) of STAT3: c.1110-3C>G, predicted to result in defective splicing in exon 12. Interestingly, a number of other patients with AD-HIES have mutations affecting the same splice-site, suggesting this may be a hot-spot for mutagenesis.Conclusion: Splice-site mutations in the DBD of STAT3 are increasingly identified as a cause of AD-HIES. Future work is required to delineate whether patients with splice-site mutations have unique clinical characteristics, supporting efforts for genotype-phenotype correlation in this disease.Statement of Novelty: We present a novel splice-site mutation in the DNA-binding domain of STAT3 leading to autosomal dominant hyper-IgE syndrome.
- FREE ACCESSIntroduction: NF-κB proteins are transcription factors that modulate various functions of the immune system. NF-κB2 (or p100/p52) has particularly important roles in B cell development and function. Primary immunodeficiency due to mutations in the NFKB2 gene, encoding NF-κB2, range from combined immunodeficiency with susceptibility to viral or opportunistic infections to primarily antibody deficiency.Methods: A comprehensive chart review of our patient was performed.Results: Our patient, currently a 19-year-old male, presented with multiple autoimmune cytopenia resistant to treatment and generalized granulomatous lymphadenopathy. Whole exome sequencing identified a novel pathogenic variant in NFKB2 (c.1700C>T; p.A567V) that is the cause of our patient’s presentation.Conclusion: We present a novel pathogenic variant in NFKB2 with an unusual presentation.Statement of novelty: Here, we report a novel mutation in NFKB2 and the clinical presentation of the affected patient, which helps in further understanding the NF-κB2 pathway and its associated disease.
- FREE ACCESSBackground: Eosinophilic gastrointestinal disease (EGID) is an umbrella term for a heterogeneous group of disorders affecting the GI tract. In contrast to the relatively common eosinophilic esophagitis (EoE), eosinophilic gastroenteritis (EGE) remains poorly understood in terms of both its pathophysiology and genetic etiology, while treatment options remain limited.Aim: To expand the genotypic spectrum of EGE and describe our long-term experience of treatment with ketotifen.Methods: Case report of a patient with EGE followed by our team for over 27 years.Results: Our patient was diagnosed with EGE at the age of 4 years, accompanied by multiple other atopic manifestations and serum eosinophilia. He was later diagnosed with a heterozygous variant in RUNX1, a gene implicated in multi-lineage hematopoiesis, inhibition of Th2 polarization and T regulatory cell function. The patient has experienced long-term symptom improvement while treated with the mast cell stabilizing H1 antihistamine, ketotifen, with substantial symptomatic worsening after this agent was briefly stopped.Conclusion: We expand the genotypic spectrum of EGID etiology to include mutations in RUNX1, and suggest ketotifen as a viable option for patients with treatment-refractory EGE.Statement of novelty: This case reports on a possible novel genetic cause of EGID and describes long-term successful clinical management with ketotifen.
- OPEN ACCESS
- Laura Abrego Fuentes,
- Jenny Garkaby,
- Ori Scott,
- Jessica Willet Pachul,
- Harjit Dadi,
- Daniele Merico, and
- Linda Vong
Introduction: The phosphoinositide 3-kinase (PI3K) pathway plays critical roles in diverse cellular processes, including differentiation, proliferation, motility, survival, and growth. PI3Kδ, comprised of the catalytic subunit p110δ and regulatory subunit p85α, is essential for normal lymphocyte and myeloid development and function. Gain-of-function mutations in PIK3CD (encoding p110δ) cause a combined immunodeficiency known as activated PI3Kδ syndrome (APDS), in which patients frequently present with recurrent respiratory infections, severe recurrent (or persistent) infections with herpes family viruses, and lymphadenopathy.Aim: To describe the clinical presentation, immune evaluation, and genetic work-up of 2 patients (daughter and mother) with recurrent sinopulmonary, soft tissue, and skin infections.Results: Both daughter and mother presented with recurrent sinopulmonary and soft tissue infections. Immune evaluation of the daughter revealed intermittent hypogammaglobulinemia and abnormal specific vaccine responses, while immune parameters of her mother were normal. Whole exome sequencing identified a novel mutation in PIK3CD (NM_005026), c.C719T, resulting in p.T240M. Western blot analysis of downstream AKT levels revealed increased basal phosphorylation, in line with gain-of-function mutations of PIK3CD.Conclusion: The novel missense mutation in PIK3CD occurs in the region encoding the Ras-binding domain (RBD) of p110δ, and likely alters the structural configuration of the domain. To date, pathogenic mutations targeting the RBD of p110δ have not yet been described. Our results expand on the genotypic spectrum of APDS.Statement of Novelty: We describe a novel mutation in the Ras-binding domain of PIK3CD leading to a presentation of recurrent sinopulmonary and soft tissue infections in the context of APDS.
