Case of 22q11.2 deletion syndrome not identified by TBX1 screening with a positive SCID newborn screen

Individuals with 22q11.2 deletion syndrome (22q11.2DS) have an embryological midline fusion defect, which can result in a syndrome including congenital heart disease, cleft palate, hypoparathyroidism, thymic hypoplasia, immunologic abnormalities, and developmental delay. The majority of patients have a 3 megabase deletion, which contains multiple genes, including the T-box transcription factor (TBX1) gene. Definitive diagnosis is made through fluorescent in situ hybridization (FISH) or chromosomal microarray (CMA). Newborn screening (NBS) for severe combined immune deficiency (SCID) via low T-cell receptor excision circles (TRECs) can also identify this population if thymic output is low. Samples from infants who screen positive undergo further testing, which includes a purine profile and TBX1 deletion analysis. Diagnostic follow-up testing is centre-dependent and may not include more definitive testing for 22q11.2DS by FISH or CMA. We report a case of a newborn with 22q11.2DS, detected by low TRECs on the SCID NBS, with a normal screening TBX1 result, who was subsequently found to have a TBX1 gene deletion on follow-up 22q11.2 FISH and CMA. This case highlights the limitations of the TBX1 screening assay and the importance of performing diagnostic testing with FISH and (or) CMA regardless of the initial TBX1 result. It also emphasizes the need for a standardized follow-up testing algorithm across institutions for newborns who screen positive for SCID. Statement of novelty: To our knowledge, this is the first case to be described in the literature where a newborn with 22q11.2DS with a typical deletion encompassing the TBX1 gene was not identified by initial TBX1 screening, highlighting the limitations of this test as a standalone screening assay.