T cell receptor excision circle (TREC)-based newborn screening enables early detection of severe combined immunodeficiency (SCID), but it also identifies infants with mild or asymptomatic non-SCID primary immunodeficiencies, for whom optimal management remains unclear.
We identified two female infants with heterozygous novel TBX1 variants after abnormal TREC-based newborn screening. Case 1, born at 38 weeks and 5 days of gestation, was admitted on day 13 of life because of low TRECs. She showed T cell lymphopenia (CD4+ 483/μL, CD8+ 161/μL, CD4+CD45RA+ 15.2%, phytohemagglutinin stimulation index 42.5) and hypocalcemia due to hypoparathyroidism, without structural cardiac abnormalities. G-banding and fluorescence in situ hybridization for 22q11.2 were normal. Genetic testing identified a heterozygous novel TBX1 variant (NM_080647.1:c.1439C>T), classified as a variant of uncertain significance (VUS). The same variant was detected in her mother, whose T cell counts were normal. Case 2, born at 40 weeks and 6 days of gestation, was evaluated on day 18 of life because of mildly low TRECs. She showed mild T cell lymphopenia (CD4+ 1,416/μL, CD8+ 650/μL, CD4+CD45RA+ 22.3%) without cardiac abnormalities or hypocalcemia. G-banding and fluorescence in situ hybridization for 22q11.2 were normal. Genetic testing identified a heterozygous novel TBX1 variant (NM_080647.1:c.1446_1464del), also classified as a VUS. The same variant was detected in her mother, whose T cell counts were normal.
These cases suggest that infants with abnormal TRECs may have novel TBX1 variants even in the absence of 22q11.2 deletion or major cardiac anomalies. However, both variants were classified as VUS and were also present in mothers with normal T cell counts and no apparent immunodeficiency; therefore, their pathogenic significance remains uncertain. As newborn screening increasingly identifies infants with non-SCID immunological abnormalities and variants of uncertain clinical relevance, standardized management strategies and careful longitudinal follow-up are needed.
