Newborn Screening Aids Discovery of Novel Gene Variants

NIAID Now | August 22, 2019

Blood from a heel stick is taken for newborn screening.

Credit: U.S. Air Force

Variations in a single copy of a gene called FOXN1 can cause a positive newborn screening test for severe combined immunodeficiency (SCID), a rare and life-threatening condition typically treated by bone marrow transplantation. The screening test measures a byproduct of T-cell development and can indicate low levels of immune T cells, one of the characteristics of SCID.

Infants with FOXN1 haploinsufficiency, in which one of a person’s two FOXN1 copies harbors mutations that hamper its function, may have low T-cell levels at birth and thus be at increased risk for infections, a new study by NIAID scientists and colleagues has revealed. However, these infants do not have SCID and do not require or benefit from bone marrow transplantation, a procedure that can be life-saving for those who need it but can have serious side effects. The researchers found that for most individuals with FOXN1 haploinsufficiency, the T-cell deficiency appears to improve over time. They report their findings in the American Journal of Human Genetics.

Widespread implementation of newborn screening for SCID is leading to identification of a growing number of infants with low T cells at birth. Properly defining the cause of low T-cell levels is critical to prompt appropriate surveillance, prevention and treatment, the authors emphasize.

The FOXN1 gene provides instructions for a protein that plays a critical role in the formation of the thymus, the gland in which T cells mature and become functional. The FOXN1 protein also is important for development of the hair, nails and skin. Each person has two copies of the FOXN1 gene—one inherited from each parent. Babies with mutations in both FOXN1 copies have no hair, may have misshapen or damaged nails, and are at high risk for life-threatening infections due to very low to undetectable T-cell levels at birth.

The new study, led by NIAID’s Luigi Notarangelo, M.D., focused on 25 infants with FOXN1 haploinsufficiency, 21 of whom were identified by a positive newborn screening test for SCID. The other four infants were identified due to severe, recurrent infections and low T-cell counts. The researchers also evaluated 22 adults with FOXN1 haploinsufficiency.

Most of the infants—18 out of 25, or 72%—experienced infections, especially viral infections and infections of the upper respiratory tract. However, severe infections occurred only in 5 out of 25 infants, or 20%. Furthermore, only six of the 22 adults, or 27%, had a history of recurrent infections. Some infants and adults experienced other symptoms potentially attributable to FOXN1 mutations, including thin hair or hair loss, skin conditions like eczema, and misshapen or damaged nails. 

T cells can be broadly divided into two categories: CD8+ T cells, which are crucial for recognizing and removing infected and damaged cells, and CD4+ T cells, which help coordinate immune responses against pathogens. Children with FOXN1 haploinsufficiency had low levels of both types of T cells early in life, but levels of CD4+ T cells began to increase after 2 years of age. Most adults with the condition had CD4+ T-cell levels in the normal range, while CD8+ T-cell levels remained low.

Experiments with a mouse model of FOXN1 haploinsufficiency further supported the conclusion that FOXN1 is most critical during the embryonic period and early life, with FOXN1 haploinsufficiency causing low T-cell levels at birth that progressively improve with age.

The researchers suggest that infants with FOXN1 haploinsufficiency be closely medically monitored due to the risk of infections. Additional studies of FOXN1 haploinsufficiency are needed to improve understanding of the condition and help guide treatment options.


M Bosticardo et al. Heterozygosity for Forkhead Box N1 (FOXN1) gene variants may cause low TRECs and severe T cell lymphopenia at birth, revealing a critical role of FOXN1 levels in supporting thymopoiesis early in life. American Journal of Human Genetics DOI: 10.1016/j.ajhg.2019.07.014 (2019).

Contact Information

Contact the NIAID Media Team.