A novel splice site variant in FOXN1 in a patient with abnormal newborn screening for severe combined immunodeficiency and congenital lymphopenia
Abstract
Background: The Forkhead box protein N1 (FOXN1) is a key regulator of thymic epithelial development, and its complete deficiency leads to a nude-severe combined immunodeficiency (SCID) phenotype. More recently, heterozygous mutations in FOXN1 have been linked with a syndrome of congenital lymphopenia and a wide clinical spectrum, with most cases being caused by missense mutations.
Aim: To broaden the genotypic and phenotypic spectrum of heterozygous FOXN1 deficiency.
Methods: Case report of a patient with FOXN1 haploinsufficiency due to a novel splice-site mutation.
Results: Our patient was identified at 3 weeks of life given an abnormal newborn screen (NBS) for SCID, and was found to have congenital lymphopenia preferentially affecting CD8+ T-cells. Her cellular and humoral function were both excellent, and she has remained entirely asymptomatic and thriving for the first 3 years of her life. The patient was found on whole exome sequencing to carry a heterozygous splice-site mutation in the FOXN1 gene, affecting the Forkhead domain. The mutation was also identified in her asymptomatic mother.
Conclusion: Heterozygous FOXN1 mutations are an increasingly-recognized cause of congenital lymphopenia. Our experience suggests most patients remain clinically well, with main manifestation including T-lymphopenia, mostly affecting CD8+ cells. Identification of the same variant in an asymptomatic parent suggests age-dependent improvement in T-cell counts and an overall benign course, while provides impetus for diligent conservative management with regular follow-up.
Statement of novelty: Heterozygous FOXN1 deficiency is a relatively new entity, attributed in most cases to missense mutations in FOXN1. To further expand the knowledge basis regarding this emerging disorder, as well as its genotypic repertoire, we herein report a case of heterozygous FOXN1 deficiency caused by a splice site mutation.
Formats available
You can view the full content in the following formats:
REFERENCES
Bosticardo M., Yamazaki Y., Cowan J., Giardino G., Corsino C., Scalia G., Prencipe R., Ruffner M., Hill D.A., Sakovich I., and Yemialyanava I. 2019. Heterozygous FOXN1 variants cause low TRECs and severe T cell lymphopenia, revealing a crucial role of FOXN1 in supporting early thymopoiesis. Am. J. Hum. Genet. 105(3): 549–561.
Flanagan S.P. 1966. ‘Nude’, a new hairless gene with pleiotropic effects in the mouse. Genet. Res. 8(3): 295–309.
Frank J., Pignata C., Panteleyev A.A., Prowse D.M., Baden H., Weiner L., Gaetaniello L., Ahmad W., Pozzi N., Cserhalmi-Friedman P.B., and Aita V.M. 1999. Exposing the human nude phenotype. Nature, 398(6727): 473–474.
Lam E.W., Brosens J.J., Gomes A.R., and Koo C.Y. 2013. Forkhead box proteins: Tuning forks for transcriptional harmony. Nat. Rev. Cancer, 13(7): 482–495.
Nowell C.S., Bredenkamp N., Tetelin S., Jin X., Tischner C., Vaidya H., Sheridan J.M., Stenhouse F.H., Heussen R., Smith A.J., and Blackburn C.C. 2011. Foxn1 regulates lineage progression in cortical and medullary thymic epithelial cells but is dispensable for medullary sublineage divergence. PLoS Genet. 7(11): e1002348.
Pignata C., Fiore M., Guzzetta V., Castaldo A., Sebastio G., Porta F., and Guarino A. 1996. Congenital alopecia and nail dystrophy associated with severe functional T‐cell immunodeficiency in two sibs. Am. J. Med. Genet. 65(2): 167–170.
Romano R., Palamaro L., Fusco A., Giardino G., Gallo V., Del Vecchio L., and Pignata C. 2013. FOXN1: A master regulator gene of thymic epithelial development program. Front. Immunol. 4: 187.
Žuklys S., Handel A., Zhanybekova S., Govani F., Keller M., Maio S., Mayer C.E., Teh H.Y., Hafen K., Gallone G., and Barthlott T. 2016. Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells. Nat. Immunol. 17(10): 1206–1215.
Information & Authors
Information
Published In
LymphoSign Journal
Volume 8 • Number 1 • March 2021
Pages: 1 - 4
History
Received: 4 February 2021
Accepted: 25 February 2021
Accepted manuscript online: 26 February 2021
Copyright
© 2021.
Authors
Metrics & Citations
Metrics
Other Metrics
Citations
Cite As
OriScott, JennyGarkaby, JessicaWillett-Pachul, Amarilla B.Mandola, DanieleMerico, and YehonatanPasternak. 2021. A novel splice site variant in FOXN1 in a patient with abnormal newborn screening for severe combined immunodeficiency and congenital lymphopenia. LymphoSign Journal.
8(1): 1-4. https://doi.org/10.14785/lymphosign-2021-0013
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
Cited by
1. Management of newborn screening for severe combined immunodeficiency at a quaternary referral centre—an updated algorithm
2. An unusual presentation of DiGeorge syndrome
3. Novel heterozygous FOXN1 mutation identified following newborn screening for severe combined immunodeficiency is associated with improving immune parameters
4. A novel mutation in TRAC in a patient with abnormal newborn screening for severe combined immunodeficiency
View Options
Get Access
Login options
Check if you access through your login credentials or your institution to get full access on this article.
