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Identification of 22q11.2 Deletion Syndrome via Newborn Screening for Severe Combined Immunodeficiency

Abstract

Purpose

Chromosome 22q11.2 deletion syndrome (22q11.2DS), the most common cause of DiGeorge syndrome, is quite variable. Neonatal diagnosis traditionally relies on recognition of classic features and cytogenetic testing, but many patients come to attention only following identification of later onset conditions, such as hypernasal speech due to palatal insufficiency and developmental and behavioral differences including speech delay, autism, and learning disabilities that would benefit from early interventions. Newborn screening (NBS) for severe combined immunodeficiency (SCID) is now identifying infants with 22q11.2DS due to T cell lymphopenia. Here, we report findings in such neonates, underscoring the efficacy of early diagnosis.

Methods

A retrospective chart review of 1350 patients with 22q11.2DS evaluated at the Children’s Hospital of Philadelphia identified 11 newborns with a positive NBS for SCID.

Results

Five out of 11 would have been diagnosed with 22q11.2DS without NBS, whereas early identification of 22q11.2DS in 6/11 led to the diagnosis of significant associated features including hypocalcemia, congenital heart disease (CHD), and gastroesophageal reflux disease that may have gone unrecognized and therefore untreated.

Conclusions

Our findings support rapidly screening infants with a positive NBS for SCID, but without SCID, for 22q11.2DS even when typically associated features such as CHD are absent, particularly when B cells and NK cells are normal. Moreover, direct NBS for 22q11.2DS using multiplex qPCR would be equally, if not more, beneficial, as early identification of 22q11.2DS will obviate a protracted diagnostic odyssey while providing an opportunity for timely assessment and interventions as needed, even in the absence of T cell lymphopenia.

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Acknowledgements

The authors would like to thank the patients with 22q11.2 deletion syndrome and their families for their generous contributions to this and related research studies. The authors also express gratitude to the students, research assistants, and staff affiliated with the 22q and You Center at the Children’s Hospital of Philadelphia. Special thanks to Madeline Baxter, Danielle DiCicco, Alex Melchiorre, Adam Silverman, Dr. Kathryn Kadash-Edmondon, and Dr. Marta Unolt. This work was supported by grants from the National Institute of Health (PO1-HD070454) and the National Institute of Mental Health (R01 MH087636-01A1 and 1U01MH101720-02).

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Correspondence to Donna M. McDonald-McGinn.

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Funding

This work was supported by grants from the National Institute of Health (PO1-HD070454) and the National Institute of Mental Health (R01 MH087636-01A1 and 1U01MH101720-02).

Conflict of Interest

Professor McDonald-McGinn has given lectures on 22q11.2DS for Natera. The remaining authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

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Barry, J.C., Crowley, T.B., Jyonouchi, S. et al. Identification of 22q11.2 Deletion Syndrome via Newborn Screening for Severe Combined Immunodeficiency. J Clin Immunol 37, 476–485 (2017). https://doi.org/10.1007/s10875-017-0403-9

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Keywords

  • 22q11.2 deletion
  • DiGeorge syndrome
  • newborn screening
  • SCID
  • TREC