Novel heterozygous FOXN1 mutation identified following newborn screening for severe combined immunodeficiency is associated with improving immune parameters

Author:

Abrego Fuentes Laura Edith1,Garkaby Jenny1,Willett Pachul Jessica1,Watts-Dickens Abby2,Fraser Meghan2,Kim Vy H.D.1,Roifman Chaim M.13

Affiliation:

1. Division of Clinical Immunology and Allergy, Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, ON

2. Newborn Screening Program, Department of Clinical and Metabolic Genetics, Hospital for Sick Children and University of Toronto, Toronto, ON

3. Canadian Centre for Primary Immunodeficiency and the Jeffrey Modell Research Laboratory for the Diagnosis of Primary Immunodeficiency, Research Institute, Hospital for Sick Children, Toronto, ON

Abstract

Background: Forkhead-box protein N1 (FOXN1) plays a critical role in the proper development and function of thymic epithelial cells, required for T cell ontogeny. Homozygous variants in the FOXN1 gene, encoding FOXN1, cause severe combined immunodeficiency (SCID), whereas heterozygous mutations are associated with variable presentations and over time, improving T cell function. Aim: To highlight the importance of broader genetic investigations to attain a definitive molecular diagnosis following abnormal newborn screening for SCID. Methods: Case report of a patient with immunodeficiency due to a novel de novo FOXN1 mutation. Results: The patient was identified following abnormal newborn screening for SCID in which T cell receptor excision circles were absent/very low. Initial immune investigations revealed severe T cell lymphopenia and poor lymphocyte function and she was diagnosed with T-B+NK+SCID. During work-up for hematopoietic stem cell transplantation, extensive genetic investigations identified a novel heterozygous mutation in FOXN1. A more conservative management approach was taken, and over the following months, the patient’s immune parameters improved. Conclusion: Newborn screening for SCID has facilitated the detection of SCID, as well as other T cell immunodeficiencies, before infectious complications and organ damage occur. Heterozygous mutations in FOXN1 are associated with more variable presentations including improving immune indices with age. Here, results of genetic investigations were essential for informing the management of this case. Statement of Novelty: We report a novel heterozygous mutation in FOXN1, presenting initially as T-B+NK+ SCID with gradual improvement of immune parameters over time.

Publisher

LymphoSign Journal Limited Partnership

Subject

General Earth and Planetary Sciences,General Environmental Science

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