Utilization of next-generation sequencing to define the role of heterozygous FOXN1 variants in immunodeficiency.

Autor:	Pasternak Y; Division of Immunology and Allergy, Department of Paediatrics, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada., Vong L; Division of Immunology and Allergy, Department of Paediatrics, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada.; Canadian Centre for Primary Immunodeficiency and the Jeffrey Modell Research Laboratory for the Diagnosis of Primary Immunodeficiency, The Hospital for Sick Children and Research Institute, Toronto, Ontario, Canada., Merico D; Vevo Therapeutics, San Francisco, Calif.; The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada., Abrego Fuentes L; Division of Immunology and Allergy, Department of Paediatrics, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada., Scott O; Division of Immunology and Allergy, Department of Paediatrics, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada., Sham M; Division of Immunology and Allergy, Department of Paediatrics, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada., Fraser M; Newborn Screening Program, Department of Clinical and Metabolic Genetics, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada., Watts-Dickens A; Newborn Screening Program, Department of Clinical and Metabolic Genetics, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada.; Department of Molecular Genetics and the McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada., Willett Pachul J; Division of Immunology and Allergy, Department of Paediatrics, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada., Kim VHD; Division of Immunology and Allergy, Department of Paediatrics, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada., Marshall CR; Division of Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada., Scherer S; The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.; Department of Molecular Genetics and the McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada., Roifman CM; Division of Immunology and Allergy, Department of Paediatrics, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada.; Canadian Centre for Primary Immunodeficiency and the Jeffrey Modell Research Laboratory for the Diagnosis of Primary Immunodeficiency, The Hospital for Sick Children and Research Institute, Toronto, Ontario, Canada.
Jazyk:	angličtina
Zdroj:	The journal of allergy and clinical immunology. Global [J Allergy Clin Immunol Glob] 2024 Apr 23; Vol. 3 (3), pp. 100267. Date of Electronic Publication: 2024 Apr 23 (Print Publication: 2024).
DOI:	10.1016/j.jacig.2024.100267
Abstrakt:	Background: Forkhead box protein N1 (FOXN1) transcription factor plays an essential role in the development of thymic epithelial cells, required for T-cell differentiation, maturation, and function. Biallelic pathogenic variants in FOXN1 cause severe combined immunodeficiency (SCID). More recently, heterozygous variants in FOXN1, identified by restricted gene panels, were also implicated with causing a less severe and variable immunodeficiency. Objective: We undertook longitudinal follow-up and advanced genetic investigations, including whole exome sequencing and whole genome sequencing, of newborns with a heterozygous variant in FOXN1. Methods: Five patients (3 female, 2 male) have been followed since they were first detected with low T-cell receptor excision circles during newborn screening for SCID. Patients underwent immune evaluation as well as genetic testing, including a primary immunodeficiency panel, whole exome sequencing, and whole genome sequencing in some cases. Results: Median follow-up time was 6.5 years. Initial investigations revealed low CD3 + T lymphocytes in all patients. One patient presented with extremely low lymphocyte counts and depressed phytohemagglutinin responses leading to a tentative diagnosis of SCID. Over a period of 2 years, CD3 + T-cell counts rose, although in some patients it remained borderline low. One of 5 children continues to experience recurrent upper respiratory infections and asthma episodes. The remaining are asymptomatic except for eczema in 2 of 5 cases. Lymphocyte proliferation responses to phytohemagglutinin were initially low in 3 patients but normalized by age 10 months. In 3 of 5 cases, T lymphocyte counts remain low/borderline low. Conclusion: In cases of monoallelic FOXN1 variants, using whole exome sequencing and whole genome sequencing to rule out possible other significant pathogenic variants allowed us to proceed with confidence in a conservative manner, even in extreme cases consistent with newborn screen-positive early presentation of SCID. Competing Interests: Supported by Immunodeficiency Canada’s Distinguished Professorship in Immunology (C.M.R.), the Program for Immunogenomics and the Canadian Centre for Primary Immunodeficiency (C.M.R.), and the Jeffrey Modell Foundation and Immunodeficiency Canada (C.M.R.). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. (© 2024 The Authors.)
Databáze:	MEDLINE
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