Submission Details

FOXN1 has been noted to be associated with the following disease entities: autosomal recessive T-cell immunodeficiency, congenital alopecia, and nail dystrophy (OMIM: 601705) and autosomal dominant T-cell lymphopenia, infantile, with or without nail dystrophy (OMIM: 618806). We found no definitive difference in the molecular mechanisms of these two, and there is significant overlap in their phenotypes suggestive of a disease spectrum. Therefore, per criteria outlined by the ClinGen Lumping and Splitting Working Group, these have been lumped into one disease entity, semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy.

FOXN1 was first reported in relation to T-cell immunodeficiency, congenital alopecia, and nail dystrophy in 1999 (Frank et al., PMID: 10206641). In this report two siblings from a small village in southern Italy were identified as homozygous for the variant c.763C>T (p.R255*). In 2004, population screening of this Italian village identified 55 heterozygous carriers of p.R255* representing 6.5% of the individuals tested. Genealogical study of these individuals identified a common ancestor, and haplotype analysis supported this to be an ancestral founder variant (Adriani et al., PMID: 15180707). Additional study of some of these heterozygous adults in 2019 found several with a mild phenotype including nail dystrophy and CD8+ T cell lymphopenia (Bosticardo et al., PMID: 31447097).

Eleven variants (missense, in-frame indel, nonsense, and frameshift) that have been reported in 9 probands in 8 publications (PMIDs: 10206641, 25173801, 30903456, 31566583, 20978268, 33464451, 31447097, 31151968) are included in this curation. These probands include those with biallelic pathogenic variants as well as those with monoallelic pathogenic variants. Probands with biallelic pathogenic variants have T-B+NK+ severe combined immunodeficiency (SCID). Some, but not all, have associated congenital alopecia and/or nail dystrophy (PMID: 10206641, 25173801, 30903456, 20978268, 31151968). The phenotype of those with monoallelic pathogenic variants is typically milder but spans a broad range from some who are apparently unaffected to others with only subtle features such as nail dystrophy to others with SCID (PMID: 31447097, 33464451, 31566583). It has been suggested that the heterozygotes’ CD4+ T cell lymphopenia normalizes in adulthood (PMID: 31447097). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.

This gene-disease association is also supported by expression studies, functional assays, animal models, and rescue assays (PMIDs: 10206641, 8629026, 21507891, 7969402). FOXN1 encodes a protein that acts as a transcription factor and is expressed in both the thymus and skin (PMID: 10206641, 8629026). In human cells with biallelic pathogenic variants, there is a total blockage of CD4+ T cell maturation (PMID: 21507891). In mice, biallelic disruption of FOXN1 results in a “nude” phenotype characterized by hairlessness as well as athymia and immunodeficiency (PMID: 7969402, 8629026). Insertion of a wild-type FOXN1 transgene has been demonstrated to rescue this phenotype, restoring both thymus function and hair growth (PMID: 12016512). The mechanism of pathogenicity is reported to be loss of function. There was no experimental evidence supporting a dominant negative molecular mechanism at the time of curation.

In summary, FOXN1 is definitively associated with semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID/CID GCEP on the meeting date October 21, 2021 (SOP Version 8).