Research

Original Investigation

Newborn Screening for Severe Combined Immunodeficiency
in 11 Screening Programs in the United States
Antonia Kwan, PhD, MRCPCH; Roshini S. Abraham, PhD; Robert Currier, PhD; Amy Brower, PhD; Karen Andruszewski, BS; Jordan K. Abbott, MD;
Mei Baker, MD; Mark Ballow, MD; Louis E. Bartoshesky, MD; Vincent R. Bonagura, MD; Francisco A. Bonilla, MD, PhD; Charles Brokopp, DrPH;
Edward Brooks, MD; Michele Caggana, ScD; Jocelyn Celestin, MD; Joseph A. Church, MD; Anne Marie Comeau, PhD; James A. Connelly, MD;
Morton J. Cowan, MD; Charlotte Cunningham-Rundles, MD; Trivikram Dasu, PhD; Nina Dave, MD; Maria T. De La Morena, MD; Ulrich Duffner, MD;
Chin-To Fong, MD; Lisa Forbes, MD; Debra Freedenberg, MD; Erwin W. Gelfand, MD; Jaime E. Hale, BS; I. Celine Hanson, MD; Beverly N. Hay, MD;
Diana Hu, MD; Anthony Infante, MD, PhD; Daisy Johnson, BSN; Neena Kapoor, MD; Denise M. Kay, PhD; Donald B. Kohn, MD; Rachel Lee, PhD;
Heather Lehman, MD; Zhili Lin, PhD; Fred Lorey, PhD; Aly Abdel-Mageed, MD, MBA; Adrienne Manning, BS; Sean McGhee, MD; Theodore B. Moore, MD;
Stanley J. Naides, MD; Luigi D. Notarangelo, MD; Jordan S. Orange, MD; Sung-Yun Pai, MD; Matthew Porteus, MD, PhD;
Ray Rodriguez, MD, JD, MPH, MBA; Neil Romberg, MD; John Routes, MD; Mary Ruehle, MS; Arye Rubenstein, MD; Carlos A. Saavedra-Matiz, MD;
Ginger Scott, RN; Patricia M. Scott, MT; Elizabeth Secord, MD; Christine Seroogy, MD; William T. Shearer, MD, PhD; Subhadra Siegel, MD;
Stacy K. Silvers, MD; E. Richard Stiehm, MD; Robert W. Sugerman, MD; John L. Sullivan, MD; Susan Tanksley, PhD; Millard L. Tierce IV, DO;
James Verbsky, MD, PhD; Beth Vogel, MS; Rosalyn Walker, MD; Kelly Walkovich, MD; Jolan E. Walter, MD, PhD; Richard L. Wasserman, MD, PhD;
Michael S. Watson, MS, PhD; Geoffrey A. Weinberg, MD; Leonard B. Weiner, MD; Heather Wood, MS; Anne B. Yates, MD; Jennifer M. Puck, MD
Editorial page 701
IMPORTANCE Newborn screening for severe combined immunodeficiency (SCID) using

assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID
was added to the national recommended uniform panel for newborn screened disorders in
2010. Currently 23 states, the District of Columbia, and the Navajo Nation conductpopulation-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in
100 000 births.

Supplemental content atjama.com

OBJECTIVES To present data from a spectrum of SCID newborn screening programs, establish
population-based incidence for SCID and other conditions with T-cell lymphopenia, anddocument early institution of effective treatments.
DESIGN Epidemiological and retrospective observational study.
SETTING Representatives in states conducting SCID newborn screening were invited tosubmit their SCID screening algorithms, test performance data, and deidentified clinical andlaboratory information regarding infants screened and cases with nonnormal results. Infants
born from the start of each participating program from January 2008 through the mostrecent evaluable date prior to July 2013 were included. Representatives from 10 states plus
the Navajo Area Indian Health Service contributed data from 3 030 083 newborns screened
with a TREC test.
MAIN OUTCOMES AND MEASURES Infants with SCID and other diagnoses of T-cell
lymphopenia were classified. Incidence and, where possible, etiologies were determined.
Interventions and survival were tracked.
RESULTS Screening detected 52 cases of typical SCID, leaky SCID, and Omenn syndrome,affecting 1 in 58 000 infants (95% CI, 1/46 000-1/80 000). Survival of SCID-affected infants
through their diagnosis and immune reconstitution was 87% (45/52), 92% (45/49) for infants
who received transplantation, enzyme replacement, and/or gene therapy. Additional
interventions for SCID and non-SCID T-cell lymphopenia included immunoglobulin infusions,preventive antibiotics, and avoidance of live vaccines. Variations in definitions and follow-up
practices influenced the rates of detection of non-SCID T-cell lymphopenia.
CONCLUSIONS AND RELEVANCE Newborn screening in 11 programs in the United States
identified SCID in 1 in 58 000 infants, with high survival. The usefulness of detection of
non-SCID T-cell lymphopenias by the same screening remains to be determined.

JAMA. 2014;312(7):729-738. doi:10.1001/jama.2014.9132

Author Affiliations: Author
affiliations are listed at the end of thisarticle.
Corresponding Author: Jennifer M.
Puck, MD, Department of Pediatrics,
HSE-301A, University of California,
San Francisco, 513 Parnassus Ave, San
Francisco, CA 94143 (puckj@peds.ucsf.edu).

729

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Research Original Investigation

Newborn Screening for Severe Combined ImmunodeficiencyT

he purpose of newborn screening is early detection ofinborn conditions for which prompt treatments mitigate mortality or irreversible damage. The first heritable immune disorders to which newborn screening has been
applied are those that together comprise severe combined immunodeficiency (SCID), caused by defects in any of a diverse
group of gene products essential for development of adaptive immunity provided by T and B lymphocytes.1,2 A featureof all SCID is defective production of T cells. In most SCID,
B cells are also defective, but even normal B cells cannot produce antibodies without T-cell help. Thus, infants with SCID
are susceptible to life-threatening infections. Early detection
and treatment optimize survival.3-5 Provided that SCID is diagnosed before infections become overwhelming, affected infants can be rescued with hematopoietic stem cell transplantation; gene therapy; or, for adenosine deaminase deficiency,
enzyme replacement therapy.2,5-8
Population-based screening is the only means to detect
SCID prior to the onset of infections in most cases, as more than
80% lack a positive family history.9,10 T-cell receptor excision
circles (TRECs), a biomarker for T lymphopoiesis,11 can be measured by polymerase chain reaction (PCR) using DNA isolated
from infant dried blood spots collected for newborn screening.9
Dried blood spots from apparently healthy newborns who werelater diagnosed with SCID lacked TRECs.9 Confirmation of theutility of the TREC test,12 adaptation for pilot newborn screening programs in Wisconsin13 and Massachusetts,14 and an evidence-based review led to the recommendation by the US Department of Health and Human Services Secretary in 2010 that
SCID be added to the Uniform Screening Panel for all newborns, with related T-cell deficiencies added to the list of secondary targets.15 Currently, 23 states, the District of Columbia, and the Navajo Nation screen approximately two-thirdsof all infants born in the United States for SCID. Individual states
have confirmed detection of SCID as well as additional disorders with low T-cell numbers, which also may benefit from further assessment of immune dysfunction and from protective
treatments.13,16-18 Here we present the first combined analysis of more than 3 million infants screened for SCID in 10 states
and the Navajo Nation, providing a population-based overview of SCID and non-SCID T-cell lymphopenia.

(February 1, 2012, to June 30, 2013). Five states had insufficient data due to short SCID screening program duration:
Iowa began June 3, 2013, and had fewer than 3000 births
screened by the close of our study, based on published summaries of national vital statistics19; Pennsylvania, Utah, andWyoming began July 1, 2013; and Ohio began July 29, 2013;
thus, these states had no screened births prior to the close of
our study. Florida started screening October 1, 2012, andscreened an estimated 160 000 infants for SCID during thestudy period while Minnesota started January 7, 2013, accruing data for around 33 000 infants during the study period. In
both states an administrative decision not to participate wasmade based on programmatic constraints. An estimatedmaximum of 196 000 screened births could have been
included in the study if all programs had participated (a 6.5%
increase above the total included in the 11 participating
programs).19 All programs, whether participating in the study
or not, conformed to the approved guidelines for implementation of SCID screening developed by the Clinical and Laboratory Standards Institute.20
Institutional review board approvals for research with human subjects or waivers for submitting data for this study wereobtained in accord with requirements of each participating program. Deidentified SCID screening information was captured
either via the R4S database,21 a tool for quality improvementof newborn screening supported by the Newborn Screening
Translational Research Network, or via electronic spreadsheets. As defined in Table 1, typical SCID, leaky SCID, andOmenn syndrome, which require immune system restoration for survival, were the primary targets of SCID screening,
while additional diagnoses were detected as secondary
targets.5,20,22 Infants with abnormal TREC results had flow cytometry to enumerate lymphocyte subsets; HIV PCR or maternal serodiagnosis; and further evaluation to establish a diagnosis. To ensure follow-up and ascertainment of SCID cases,
public health programs engaged as advisors the immunologists and transplant clinicians who have diagnosed and cared
for infants with SCID in each state. Regular reviews were conducted between public health personnel and clinical experts
in each program to uncover any missed (false-negative) cases
and monitor screening test performance and follow-up.

Aggregate Population Data and Case Data

Methods
All SCID newborn screening programs active as of July 31,
2013, were invited, and 11 provided data for this study withthe following accrual dates: California (August 16, 2010, to
May 31, 2013), Colorado (February 1, 2012, to March 31, 2013),
Connecticut (October 1, 2011, to May 1, 2013), Delaware (July6, 2012, to June 30, 2013), Massachusetts (February 1, 2009, toJanuary 31, 2013), Michigan (October 1, 2011, to March 31,2013), Mississippi (January 1, 2012, to December 31, 2012),
New York (September 29, 2010, to September 28, 2012), Texas(December 1, 2012, to May 31, 2013), Wisconsin (January 1,
2008, to December 31, 2012), and the Navajo Nation spanningparts of Arizona, New Mexico, and Utah, where health care isprovided through the Navajo Area Indian Health Service
730

Programs provided accrual dates, numbers of newborns
screened, and data about infants with nonnormal TREC results (after 1 or multiple dried blood spot samples) in each diagnosis category. State-designated immunologists provided deidentified data in consultation with screening program officials
to ensure compliance with privacy policies. Gene and syndrome diagnoses were requested. Numbers of infants withT cells within designated ranges and interventions and outcomes were reported by public health programs and by participating immunologists who evaluated and followed up or
referred infants for treatment.

TREC Newborn Screening

See the eMethods and eTable in the Supplement for individual program details beyond those published.13,14,17,18,20 All

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jama.comOriginal Investigation Research

Newborn Screening for Severe Combined Immunodeficiency

Table 1. Classification of Conditions With Low T-Cell Receptor Excision Circles and Low T-Cell Numbers Found by
Newborn Screening
Definition of Condition
CD3 T Cells/μL

Proliferation
to PHA

Other Supporting Features

Primary Targets of Newborn Screening
Typical SCIDa<300(autologous)<10% of normal

Leaky SCIDa

300-1500, few
naive T cells

Reduced (10%-50% No maternal T cells detectable; incomplete defect(s)of normal)
in a known SCID gene

Omenn syndrome

Oligoclonal
T cells

Reduced (10%-50% Erythroderma, hepatosplenomegaly, eosinophilia,of normal)
and elevated levels of serum IgE antibody

Detectable maternal T cells in peripheral blood;
proven deleterious defect(s) in a known SCID gene

Secondary Targets of Newborn Screening
Syndrome with low
T-cell numbers

Recognized genetic syndrome that includes low T-cell numbers within its spectrum of clinicalfindings

Secondary T-cell
lymphopenia

Congenital malformation or disease process without an intrinsic defect in productionof circulating T cells

Preterm birth alone

Preterm birth and low birth weight, with low T-cell numbers early in life that normalize
over time

Idiopathic T-cell
lymphopenia, also
called variant SCID

Low T-cell numbers without recognized cause; 6 programs used 300-1500 autologous
T cells/μL plus evidence of functional immune cell impairment, while other programs
included infants with higher T-cell numbers (see Table 4).b

programs conformed to the guidelines that included reporting any nonnormal TREC test results within the first 3 weeks
of life and performing flow cytometry, where indicated, by 4
to 5 weeks of age. In addition, all programs participated in the
TREC Proficiency Quality Assurance Program, cosponsored by
the Centers for Disease Control and Prevention and the Association of Public Health Laboratories.23

Statistical Analyses

Statistical analyses were conducted in SAS version 9.3 (SAS Institute). Confidence intervals were derived from normal approximation of binomial data or from inversion of cumulative binomial distribution, as appropriate, but not calculated
where numbers were too small. Confidence intervals were2-sided, except that when the number of cases or noncases was
5 or fewer, 1-sided intervals were calculated. P values less than
.05 were considered statistically significant.

Results
This study included data for 3 030 083 infants from 11 programs (Table 2). Nonparticipating programs cited insufficientdata, lack of personnel to assemble data, or privacy concerns.
California, with nearly 3 years of screening and 12.5% of all USbirths,23 contributed 46%, followed by New York with 16% from
2 years. Wisconsin and Massachusetts, with fewer annual births
but longer program durations, contributed 11% and 10%, respectively.

Detection of SCID

There were 52 SCID cases (42 with typical SCID, 9 with leaky
SCID, and 1 with Omenn Syndrome), an overall incidence of 1
in 58 000 births (95% CI, 1/46 000-1/80 000) (Table 2). The incidence was not significantly different in any state program but
as expected was higher in the Navajo Nation (1/3500; 95% CI,
1/630-1/4000), where a frequent founder mutation in DCLRE1C,
encoding a DNA repair protein, causes SCID in an estimated 1

Abbreviations:
PHA, phytohemagglutinin;
SCID, severe combined
immunodeficiency.
a

As adopted by the Primary Immune
Deficiency Treatment Consortium
and R4S Laboratory Performance
Database, SCID and leaky SCID were
defined by laboratory criteria rather
than infectious complications.

b

On discovery of an etiology for low
T cells, the affected individual was
moved to the appropriate
alternative category.

in 2000 births.24,25 No cases of SCID as defined in Table 1 were
initially missed by TREC screening but detected later, and overdiagnosis of SCID when not clinically present was avoided byhaving flow cytometric determination of T-cell numbers, a definitive test, mandated for all infants with very low or undetectable TRECs (eTable in the Supplement).
Genetic causes and outcomes of the 52 infants with conditions that were primary targets of TREC newborn screening
are shown in Table 3 and included 42 infants (81%) with typical and 10 (19%) with leaky SCID. Mutations in the X chromosome–linked IL2RG gene, encoding the cytokine receptor common γ chain, accounted for only 19% of cases. Recombinase
activating gene 1 (RAG1) defects, causing impairment of V(D)Jlymphocyte antigen receptor recombination, were detected in
4 typical and 4 leaky SCID cases, 1 of the latter with Omenn
syndrome, accounting for 15% of all 52 cases. Interleukin-7 defects and adenosine deaminase deficiency contributed 12% and11%, respectively. New SCID gene defects included mutationsof tetratricopeptide repeat domain 7A (TTC7A) that disrupted not only T-cell development, but also intestinal epithelial polarity, leading to multiple bowel atresias.26,27 In
addition, typical SCID was diagnosed in a case of PallisterKillian syndrome, in which congenital diaphragmatic defects
associated with tetrasomy 12p are frequently incompatible withlife, as in this case. Although not previously recognized as an
immune deficiency, Pallister-Killian syndrome has been known
for poor lymphocyte proliferation in the context of cytogenetic analysis.28
Of the 12 infants without a molecular diagnosis, no genetest results were available for 2, and 2 males with T−B+NK− phenotype died prior to testing (Table 3). However, in 6 typical and2 leaky SCID cases (15% of all typical and leaky SCID cases
found), no molecular defects were identified in known SCID
genes: the common γ chain or interleukin-7 receptors, adenosine deaminase or purine nucleoside phosphorylase enzymes, janus kinase-3, recombinase activating genes, the DNA
repair enzyme Artemis, or components of the CD3 receptor
complex.
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731

Research Original Investigation

Newborn Screening for Severe Combined Immunodeficiency

Table 2. Infants Screened and Incidence of SCID (Including Leaky SCID) in 11 Contributing Programs
California Colorado Connecticut Delaware Massachusetts Michigan Mississippi

New York

Texas

Wisconsin

Duration of
screening
included,
mo

34

13

19

12

48

18

12

17

24

6

60

Infants
screened,
No.a

1 384 606

70 98957 136

11 202

293 371

162 528

37 6133498

485 912183 191

340 037

3 030 083

Flow
cytometryreferrals,bNo. (%)[95% CI]c206(14.9)[12-17]10(14.1)[5.4-23]22(38.5)[22-55]9(80.3)[28-133]

63(21.5)[16-27]114(70.1)[57-83]5(13.3)[1.6-25]1(28.6)

249
478(135.9)(98.4)[90-107] [119-153]

108(31.8)[26-38]1265(41.8)[39-44]23

SCID cases

1

3

1

4

2

1

1

10

2

4

52

1/60 000 1/71 000

1/19 000d

1/11 000d

1/73 000

1/81 000

1/38 000

1/3500d

1/49 000

1/92 000

1/85 000

1/58 000[1/46 0001/80 000]

SCID
cases per
100 000
screened,
No.
[95% CI]c1.7
1.4[1.0-2.3] [0.3-5.2]

5.2[1.9-15]

8.9[2.2-49]

1.4[0.4-3.5]

1.2[0.4-4.4]

2.7[0.6-5]29
2.0[6.9-159] [0.8-3.3]

1.1[0.3-3.9]

1.2[0.3-3.0]

1.72[1.3-2.2]

3/3
(100)

1/1
(100)

4/4
(100)

1/2
(50)

0/1

0/2

4/4
(100)

45/52f(86)[79-98]1/1(100)Abbreviation: SCID, severe combined immunodeficiency.
Includes 175 nonviable infants (<0.006% from all programs) who had anonnormal TREC result, but died before further testing could be done;
although causes of these deaths were not available and it is theoreticallypossible that some of these infants had SCID, SCID is not known to lead todeath in the newborn period.

b

Per 100 000 screened. Referral criteria for flow cytometry varied according toindividual program algorithms (see the eTable in the Supplement).

c

Confidence intervals derived from normal approximation of binomial data or
inversion of cumulative binomial distribution, as appropriate. No CI given
where numbers were too small.

Definitions and Incidence of Abnormal TRECs
and Low T Cells

Although all programs identified SCID cases with undetectable or very low TRECs, differences in intermediate steps forarriving at a SCID diagnosis influenced rates of follow-up testing and capture of non-SCID conditions (Table 1 and Table 4).20
After an abnormal TREC screen, flow cytometry to enumerate T, B, and NK cells, as well as naive and memory phenotype T cells, was standard for all programs. However, different TREC cutoffs resulted in different referral rates for flow
cytometry; therefore, neither aggregate analysis nor interprogram comparison of incidences of infants with particular TREC
cutoff values was possible. Rates of referral for flow cytometry were less than 15 per 100 000 in California, Colorado, andMississippi but 7- to 9-fold higher in New York and Texas(Table 4).
Furthermore, definitions of T-cell lymphopenia varied.
Healthy newborns have abundant T cells (mean, 3100/μL;
range, 2500-5500).29 While 6 screening programs defined significant T-cell lymphopenia as T-cell count less than 1500/μL
and opted not to recall infants with higher T-cell numbers
as long as the proportion of naive cells was adequate,
4 programs used T-cell cutoffs of 2500/μL or more, andNew York left it to individual immunologists to define T-cell
732

Total

SCID
incidence

SCID infant 21/23
survival,(91)
No./Total[83-100]
No. (%)[95% CI]c,ea

NavajoNation

1/1
(100)

9/10
(90)
[70-100]d

Navajo SCID incidence was an outlier, consistent with the known foundermutation of this population. Because of the low numbers screened, apparent
higher incidences in Connecticut and Delaware were not significantly different(P > .05) from the other states.

eSurvival percentage CI for California and New York is the exact 1-sided binomial
CI; total survival percentage CI is 2-sided.

f

Of the 7 deceased infants, 1 each in Mississippi, New York, and Texas died prior
to receiving immune restoring therapy because of complications present
before referral for hematopoietic cell transplantation; the remaining 4 diedafter transplantation.

lymphopenia.30 Different TREC and T-cell lymphopenia cutoffs thus resulted in variable false-positive rates, defined
here as nonnormal TREC results that require a follow-up flow
cytometry test, which when performed shows T cells above
the program cutoff for T-cell lymphopenia (Table 4). These
false-positive rates ranged from 0 in Mississippi and the
Navajo Nation, where all infants referred to flow cytometry
had T-cell lymphopenia by program definitions (<2500/μL
and <1500/μL, respectively), to 82% in New York, where 478
infants were referred for flow cytometry, but only 84 (18%)
had T-cell lymphopenia as determined by treating physicians(Table 4). A subgroup analysis for the 6 programs defining
T-cell lymphopenia as a T-cell count less than 1500/μL
showed a positive predictive value of 36% (95% CI, 32%-41%)
for a nonnormal TREC test to indicate this degree of T-cell
lymphopenia.
Regardless of selected T-cell lymphopenia cutoff, all programs identified predominantly male infants; the 6-program
subgroup had 66% of males with T-cell lymphopenia (95% CI,
59%-73%). Programs did not report preterm infants with low
T cells in a uniform manner, partly due to automatically repeated TREC testing of preterm infants in neonatal intensive
care units in some screening programs (eMethods in the
Supplement). However, 13% (95% CI, 8.4%-18%) of infants with

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jama.comOriginal Investigation Research

Newborn Screening for Severe Combined Immunodeficiency

Table 3. Diagnosis and Course of 52 Infants With Primary Target Conditions: SCID and Leaky SCID
Treatmentsa
Gene Diagnosis

No. ofInfants

Typical SCID

42

Hematopoietic
Cell Transplant

Gene
Therapy

Adenosine Deaminase
Enzyme Replacement
Therapy

Outcomes(to Age ≥11 Months)

IL2RG(NP_000197.1)

9

9

1

0

Surviving, engrafted

IL7RA(NP_002176.2)

6

6

0

0

Surviving, engrafted

ADA(NP_000013.2)

5

0

3

2

Surviving, 3 with genemodified T cells and 2 withT cells after having received
enzyme replacement

RAG1(NP_000439.1)

4

4

0

0

3 surviving, engrafted;
1 died posttransplant due tobusulfan toxicityb

JAK3(NP_000206.2)

3

3

0

0

Surviving, engrafted

DCLRE1C(NP_001029027.1)

1

1

0

0

Surviving, engrafted

RAG2(NP_000527.2)

1

1

0

0

Surviving, engrafted

CD3D(NP_000723.1)

1

1

0

0

Surviving, engrafted

TC7A(NP_001275880.1)

1

1

0

0

Surviving, engrafted

Pallister-Killian
syndrome withtetrasomy 12p

1

0

0

0

Died due to severe
diaphragmatic defectNo mutation
found, withknown SCID
genes excluded

6

5

0

0

4 surviving, engrafted;
1 died posttransplant due tocytomegalovirus present at
diagnosis; 1 not treated,
died due to severecongenital anomalies

Genetic testing
not completed

4

3

0

0

2 surviving, engrafted;
1 died posttransplant due torespiratory illness present at
diagnosis; 1 not treated,
died before transplant

Leaky SCID

10

RAG1
(NP_000439.1)

4

4 (1 withOmenn
syndrome)

00Surviving, engrafted

RMRP(NR_003051.3)

2

2

0

0

1 surviving, engrafted;
1 died posttransplant due tobusulfan toxicityb

IL2RG(NP_000197.1)

1

1

0

0

Surviving, engrafted

DCLRE1C(NP_001029027.1)

1

1

0

0

Surviving, engrafted

No mutation
found, withknown SCID
genes excluded

2

2

0

0

Surviving, engrafted

T-cell lymphopenia in the 6-state subgroup had prematurity
or low birth weight as the only identified cause. As previously reported, T-cell lymphopenia of prematurity resolved tonormal over time.13,18 After excluding infants with SCID andprematurity, the rate of non-SCID T-cell lymphopenia in thesubgroup was 1 in 14 000 infants (95% CI, 1/11 600-1/16 400),
whereas more inclusive definitions led to 1 in 2100 in Michigan, 1 in 6500 in Massachusetts and New York, and 1 in 8100
in Wisconsin (Table 4).

Causes of Non-SCID T-Cell Lymphopenia

Of 411 infants with non-SCID T-cell lymphopenia (Table 1 andTable 5), 136 (33%) were reported to have a recognized con-Abbreviation: SCID, severe combined
immunodeficiency.
aSome infants had >1 treatment
modality.

b

Hepatic sinusoidal obstructive
syndrome, a known complication ofbusulfan chemotherapy.

genital syndrome associated with T-cell impairment. Of these
syndromic infants, 78 (57%) had DiGeorge syndrome/chromosome 22q11.2 deletion, followed by 21 (15%) with trisomy 21. The remaining specified syndrome diagnoses included repeated instances of ataxia telangiectasia31 and trisomy
18 (each 3%), CHARGE (coloboma, heart defect, atresia choanae, retarded growth and development, genital and ear abnormalities) syndrome (2%), and other rare entities as listed(Table 5).32
There were 117 cases of T-cell lymphopenia attributed toother medical conditions (28% of all non-SCID T-cell lymphopenia cases) (Table 5), the most predominant being congenital heart disease in 30 cases (26%), followed by other congenJAMA August 20, 2014 Volume 312, Number 7

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Research Original Investigation

Newborn Screening for Severe Combined Immunodeficiency

Table 4. Infants With Non-SCID T-Cell Lymphopenia Followed Up in Each Program After Nonnormal TREC Results<1500 T Cells/μL Cutoff

b

Texas

Subgroup
Summary

Massachusetts

Mississippi Wisconsin

Michigan

New
York

TCLa

California

Colorado

Connecticut Delaware

Infants
with TCL/
Total No.
referred
to flowcytometryb(%)[95% CI]c80/206(39)[28-50]

4/10(40)[12-65]

9/22(41)[8.8-73]

4/9(44)[14-70]1/1(100)

82/249(33)[23-43]

180/479(36)[32-41]

5/5
51/63
(100)
(81)
[62-86] [55-100]

49/108(45)[31-60]78/114(68)[58-79]84/478(18)[8-24]

Falsepositive
rated [95%CI]c61
[50-72]60[35-88]59[27-91]56[30-86]

0

67[57-77]64[59-68])19[14-38]0[0-45]

55[40-69]32[21-42]

82[76-92]

Males with
TCL/Total
No. with
TCL (%)[95% CI]c

47/80
(59)
[48-70]

3/4
(75)

6/9
(67)
[36-98]

3/4
(75)

0/1

60/82
(73)
[64-83]

119/180(66)[59-73]35/51(69)[54-80]3/5(60)[15-85]37/49(76)[64-88]52/78(67)[56-77]

57/97(59)[49-70]Preterm
alone
infants
with TCL/
Total No.
with TCL(%)[95% CI]c

14/80
(18)
[9.2-26]

0/4

1/9
(11)
[2.8-34]

0/4

0/1

9/82
(11)
[4.2-18]

24/180(13)[8.4-18]

1/51(2)[0.5-7.0]

1/5(20)[5.3-52]

3/49(6)[2.3-14]0/78[0-3.8]0/84[0-3.5]

Incidenceof all nonSCID TCL

1/32 000 1/26 000

1/11 000

1/37001/35001/26001/14 000e

1/64001/13 000

1/81001/21001/6600Non-SCID
TCL cases
per
100 000
screened[95% CI]c

3.1[2.2-4.0]

8.8[1.1-16]26
29[9.7-64] [6.9-105]

39[30-48]7.4[6.1-8.6]

16[11-20]8.0[2.9-19]12[8.6-16]47[36-57]15[12-19]4.2[1.5-10]T-cell lymphopenia also included lack of naive T cells (Table 1, eTable). Texas
data are from Texas Children’s Hospital, Houston, and University of Texas
Southwestern, Dallas. In New York, immunology experts diagnosed TCL attheir own discretion, without a predefined cutoff.
See Table 2 for rates of referral to flow cytometry.

ital anomalies, vascular leakage and hydrops (grouped as loss
into third space), gastrointestinal anomalies including gastroschisis, and 4 neonatal leukemias. No cases of HIV infection were detected.
Idiopathic T-cell lymphopenia, also termed variant SCID,
was found in only 3% of non-SCID T-cell lymphopenia cases(12/411, or 1/250 000 births); these infants did not meet the diagnostic criteria for leaky SCID but had persistent T-cell lymphopenia and immune dysfunction without defects in known
SCID genes (Table 1).18,30 One of these 12 infants eventually required hematopoietic cell transplantation. The screening program in New York identified 30 further cases as having idiopathic T-cell lymphopenia,30 included in Table 5 among theunspecified T-cell lymphopenia cases because their T-cellcounts were not available.

Interventions for Infants With Deficient T Cells Identified
Through SCID Newborn Screening

Of the 52 infants detected with SCID in the first weeks of life,
49 received immunity restoring therapies. Forty-four had hematopoietic cell transplants, 4 had gene correction of IL2RG
734

No
DefinedCutoff<2500 T Cells/μL Cutoff

NavajoNationAbbreviations: SCID, severe combined immunodeficiency; TCL, T-cell
lymphopenia; TREC, T-cell receptor excision circle.
a<3505
T Cells/μL
Cutoffc

Confidence intervals derived from normal approximation of binomial data or
inversion of cumulative binomial distribution, as appropriate. One-sided CI
used when frequency = 0. No CI given where numbers were too small.

d

False-positive rate defined as infants referred to flow cytometry due tononnormal TREC screen but having T cells by flow cytometry that were above
the program cutoff for TCL.

e

95% CI, 1/11 600-1/16 400.

and ADA defects by ex vivo transduction of a normal gene sequence into autologous hematopoietic stem cells (1 of whom
required subsequent hematopoietic cell transplant due to inadequate correction), and 2 had adenosine deaminase enzyme injection therapy. In addition, non-SCID cases requiring immune restorative treatment included 1 infant with Rac2
deficiency (a syndrome of defective neutrophil adhesion) and1 with variant SCID who received hematopoietic cell transplantation, and 2 infants with complete DiGeorge syndrome
who received thymus transplantation (Table 3 and Table 5). Of
7 deaths among the 52 infants with typical SCID and leaky SCID,
3 were due to perinatal complications, including 1 with PallisterKillian syndrome, 1 with intestinal malrotation and severe respiratory distress,30 and 1 with undescribed medical problems that precluded transport to a center where hematopoietic
cell transplant could be done. Four infants with SCID died after transplant. Thus, overall SCID survival was 45 of 52 (87%),
while 45 of 49 treated infants (92%) survived, comparable withexperience from transplant centers for uninfected SCID patients treated early in life.4-7 Posttreatment deaths were due
to cytomegalovirus infection acquired early postnatally in 1,

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Newborn Screening for Severe Combined Immunodeficiency

pretransplant respiratory compromise in 1, and hepatic sinusoidal obstructive disease secondary to pretransplant busulfan chemotherapy in 2 (Table 3).
All infants with T-cell lymphopenia were directed to avoid
infectious exposures, transfusions (except with cytomegalovirus-negative, irradiated blood products), and live rotavirus
vaccines until such time as immune compromise was no longer present. Prophylactic antimicrobials and immunoglobulin
infusions were given as indicated by immunology specialists.

Table 5. Diagnoses of 411 Infants With Non-SCID T-Cell Lymphopenia
Identified by Newborn Screening
Condition

Discussion
To our knowledge, this is the first multistate report of resultsof newborn screening for SCID, a core condition in the US Recommended Uniform Screening Panel. Our experience has demonstrated the feasibility of assaying for TRECs, a biomarker for
naive T-cell lymphopoiesis, followed by confirmatory flow cytometry, as a means to identify SCID. Newborn screening has
provided a new, population-based incidence of SCID of 1 in
58 000 births, higher than the incidence of 1 in 100 000 suggested from retrospective clinical diagnoses.33-35 Furthermore, the proportion of IL2RG deficient X-linked SCID in ourstudy (19%) is in contrast to nearly half of cases in publishedcohorts from referral centers that treat SCID.5-8 Because Xlinked disorders with severe phenotype maintain constant frequency due to replenishment in the gene pool by new
mutations,36 our lower proportion of IL2RG-deficient SCID is
likely to reflect increased ascertainment of autosomalrecessive SCID cases by population-based screening. Moreover, compared with series from large transplant centers, inwhich less than 10% of cases lacked a molecular diagnosis,5,8
our newborn screened cases had a higher proportion of leaky
SCID and more than 15% of typical and leaky SCID without aproven molecular diagnosis despite extensive gene sequencing (Table 3). These findings support the view that SCID has
previously been underdiagnosed in infants with fatal infections. Furthermore, proportions of typical SCID, leaky SCID,
and Omenn syndrome in our cohort appear distinct from thosepreviously reported for older infants; features of Omenn syndrome develop over months after birth, and the clinical diagnosis of leaky SCID can be delayed for years.37
Additional data collection may reveal new demographic
patterns, such as the known high Navajo incidence of SCID due
to a DCLRE1C founder mutation and Amish and Mennonite
founder mutations in ADA, IL7R, and RAG1.38,39 Inclusion ofdata from more SCID screening programs in additional states
would be required to know if the results from the 11 participating programs included here are fully generalizable. Whether
the excess of males with abnormal SCID newborn screens is
explained by the known higher rate of male preterm births aswell as the common X-linked SCID gene IL2RG also needs tobe explored. The unanticipated high proportion of SCID without a defined genotype and new discovery of non-SCID T-cell
lymphopenias illustrate how unbiased population screening
reveals a wide phenotypic spectrum and affords opportunities to discover previously unknown genes essential to human T-cell development.

No. of Infants

Syndromes with T-cell impairmenta

136

DiGeorge

78b

Trisomy 21

21

Ataxia telangiectasia

4Trisomy 18

4

CHARGE

3

Jacobsen

2

CLOVES

1

ECC

1

Fryns

1

Nijmegen breakage

1

Noonan1

Rac2 defect1cRenpenning

1

TAR

1

Not specified

10

Cytogenetic abnormalitiesd

6

Secondary T-cell impairment

117

Cardiac anomalies

30

Multiple congenital anomalies

23

Loss into third space

15

Gastrointestinal anomalies

15

Neonatal leukemia

4

Not specified

30

Preterm birth alone

29

Variant SCID

12e

Unspecified T-cell lymphopeniaf

117

Abbreviations: CHARGE, coloboma, heart defect, atresia choanae, retarded
growth and development, genital and ear abnormality; CLOVES, congenital
lipomatous overgrowth, vascular malformations, epidermal nevi, andspinal/skeletal anomalies; ECC, ectodermal dysplasia, ectrodactyly, and clefting;
SCID, severe combined immunodeficiency; TAR, thrombocytopenia and absent
radius.
a

Eponymous syndromes: DiGeorge, cardiac defects, hypocalcemia, thymus
dysplasia, and other anomalies, most often with chromosome 22q11.2
interstitial deletion; Jacobsen, growth and psychomotor retardation andcongenital anomalies with chromosome 11qter deletion; Fryns, diaphragmatic
hernia and other congenital anomalies; Noonan, multiple congenital
anomalies; Renpenning, X chromosome–linked mental retardation with
distinctive facies.

b

Included 3 infants with complete DiGeorge syndrome and absent T cells, 2 ofwhom received a thymus transplant.

c

Eventual hematopoietic cell transplant performed.17dIncluded chromosome 6p deletion, ring chromosome 14, ring chromosome 17,chromosome 17q duplication, and 2 siblings with unspecified chromosome
abnormalities.

e

Eventual hematopoietic cell transplant performed for 1 case.

fIncludes infants from Michigan (46), New York (30), Massachusetts (25),
Wisconsin (13), Connecticut (2), and Delaware (1); further information was notavailable for these infants, although those from New York were reported torequire ongoing monitoring or treatment for a deficiency of T cells.30

Now that infants with SCID are being detected at a very
young age in diverse medical settings, it is imperative to tailor protocols for their treatment, including choice and pharmacokinetic monitoring of drugs administered to facilitate hematopoietic cell engraftment. Busulfan chemotherapy led to
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Research Original Investigation

Newborn Screening for Severe Combined Immunodeficiency

fatal hepatic sinusoidal obstruction, also known as venoocclusive disease, in 2 infants diagnosed with SCID by newborn screening. Prospective studies conducted by the Primary Immune Deficiency Treatment Consortium will address
whether dose adjustments based on age or alternate regimens will provide enhanced safety while still affording longlasting immune reconstitution.5,8,21,40
A major limitation of this study was the lack of uniformity of assay methodology and rules for retesting among theindividual newborn screening programs, despite general adherence to the Clinical and Laboratory Standards Instituteguidelines.20 Use of different TREC assays and test algorithms resulted in a variety of rates both for recall for additional testing and for having T cells by flow cytometry in a range
defined as normal. Specific information about the ages at whichsamples for TREC screening and for flow cytometry were obtained were not available. No program identified a falsenegative test for SCID, the primary target condition. Furthermore, although the definitive flow cytometry test was
universally used as follow-up for infants whose TRECs were
not normal, different cutoffs were used to define non-SCID secondary targets of screening. Therefore, the incidence of Tcell lymphopenia cases referred for follow-up varied from 3 to
47 cases per 100 000 infants (Table 4).
While unsuspected non-SCID immunodeficiency syndromes were identified and 4 infants had immune defects sufficiently serious to require hematopoietic cell or thymus transplantation, these benefits must be weighed against the burdensof heightened parental anxiety and costs of further testing ininfants with less profound T-cell lymphopenias. As with development of each newborn screening test since the original
one for phenylketonuria,41 different initial approaches for SCID
screening are anticipated to evolve and become standardized
over time, as evident in adjustments to TREC screening algorithms that have already occurred.17,30 Specific data regarding persistence of non-SCID T-cell lymphopenia over time and
ARTICLE INFORMATION
Author Affiliations: Department of Pediatrics,
University of California, San Francisco, San
Francisco (Kwan, Cowan, Puck); UCSF Benioff
Children’s Hospital, San Francisco, California (Kwan,
Cowan, Puck); Department of Laboratory Medicine
and Pathology, Mayo Clinic, Rochester, Minnesota(Abraham); Genetic Disease Screening Program,
California Department of Public Health, Richmond(Currier, Lorey); Newborn Screening Translational
Research Network, American College of Medical
Genetics and Genomics, Bethesda, Maryland(Brower, Watson); Michigan Department ofCommunity Health, Lansing (Andruszewski, Wood);
Division of Allergy and Immunology, Department ofPediatrics, National Jewish Health, Denver,
Colorado (Abbott, Gelfand); Newborn Screening
Laboratory, Wisconsin State Laboratory of Hygiene,
Madison (Baker); Department of Pediatrics,
University of Wisconsin School of Medicine andPublic Health, Madison (Baker); Women andChildren’s Hospital of Buffalo, Buffalo, New York
(Ballow, Lehman); Department of Pediatrics,
Christiana Care Health System, Wilmington,
Delaware (Bartoshesky); Department of Medicine,736

functional T-cell abnormalities were not available for our analysis but should in the future be collected to clarify which infants require interventions, such as avoidance of live rotavirus vaccination, which can cause serious diarrheal disease ininfants with immunodeficiency.42,43
Differences in cutoffs between the SCID screening programs in this study may prove helpful for public health programs in other states and countries considering instituting SCID
newborn screening. In addition, the R4S SCID database will permit future analytical and clinical correlations to optimize cutoffs for key markers, such as T-cell numbers, to inform bestpractices.19,44
The TREC assay has proven excellent for detecting disorders with poor T-cell production or inadequate numbers of circulating T cells, but finding additional immune defects prior
to onset of recurrent or life-threatening infections will require further methods. A few more entities may be captured
by screening for the circular by-products of B-cell immunoglobulin gene rearrangement,45 and mild as well as severe casesof adenosine deaminase deficiency may be identified by amodification of the current mass spectrometry already widelyused for newborn screening.46 However, infants with defects
affecting T cells beyond the developmental stage of recombination of T-cell receptors (eg, major histocompatibility complex class II deficiency47) have normal TRECs but impaired Tcell function. Genomic sequencing may be required to detect
deleterious mutations in primary immune defects, of which
nearly 200 are known.1

Conclusions
Newborn screening in 11 programs in the United States identified SCID in 1 in 58 000 infants, with high survival. The usefulness of detection of non-SCID T-cell lymphopenias by thesame screening remains to be determined.

Boston Children’s Hospital, Boston, Massachusetts(Bonilla, Notarangelo, Pai); Harvard Medical School,
Boston, Massachusetts (Bonilla, Notarangelo, Pai);
Department of Population Health Sciences,
University of Wisconsin School of Medicine andPublic Health, Madison (Brokopp); Department ofPediatrics, University of Texas Health Science
Center at San Antonio (Brooks, Infante); Newborn
Screening Program, Wadsworth Center, New YorkState Department of Health, Albany (Caggana, Kay,
Saavedra-Matiz, Vogel); Division of Allergy and
Immunology, Albany Medical College, Albany, NewYork (Celestin); Department of Pediatrics,
University of Southern California, Los Angeles(Church, Kapoor); Children’s Hospital Los Angeles,
Los Angeles, California (Church, Kapoor); New
England Newborn Screening Program, University of
Massachusetts Medical School, Jamaica Plain(Comeau, Hale); University of Michigan C. S. Mott
Children’s Hospital, Ann Arbor (Connelly,
Walkovich); Mount Sinai Medical Center, New York,New York (Cunningham-Rundles); Clinical
Immunodiagnostic and Research Laboratory,
Medical College of Wisconsin, Milwaukee (Dasu);
Department of Pediatrics, University of Mississippi
Medical Center, Jackson (Dave, Rodriguez, Walker,

Yates); Department of Pediatrics, University ofTexas Southwestern Medical Center, Dallas (De La
Morena); Division of Blood and Bone Marrow
Transplantation, Helen DeVos Children’s Hospital,
Grand Rapids, Michigan (Duffner, Abdel-Mageed);
University of Rochester School of Medicine andDentistry, Rochester, New York (Fong, Weinberg);
Department of Pediatrics, Baylor College ofMedicine, Houston, Texas (Forbes, Hanson, Orange,
Shearer); Texas Children’s Hospital, Houston(Forbes, Hanson, Orange, Shearer); Texas
Department of State Health Services, Austin(Freedenberg, Johnson, Lee, G. Scott, Tanksley);
Department of Pediatrics, University of
Massachusetts Medical School, Worcester(Comeau, Hay, Sullivan); Tuba City Regional HealthCare, Tuba City, Arizona (Hu); Department ofPediatrics, University of California, Los Angeles, Los
Angeles (Kohn, Moore, Stiehm); PerkinElmer
Genetics, Bridgeville, Pennsylvania (Lin);
Connecticut Department of Public Health
Laboratory, Rocky Hill (Manning); Department ofPediatrics, Stanford University School of Medicine,
Palo Alto, California (McGhee, Porteus); Lucille
Packard Children’s Hospital, Palo Alto, California(McGhee, Porteus); Immunology Department,

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Quest Diagnostics Nichols Institute, San Juan
Capistrano, California (Naides); Division of Allergy
and Clinical Immunology, Department of Pediatrics,
Yale University School of Medicine, New Haven,
Connecticut (Romberg); Department of Pediatrics,
Children’s Research Institute, Medical College of
Wisconsin, Milwaukee (Routes, Verbsky); Children’s
Hospital of Michigan, Detroit (Ruehle, Secord,
Tierce); Division of Allergy and Immunology,
Montefiore Medical Park, Bronx, New York
(Rubenstein); Newborn Screening Program,
Delaware Public Health Laboratory, Smyrna(P.M. Scott); Department of Pediatrics, University of
Wisconsin School of Medicine and Public Health,
Madison (Seroogy); New York Medical College,
Westchester Medical Center, Valhalla, New York
(Siegel); Medical City Children’s Hospital, Dallas,
Texas (Silvers, Sugerman, Wasserman); Departmentof Pediatrics, Massachusetts General Hospital,
Boston (Walter); Harvard Medical School, Boston,
Massachusetts (Walter); Department of Pediatrics,
State University of New York Upstate Medical
University, Syracuse (Weiner); Steven and Alexandra
Cohen Children’s Medical Center, North Shore–LIJ
Health System, Great Neck, New York (Bonagura).
Author Contributions: Drs Kwan and Puck had fullaccess to all of the data in the study and takeresponsibility for the integrity of the data and theaccuracy of the data analysis. Drs Kwan and
Abraham contributed equally to this work.
Study concept and design: Kwan, Abraham, Brower,
Bonagura, Church, Comeau, Cowan, Lee, Lorey,
Naides, Routes, Saavedra-Matiz, Secord, Shearer,
Stiehm, Tanksley, Watson, Puck.
Acquisition, analysis, or interpretation of data:
Kwan, Abraham, Currier, Brower, Andruszewski,
Abbott, Baker, Ballow, Bartoshesky, Bonagura,
Bonilla, Brokopp, Brooks, Caggana, Celestin,
Church, Connelly, Cowan, Cunningham-Rundles,
Dasu, Dave, De La Morena, Duffner, Fong, Forbes,
Freedenberg, Gelfand, Hale, Hanson, Hay, Hu,
Infante, Johnson, Kapoor, Kay, Kohn, Lehman, Lin,
Lorey, Abdel-Mageed, Manning, McGhee, Moore,
Naides, Notarangelo, Orange, Pai, Porteus,
Rodriguez, Romberg, Routes, Ruehle, Rubenstein,
Saavedra-Matiz, G. Scott, P. Scott, Secord, Seroogy,
Shearer, Siegel, Silvers, Stiehm, Sugerman, Sullivan,
Tierce, Verbsky, Vogel, Walker, Walkovich, Walter,
Wasserman, Watson, Weinberg, Weiner, Wood,
Yates, Puck.
Drafting of the manuscript: Kwan, Abraham, Baker,
Bonagura, Gelfand, Kapoor, Abdel-Mageed,
Manning, Routes, Rubenstein, P. Scott, Shearer,
Sullivan, Walker, Puck.
Critical revision of the manuscript for important
intellectual content: Kwan, Abraham, Currier,
Brower, Andruszewski, Abbott, Ballow,
Bartoshesky, Bonagura, Bonilla, Brokopp, Brooks,
Caggana, Celestin, Church, Comeau, Connelly,
Cowan, Cunningham-Rundles, Dasu, Dave,De La Morena, Duffner, Fong, Forbes, Freedenberg,
Gelfand, Hale, Hanson, Hay, Hu, Infante, Johnson,
Kay, Kohn, Lee, Lehman, Lin, Lorey, Abdel-Mageed,
Manning, McGhee, Moore, Naides, Notarangelo,
Orange, Pai, Porteus, Rodriguez, Romberg, Routes,
Ruehle, Saavedra-Matiz, G. Scott, Secord, Seroogy,
Shearer, Siegel, Silvers, Stiehm, Sugerman,
Tanksley, Tierce, Verbsky, Vogel, Walkovich, Walter,
Wasserman, Watson, Weinberg, Weiner, Wood,
Yates, Puck.
Statistical analysis: Kwan, Abraham, Currier, Abbott,
Hanson, Johnson, Kay, Lee, Lorey, Routes, G. Scott,P. Scott, Puck.

Obtained funding: Brower, Baker, Bonagura,
Brokopp, Cowan, Lorey, Abdel-Mageed,
Notarangelo, Routes, Watson, Puck.
Administrative, technical, or material support:
Currier, Brower, Abbott, Baker, Ballow, Bartoshesky,
Bonilla, Brokopp, Caggana, Celestin, Comeau,
Connelly, Cunningham-Rundles, Dasu, Duffner,
Forbes, Hale, Hay, Hu, Kapoor, Kohn, Lee, Lin,
Lorey, Abdel-Mageed, Manning, Moore, Naides,
Orange, Routes, Saavedra-Matiz, Shearer, Stiehm,
Sugerman, Sullivan, Tanksley, Tierce, Walkovich,
Walter, Watson, Weinberg, Wood, Puck.
Study supervision: Abraham, Baker, Bonagura,
Caggana, Celestin, Comeau, Cowan, Gelfand,
Infante, Lee, Lehman, Abdel-Mageed, Naides,
Routes, Rubenstein, Saavedra-Matiz, Stiehm,
Sullivan, Watson, Puck.
Conflict of Interest Disclosures: All authors havecompleted and submitted the ICMJE Form forDisclosure of Potential Conflicts of Interest. Dr
Bonagura reported receiving grants from theJeffrey Modell Foundation, Baxter Pharmaceuticals,and New York State; serving on a committee for
CSL-Behring; and serving on an advisory board for
Baxter Pharmaceuticals. No other disclosures werereported.
Funding/Support: This study received support
from the following institutions: in California:
National Institutes of Health (NIH)(HHSN267200603430C through New York, R01
FD003005-01, U01 AI1087628 [D.B.K.]; RO1
AI078248, AI105776 [J.M.P.]); HCA International
Foundation Travelling Scholarship (A.K.); Jeffrey
Modell Foundation; and Perkin Elmer Genetics. In
Colorado: Colorado Department of Public Heathand Environment. In Connecticut: state
appropriation, pursuant to Public Act 11-48,
Sections 38 and 39, which mandated the inclusionof testing for severe combined immunodeficiency(SCID) in the Connecticut Newborn Screening
Disorders Panel and provided increased agency
funding to accomplish this mandate. In Delaware:
Centers for Disease Control and Prevention (CDC)(U01 EH000454) and state funding. In
Massachusetts: CDC (U01 EH000362) and New
England Newborn Screening Program funds. In
Michigan: CDC (U01 EH000936). In Mississippi:
Mississippi State Department of Health. In the
Navajo Nation: NIH (RO3HD060311 [J.M.P.]) and agift to Navajo-area delivering hospitals from
PerkinElmer Genetics, Bridgeville, Pennsylvania. In
New York: NIH (HHSN267200603430C), Jeffrey
Modell Foundation, and New York State
Department of Health. In Texas: CDC grant through
New England Newborn Screening Program (pilot
phase), Jeffrey Modell Foundation, and the Texas
Department of State Health Services. In Wisconsin:
Jeffery Modell Foundation, Children’s Hospital of
Wisconsin, Wisconsin State Laboratory of Hygiene,
CDC (U01 EH000365), and Primary
Immunodeficiency Treatment Consortium (U54
A1082973 [M.J.C.], R13-A1094943 [M.J.C., L.D.N.]).
The Newborn Screening Translational Research
Network (NBSTRN) is a contract to the American
College of Medical Genetics and Genomics byEunice Kennedy Shriver National Institute of Child
Health and Human Development, NIH(HHSN27520080001C).
Role of the Sponsors: The sponsors had no role inthe design and conduct of the study; collection,
management, analysis, and interpretation of thedata; preparation, review, or approval of themanuscript; and decision to submit the manuscriptfor publication.
Additional Contributions: California: Vijaya
Pasupuleti; Ryan Glaraga, BASc; Jerry D. Ramirez Jr;
Zenaida Nakar, BS; Gloria Ramirez; Neil Lim, BS;
Larry Eck, BS, Quest Nichols Institute, San Juan
Capistrano. These individuals assisted with flow
cytometry determination and reporting for the
California Department of Public Health Newborn
Screening Program. Colorado: Mark Dymerski, BS,
Newborn Screening Unit, Colorado Department of
Public Health and Environment, Denver, assistedwith SCID screening and tracking of results.
Connecticut: Odelya Pagovich, MD, Yale University,
New Haven, assisted with follow-up of infants. New
York: Jason Isabelle; April Parker; Lisa DiAntonio,
MS; Allison Young; Victoria Popson, Newborn
Screening Program, Wadsworth Center, New YorkState Department of Health, Albany. These
individuals assisted with TREC testing and reportingin the New York State Newborn Screening Program.
Michigan: Karen Dahl, MD, Helen De Vos Children’s
Hospital, Grand Rapids, assisted with follow-up of
infants. Mississippi: Phillis Hoggatt, RN, and Beryl
Polk, PhD, Mississippi Department of Public Health,Jackson, assisted with sample tracking andreporting. Texas: Howard Rosenblatt, MD (Austin);
Wesley Stafford, MD (Corpus Christi); Lyndon
Mansfield, MD (El Paso); Susan Pacheco, MD(Houston); Todd Holman, MD (Longview); andRobert Mamlock, MD (Lubbock), assisted withfollow-up of infants. Wisconsin: Mary Hintermeyer,
APNP; Christine Bengtson, MS; Michael Cogley, BS;
Lisa Berkan, MT; Marcy Rowe, BS, Wisconsin State
Laboratory of Hygiene, University of Wisconsin,
Madison and Milwaukee. These individuals assistedwith TREC testing, reporting, and follow-up. R4S
and NBSTRN: Piero Rinaldo, MD, PhD, Mayo Clinic,
Rochester, MN, assisted with customizing the R4S
database SCID module and analyzing data for thisstudy. CDC Newborn Screening Branch, Atlanta,
Georgia: Robert F. Vogt Jr, PhD, provided helpfulcomments and suggestions throughout. No
compensation for the contribution was received byany person acknowledged here.
Correction: This article was corrected online
August 20, 2014, and October 14, 2014.
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