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.

A novel mutation in TRAC in a patient with abnormal newborn screening for severe combined immunodeficiency

“…Despite advanced genetic testing of known SCID genes, up to 10% of infants with SCID remain without a proven genotype. In this regard, homozygous mutations in TRAC resulting in TCR-α chain constant deficiency were not previously reported in the context of positive NBS (Kwan et al 2014;Dinur et al 2019;Mandola et al 2019;Giżewska et al 2020;Kumrah et al 2020;Scott et al 2021).…”