Heterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia, Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis

Marita Bosticardo, Yasuhiro Yamazaki, Jennifer Cowan, Giuliana Giardino, Cristina Corsino, Giulia Scalia, Rosaria Prencipe, Melanie Ruffner, David A. Hill, Inga Sakovich, Irma Yemialyanava, Jonathan S. Tam, Nurcicek Padem, Melissa E. Elder, John W. Sleasman, Elena Perez, Hana Niebur, Christine M. Seroogy, Svetlana Sharapova, Jennifer GebbiaGary Ira Kleiner, Jane Peake, Jordan K. Abbott, Erwin W. Gelfand, Elena Crestani, Catherine Biggs, Manish J. Butte, Nicholas Hartog, Anthony Hayward, Karin Chen, Jennifer Heimall, Filiz Seeborg, Lisa M. Bartnikas, Megan A. Cooper, Claudio Pignata, Avinash Bhandoola, Luigi D. Notarangelo

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4+ but lower than normal CD8+ cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth.

Original languageEnglish
Pages (from-to)549-561
Number of pages13
JournalAmerican journal of human genetics
Issue number3
StatePublished - Sep 5 2019


  • FOXN1
  • SCID
  • T cell receptor excision circles
  • T lymphocytes
  • newborn screening
  • thymopoiesis
  • thymus


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