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. 2019 Feb;143(2):e20182300.
doi: 10.1542/peds.2018-2300.

Newborn Screening for Severe Combined Immunodeficiency and T-cell Lymphopenia in California, 2010-2017

George S Amatuni  1   2 , Robert J Currier  1 , Joseph A Church  3 , Tracey Bishop  4 , Elena Grimbacher  5 , Alan Anh-Chuong Nguyen  6 , Rajni Agarwal-Hashmi  7 , Constantino P Aznar  4 , Manish J Butte  8 , Morton J Cowan  1 , Morna J Dorsey  1 , Christopher C Dvorak  1 , Neena Kapoor  3 , Donald B Kohn  8 , M Louise Markert  9 , Theodore B Moore  8 , Stanley J Naides  10 , Stanley Sciortino  4 , Lisa Feuchtbaum  4 , Rasoul A Koupaei  4 , Jennifer M Puck  11
Affiliations

Newborn Screening for Severe Combined Immunodeficiency and T-cell Lymphopenia in California, 2010-2017

George S Amatuni et al. Pediatrics. 2019 Feb.

Abstract

Objectives: Newborn screening for severe combined immunodeficiency (SCID) was instituted in California in 2010. In the ensuing 6.5 years, 3 252 156 infants in the state had DNA from dried blood spots assayed for T-cell receptor excision circles (TRECs). Abnormal TREC results were followed-up with liquid blood testing for T-cell abnormalities. We report the performance of the SCID screening program and the outcomes of infants who were identified.

Methods: Data that were reviewed and analyzed included demographics, nursery summaries, TREC and lymphocyte flow-cytometry values, and available follow-up, including clinical and genetic diagnoses, treatments, and outcomes.

Results: Infants with clinically significant T-cell lymphopenia (TCL) were successfully identified at a rate of 1 in 15 300 births. Of these, 50 cases of SCID, or 1 in 65 000 births (95% confidence interval 1 in 51 000-1 in 90 000) were found. Prompt treatment led to 94% survival. Infants with non-SCID TCL were also identified, diagnosed and managed, including 4 with complete DiGeorge syndrome who received thymus transplants. Although no cases of typical SCID are known to have been missed, 2 infants with delayed-onset leaky SCID had normal neonatal TREC screens but came to clinical attention at 7 and 23 months of age.

Conclusions: Population-based TREC testing, although unable to detect immune defects in which T cells are present at birth, is effective for identifying SCID and clinically important TCL with high sensitivity and specificity. The experience in California supports the rapid, widespread adoption of SCID newborn screening.

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Conflict of interest statement

POTENTIAL CONFLICT OF INTEREST: Dr Markert developed technology for RVT-802, which has been licensed to Enzyvant Therapeutics GmbH. Dr Markert has received royalties from Enzyvant. Portions of Dr Markert and her research team’s salaries are being paid by the funding from Enzyvant. If the technology is commercially successful in the future, Dr Markert and Duke University may benefit financially. Dr Naides is employed by Quest Diagnostics. Donald Kohn is an inventor of a lentiviral vector for gene therapy of adenosine deaminase severe combined immunodeficiency, which Orchard Therapeutics Ltd has licensed from the University of California Regents; Dr Kohn is a consultant to Orchard Therapeutics Ltd and a member of its Scientific Advisory Board. Dr Cowan serves on the Scientific Advisory Boards for Homology Medicine, Inc, and Exogen, Inc, and on the Data and Safety Monitoring Board for bluebird bio, Inc. Dr Puck discloses spousal employment at a clinical DNA sequencing company, Invitae; the other authors have indicated they have no potential conflicts of interest to disclose.

Figures

FIGURE 1
FIGURE 1
Summary of NBS for SCID in California. A, Number of infants at each stage of screening. B, Numbers and proportions of infants in regular versus intensive care nurseries at each stage of the screening process. C, Final diagnosis category for infants with TCL in each nursery type. a Total infants screened included 91% of infants who were cared for in a regular well-infant nursery or born at home, and 9% who were cared for in a NICU. b Infants (47% from regular nurseries and 53% from NICUs) with a liquid blood sample tested after 1 positive or 2 incomplete TREC test results made up 0.17% of all births, excluding 20 newborns with TREC-positive test results who either died or were lost to follow-up before a liquid blood sample could be obtained and 2 infants born in another state who had positive TREC screen results and relocated to California for follow-up. c Infants with <1500 T cells per μL or <2% naïve CD3 CD4 CD45RA T helper cells (46% in the regular nursery and 54% in the NICU) made up 0.007% of the population (1 per 15 000 births).
FIGURE 2
FIGURE 2
Conditions diagnosed in infants with TCL identified by NBS, including 50 infants with typical or leaky SCID (including Omenn syndrome), 72 infants with a final diagnosis of a syndrome associated with T-cell impairment or of a non-SCID primary immunodeficiency disorder, 25 infants with congenital defects associated with secondary TCL, 33 infants with TCL and preterm birth alone, and 55 infants with an initial diagnosis of idiopathic TCL (in whom a syndrome was later diagnosed in 22, leaving 33 idiopathic cases with no underlying defect identified). a Includes 3 cases of CHARGE syndrome, 3 cases of diabetic embryopathy, and 1 each of CLOVES syndrome, EXTL3 deficiency (immune-skeletal dysplasia with neurodevelopmental abnormalities), Fryns syndrome (multiple anomalies with diaphragmatic defects), Nijmegen breakage syndrome (defect in the DNA repair protein nibrin, causing immune defects, microcephaly, short stature, and malignancy), Noonan syndrome (congenital heart disease, characteristic facial and physical features, and short stature), and RAC2 deficiency (a non-SCID primary immunodeficiency affecting neutrophils and lymphocytes). b Includes 2 cases of maternal immunosuppressive medication (azathioprine in 1, fingolimod in the other) and 1 case of neonatal teratoma of the thymus. c Infants with TCL associated with preterm birth alone were grouped by birth weight.
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