Introduction Immunological deficiencies associated with genetic defects, if identified earlier, may lead to targeted treatment resulting in improved management. Case Description A term 7-week old male with surgically repaired truncus arteriosus and history of hypocalcemia presents to Immunology Clinic for decreased newborn screening TRECs, Ct 37.39 (normal 3 (normal 3400-7600 mm3). Microarray analysis was normal. Physical exam demonstrated micrognathia and floppy pinnae. Additional evaluation revealed decreased CD3+ (1599 cells/mm3 (normal 2500-5500)), CD4+ (939 cells/mm3 (normal 1600-4000)) and naive CD4+CD45RA+ (732 cells/mm3 (normal 1200-2700)) T cells, normal immunoglobulin levels, and normal PTH level. Genetic testing demonstrated a heterozygous W303X nonsense mutation in the TBX1 gene, predicted to cause loss of normal protein function. The patient's father, who is a physician, had required cardiac surgery at 8 months of age for congenital hemitruncus; he has no other medical problems. Paternal FISH analysis was previously negative for chromosome 22q11 deletion. Further paternal genetic testing demonstrated the same heterozygous TBX1 mutation as the patient. Discussion DiGeorge Anomaly (DGA) is principally caused by heterozygous chromosome 22q11.2 deletion in 90% of subjects. Less frequently, TBX1 gene mutation leads to DGA. This patient had a cardiac defect, dysmorphic features, hypocalcemia, abnormal TRECs, and decreased T cells; whereas the father had only a cardiac defect. The spectrum of DGA is variable and not always detected by FISH or microarray. Therefore, TBX1 gene mutation should be examined in patients with DGA phenotype.