biostudies-literatureBosticardo MMichael Smith Foundation for Health Research Health Professional-Investigator AwardDIR, NIAID, NIHNIDDK NIH HHSCenter for Clinical and Translational Research at Brown UniversityJeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies at St. Louis Children’s HospitalCenter for Cancer Research, National Cancer Institute, National Institutes of HealthNIGMS NIH HHS549-561https://www.ebi.ac.uk/biostudies/studies/S-EPMC6731368biostudies-literatureUnknown105(3)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 postulateAmerican journal of human geneticsHeterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia, Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis.PMC6731368U54 GM115677GM115677K08 DK116668Niebur HPrencipe RBhandoola ASharapova SBosticardo MGiardino GTam JSGelfand EWBiggs CKleiner GIHill DASeroogy CMHartog NSakovich IPignata CPerez ERuffner MGebbia JCooper MAHayward AYemialyanava IPadem NButte MJCowan JAbbott JKChen KHeimall JPeake JScalia GCorsino CNotarangelo LDYamazaki YSeeborg FElder MESleasman JWCrestani EBartnikas LMfalseHeterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia, Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis.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 postulate2019-01-01T00:00:00Z2019 Sep2026-05-04T18:37:18.046Z2020-10-29T08:33:05ZS-EPMC67313683144709710.1016/j.ajhg.2019.07.014