UNIVERSAL NEWBORN SCREENING
FOR SCID
DR. PETER VICKERS
WHAT IS IT?
 Newborn screening for SCID is a test that takes place immediately
after birth to ascertain whether or not a newborn child has SCID.
 It would be done at the same time as screening for PKU
(phenylketonuria) automatically take place.
 Phenylketonuria (PKU) is a rare genetic condition that is present
from birth. The body is unable to break down a substance called
phenylalanine, which builds up in the blood and brain.
 A sample of blood would be taken from a heel prick (as with
PKU) and sent to a laboratory for testing
HOW IS IT TESTED?
 Once in the lab, a polymerase chain reaction (PCR) assay is
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conducted of the blood spot from the heel prick performed
after birth.
The test uses a TREC (T-cell receptor excision circle) assay.
This simple test has transformed the possibilities of early
detection/diagnosis of SCID
TRECs are a surrogate marker for the number of naïve T
cells.
TRECs are reduced in all forms of severe T cell
lymphopaenia (SCID and others).
WHY?
 Early diagnosis of SCID is critical because of the very high risks
of infection and death within a few weeks/months of birth.
 It is a rare disease (prevalence 1:50,000 – 1:100,000 – but this
is only a guess because of the poor rate of diagnosis).
 The baby appears normal at birth, and there are usually no
signs or symptoms until after a few months, by which time it
may be too late.
 Early treatment (usually haematopoietic stem cell
transplantation – HSCT) decreases morality rates.
 Therefore, the ability to detect a case of SCID through
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newborn screening (NBS) is, at the moment, the ideal
method that we currently possess which allows us to detect
children with SCID with virtually no delay.
However, there are financial and ethical considerations that
have to be addressed before such screening takes place.
Is it cost effective?
Will it harm the child?
Is the pain caused by the heel prick a bar to this particular
screening for SCID, given the rarity of the condition?
What about false positives and the effects on the child and
family?
EXPERIENCES
 We have some knowledge and experience of NBS for SCID in
the USA, where many states have already set up this
screening.
 The costs have been worked out at between 5-6 dollars per
screening of one child.
 However, this has to be set against the cost of treating just
one child with SCID who may be diagnosed after a few
months – which are enormous
 Interestingly, there have been no reported cases of SCID in
Wisconsin that had not been identified by NBS
Current Implementation Status (2012)
Number
of States
Shading
Status
9
Statewide and
Fully
Implemented
2
Selected
Populations
9
Pilots and/or
Screening
Planned for
2012
27
Not
Implemented
4
Pilots and/or
Screening
Planned for
2013
FLORIDA NEWBORN SCREENING ALGORITHM
for SEVERE COMBINED IMMUNE DEFICIENCY (SCID)
Initial
TREC
Assay
SCID-I-01-LOW
SCID-I-01-NORM
No
Repeat TREC
with β-Actin
Yes
TREC >40
NORMAL
Full or Preterm
TREC ≤ 5
β-Actin >5,000
Full term
TREC >5-25
β-Actin >10,000
Full term
TREC >25-40
β-Actin >10,000
Full or Pre-term
TREC ≤ 5
β-Actin ≤5,000
Full term
TREC >5-25
β-Actin
≤10,000
Full term
TREC >25-40
β-Actin
≤10,000
Pre-term
TREC >5-25
β-Actin
>10,000
Pre-term
TREC >5-25
β-Actin
≤10,000
Pre-term
TREC >25-40
β-Actin
>10,000
Pre-term
TREC >25-40
β-Actin
≤10,000
Full or Pre-term
TREC >40
Presumptive
Positive
Presumptive
Positive
Previous
Borderline
Inconclusive
Inconclusive
Inconclusive
Low
Inconclusive
Low
Inconclusive
NORMAL
SCID-C-01-INC
SCID-C-03-INC
SCID-C-06-INC
SCID-C-02-LOW
SCID-C-04-INC
SCID-C-05-LOW
SCID-C-07-INC
SCID-C-01-NORM
SCID-C-01-ABNR
SCID-C-02-ABNR
Yes
Borderline
Report to CMS
for follow-up
(via Patient
Care)
SCID-C-02-BORD
No
Borderline
SCID-C-01-BORD
β-Actin – serves as amplification control
TREC – T-lymphocyte receptor excision circle
Full term – baby’s age of gestation (AOG) is ≥37 weeks
Pre-term – baby’s AOG is <37 weeks
Presumptive Positive – determination used for possible SCID, SCID variants,
or T-cell lymphopenias
Inconclusive – determination used when amplification control (β-Actin) is below the
acceptable limit and/or baby is pre-term (<37 weeks AOG)
TREC and β-Actin cutoff values may change after the validation period
Jojo Dy 05-15-2012
Request for a
repeat specimen
(Baby’s age must
be equivalent to
≥37 wks. of
gestation)
 What is the likelihood that the
referral is going to be a true SCID?
 Sensitivity is 100% (so far none have
been missed)
 False positives<0.1%
 NY (recent data – 2 years) – 475,713
screened, incidence 1/42,000; 0.1%
referred for Flow
 FL likely get 5 – 10 SCID cases per
year
 Referrals will be about 40 per year
(across 3 centers)
Clinic Nurse Manager Role
 Alert on-call (inpatient) fellow and attending of referral
 Contact family and inform them of abnormal newborn screen for SCID
 Set up confirmatory testing (T, B, NK cell enumeration)
 Must be done within 2 working days of the referral
 Discuss precautions until diagnosis is made
 Make appointment with immunologist
 Attempt schedule first with the provider - if not available any full time attending can see
patient
 Must be seen within 5 working days of the referral
 Every template has a ‘hidden/emergency slot’ – open access for new patient evaluation for
these referral (can be seen M-F)
 Contact PMD
 Keep open line of communication during this follow up process
 Keep log of patients and contact
 Note that this is the protocol for just one site in the USA
THE POSITION IN THE UK
 Despite the experiences and information obtainable from the
USA, the UK National Screening Committee decided that
they had to get their own proof that this was the way to go.
 Invitations sent out to interested groups to submit
consultation form for consideration.
 INGID was a part of this consultation, and had to consider a
whole range of criteria, including:
 The condition should be an important health problem
 The epidemiology and natural history of the condition, including
development from latent to declared disease, should be
adequately understood, and there should be a detectable risk
factor, disease marker, latent period or early symptomatic stage.
 There should be simple, safe, precise and validated screening
test.
 The test should be acceptable to the population.
 There should be an effective treatment or intervention for
patients identified through early detection, with evidence of
early treatment leading to better outcomes than late treatment.
 The benefits from the screening programme should outweigh
the physical and psychological harm (caused by the test,
diagnostic procedures and treatment.
 The costs of the screening programme should be economically
balanced in relation to expenditure on medical care.
 All other options for managing the condition should have been
considered to ensure that no more cist effective interventions
could be introduced.
 Public pressure for widening the eligibility criteria for reducing
the screening interval and for increasing the sensitivity of the
testing process should be anticipated – decisions about these
parameters should be scientifically justifiable to the public.
NBS for SCIDS has also picked up many other PIDDs
Classic SCID
13. AK2 (Reticular dysgenesis)
1. IL2RG (common g chain SCID); X linked
14. ADA (Adenosine deaminase SCID)
2. JAK3
15. PNP (Purine nucleoside
3. IL7 Ra
4. RAG1
5. RAG2
phosphorylase SCID)
16. WHN (Winged-helix-nude SCID)
17. Unknown
Variant SCID/ Leaky SCID
6. DCLRE1C (Artemis SCID)
1. NHEJ1 (Cernunnos/ XLF)
7. PRKDC (DNA-PKcs SCID)
2. AK2
8. LIG4 (DNA Ligase IV SCID)
3. PNP
9. CD3D (CD3δ SCID)
4. WHN
5. RAG1
10. CD3E (CD3ε SCID)
6. RAG2
11. CD3Z (CD3ζ SCID)
7. ADA
12. PTPRC (CD45 SCID)
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8. IL2RG
9. IL7Ra
10. LIG4
11. DCLRE1C
12. CHD7 (CHARGE syndrome)
13. RMRP (Cartilage Hair
Hypoplasia)
14. CORO1A (Coronin-1A)
15. Unknown
Non-SCID
1. DiGeorge syndrome
(del22q11.2; ~
>35 genes)
2. CHD7
3. ORA1
4. STIM1
5. CD3G (CD3γ SCID)
 6. ZAP70 (primarily affecting CD8 T
 cell development)
 7. LCK (p56lck)
 8. MHC class II deficiency (CIITA,
 RFXANK, RFX5, RFXAP)
 9. RMRP
 10. Hoyeraal-Hreidarsson syndrome,
 HHS (DKC1, TERT, TINF2,
 DCLRE1B)
 11. SLC46A1 (Hereditary folate
 metabolism, HFM); reversible SCID
 12. ATM (Ataxia telangiectasia)
 13. RAC2
 14. Down Syndrome (Trisomy 21)
 15. Jacobsen syndrome (del 11q)
 16. Lymphopenia of prematurity
 17. Idiopathic T cell lymphopenia
 18. Unknown
 Now over to you to think about and discuss:
 What are the ethical considerations to consider?
 What about false positives?
 What about the effects and arrangements in all maternity
units for this screening to take place – cost, staffing,
emotional effects, etc.
 What about the financial costs?
Thank you for your attention
References & Further Reading
 Chase, et al (2011) Newborn screening for SCID: three years of
experience. Annals of the NewYork Academy of Sciences, November;
1238 (99-105)
 Kelly, et al (2013) Screening for severe combined
immunodeficiency in neonates. Clinical Epidemiology 3:5 (363-369)