Applied Filters
- Novel mutation and VUS
- Garkaby, JennyRemove filter
- Scott, OriRemove filter
- LymphoSign JournalRemove filter
Publication Date
Author
Access Type
1 - 4of4
Save this search
Please login to be able to save your searches and receive alerts for new content matching your search criteria.
Filters
Search Name | Searched On |
---|---|
[Paper Type: Novel mutation and VUS] AND [Author: Garkaby, Jenny] AND [Author: Scot... (4) | 3 Jul 2024 |
You do not have any saved searches
- 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. - OPEN ACCESSBackground: Chronic mucocutaneous Candidiasis (CMCC) is characterized by recurrent or persistent fungal infections of the skin, nails, and oral and genital mucosae. There are several underlying genetic causes for CMCC, with mutations in Signal Transducer and Activator of Transcription-1 (STAT1) accounting for the majority of cases.Aim: To broaden the genotypic spectrum of CMCC caused by STAT1 mutations.Methods: We evaluated a young patient and her family with CMCC. Immune workup and targeted gene sequencing were performed.Results: The proband presented at 7 years of age with persistent oral thrush. Immune evaluation revealed her cellular and humoral immunity to be within normal range. Given that her family history was significant for oral lesions in father, siblings, and paternal family members, STAT1 gene sequencing was performed. A novel heterozygous missense c.G799A, predicting a p. Ala267Thr amino acid change within the coiled-coil domain, was identified in our patient and 3 of her family members.Conclusion: Gain-of-function mutations in STAT1 have been associated with a variety of phenotypes, ranging from isolated CMCC to severe fatal combined immunodeficiency, mycobacterial infections, autoimmune disorders, as well as malignancy and aneurysms. Here, we describe a novel STAT1 mutation, c.G799A, resulting in a very mild phenotype of isolated CMCC in 4 members of one kindred.Statement of novelty: We describe 4 patients with a mild phenotype of CMCC caused by a novel STAT1 heterozygous mutation.
- OPEN ACCESS
- Ori Scott,
- Jenny Garkaby,
- Jessica Willett-Pachul,
- Amarilla B. Mandola,
- Daniele Merico, and
- Yehonatan Pasternak
Background: The Forkhead box protein N1 (FOXN1) is a key regulator of thymic epithelial development, and its complete deficiency leads to a nude-severe combined immunodeficiency (SCID) phenotype. More recently, heterozygous mutations in FOXN1 have been linked with a syndrome of congenital lymphopenia and a wide clinical spectrum, with most cases being caused by missense mutations.Aim: To broaden the genotypic and phenotypic spectrum of heterozygous FOXN1 deficiency.Methods: Case report of a patient with FOXN1 haploinsufficiency due to a novel splice-site mutation.Results: Our patient was identified at 3 weeks of life given an abnormal newborn screen (NBS) for SCID, and was found to have congenital lymphopenia preferentially affecting CD8+ T-cells. Her cellular and humoral function were both excellent, and she has remained entirely asymptomatic and thriving for the first 3 years of her life. The patient was found on whole exome sequencing to carry a heterozygous splice-site mutation in the FOXN1 gene, affecting the Forkhead domain. The mutation was also identified in her asymptomatic mother.Conclusion: Heterozygous FOXN1 mutations are an increasingly-recognized cause of congenital lymphopenia. Our experience suggests most patients remain clinically well, with main manifestation including T-lymphopenia, mostly affecting CD8+ cells. Identification of the same variant in an asymptomatic parent suggests age-dependent improvement in T-cell counts and an overall benign course, while provides impetus for diligent conservative management with regular follow-up.Statement of novelty: Heterozygous FOXN1 deficiency is a relatively new entity, attributed in most cases to missense mutations in FOXN1. To further expand the knowledge basis regarding this emerging disorder, as well as its genotypic repertoire, we herein report a case of heterozygous FOXN1 deficiency caused by a splice site mutation.