Informed clinical decisions by outfoxing human FOXN1 variants.

Thymic T-cell development is orchestrated by thymic epithelial cells. The master transcriptional regulator of these cells is forkhead box N1 (FOXN1), which controls their differentiation, expansion, and function. Biallelic founder mutations in FOXN1 caused a nude/severe combined immunodeficiency phenotype due to congenital thymic aplasia and alopecia universalis. This established the critical role of FOXN1 in thymic epithelial cells and epithelial cells in the skin and nails. The emergence of newborn screening for severe T-cell deficiency via the T-cell receptor excision circle assay, along with exome and genome sequencing, has led to dramatic increases in the number of FOXN1 variants identified. The consequent impact of the FOXN1 variants ranges from pathogenic to benign, yet most FOXN1 mutations are listed as variants of unknown significance. Among monoallelic FOXN1 variants are some that act as dominant negative, resulting in a transient T-cell lymphopenia. In this review, the clinical impacts of diverse FOXN1 variants are categorized by mutation type and location. Knowing how these FOXN1 mutations affect protein function informs clinical care as well as laboratory monitoring, prophylactic measures, and allogeneic thymic implant decisions. This review provides key functional insights into FOXN1, enabling better clinical care.