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National Center for Environmental Health Centers for Disease Control and Prevention Carla Cuthbert, PhD, FACMG, FCCMG Chief, Newborn Screening and Molecular.

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Presentation on theme: "National Center for Environmental Health Centers for Disease Control and Prevention Carla Cuthbert, PhD, FACMG, FCCMG Chief, Newborn Screening and Molecular."— Presentation transcript:

1 National Center for Environmental Health Centers for Disease Control and Prevention Carla Cuthbert, PhD, FACMG, FCCMG Chief, Newborn Screening and Molecular Biology Branch, Division of Laboratory Sciences NCEH, CDC Thursday 27 th January 2011 Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children Newborn Screening for SCID: Experiences of State Laboratories Using the TREC Assa y

2 Screening for SCID Using the TREC Assay General Principles and Assay Development  SCID Screening Marker: T cell receptor excision circles (TREC)  By-products of rearrangement of T cell receptor genes during T cell maturation in the thymus  Are episomal DNA, TREC does not replicate during mitosis – diluted by cell divisions  Peripheral blood level reflects T cell production in the thymus  TREC assay – now adapted to detect SCID and other lymphopenia in newborns  Originally developed to assess thymic function in HIV-infected infants  Real Time PCR  Variations in TREC Assay procedures can be based on choice of primers/probes and DNA extraction procedures

3 Screening for SCID Using the TREC Assay General Principles and Assay Development DBS DNA Extraction TREC sequence Amplification Amplicons Quantification DBS DNA Extraction Real time PCR DBS In Situ PCR Amplicons Quantification DBS In Situ Real time PCR ClassicalConventionalDevelopmentalCDC Slide courtesy of Francis Lee

4 States Currently Screening for SCID Performed Within State Laboratories Wisconsin Massachusetts California New York

5  November – December 2006  November: JMF provides $250,000 matching contribution to fund WI NBS SCID Program  December: CHW matches JMF $250,000 donation and WSLH in-kind contribution  January 2007  Announcement of the WI NBS SCID Program  Winter and Spring 2007  Optimization of TREC assay & screen anonymized NBS cards  January 2008  WI Launched routine NBS for SCID  2008 - Current  Demonstrate efficacy of TREC assay to detect SCID  Supported by a CDC grant which started in Oct. 2008) Wisconsin’s Laboratory Experience History and Current Status

6 Wisconsin’s Laboratory Experience Results of Testing Number Screened: 206,982 – Premature (< 37 wks) 18,861 – Full term 188,121 Abnormal results: 159 – Premature (<37 wks) 93 (0.04%) – Full term 66 (0.03%) Inconclusive Results: 288 – Premature (<37 wks) 240 (0.12%) – Full term 48 (0.02%)

7 Wisconsin’s Laboratory Experience Results of Testing Severe Lymphopenia Cases  Idiopathic Lymphopenia −Regular IVIG, planning BMT  Rac 2 mutation −Successful BMT  Idiopathic Lymphopenia −BMT  T-, B-, NK+ SCID −Successful BMT—normal TRECs !!!  ADA SCID −Possible gene therapy

8 Wisconsin’s Laboratory Experience TREC Assay Performance in Full Term Babies  Sensitivity: 100% (No known false negatives reported)  Positive Predictive Value: 40% (based on Flow results)  Specificity: > 99%  Detection Rate on Severe T-cell Lymphopenia (BMT needed) in Wisconsin population 1/41,396 (5 cases in 206,982 screened newborns)

9 Funding Support Jeffrey Modell Foundation Children’s Hospital of Wisconsin Wisconsin State Laboratory of Hygiene Centers for Disease Control and Prevention

10 Massachusetts’ Laboratory Experience History and Current Status  March 2007  Massachusetts SCID NBS Working group  July 2007  Development of multiplex TREC Assay began  May 2008 and onward  IRB submissions: statewide pilot updates CDC award  February 2009 and onward  Statewide screening for SCID in MA  September 2010 and onward  Screening for SCID in parallel in MA and TX

11 Through guthrie date 12/31/10 143,172 initial specimens* 833 declined SCID NBS 0.6% 872 no recorded consent SCID NBS0.6% 1,743 Program-wide unsatisfactory1.2% 139,724 valid specimens 160 total SCID-specific unsatisfactory0.1->.03% 139,219 screen negative99.6 345 screen positive0.26 29 referred to flow cytometry *by current algorithm Massachusetts’ Laboratory Experience Results of Testing

12 Massachusetts’ Laboratory Experience Results of Testing Abnormal SCID NBS & Referred to Flow Cytometry: 29 –Abnormal Flow result 18 –Pending Flow / Rpt NBS7 –Flow within normal limits1 –Closed1 –Expired2

13 Massachusetts’ Laboratory Experience Results of Testing Abnormal SCID NBS & Abnormal Flow Cytometry: 18 –SCID1 –DiGeorge Syndrome4 –Multiple Congenital Anomalies1 –T-cell Lymphopenia3 (Not SCID, no further testing needed) –T-cell Lymphopenia 6 (Not SCID, final diagnosis pending) –T-cell Lymphopenia 3 (SCID unlikely, pending further work-up) Sensitivity: 100% (no known missed cases)

14 Funding Support Centers for Disease Control and Prevention

15  July 2010  NIH provides $480,000 for CA NBS SCID Pilot Program. CA will provide data to NIH.  JMF agrees to provide up to $800,000 matching contribution to fund CA NBS SCID Pilot Program.  August 2010  Pilot begins 8/16/2010 with Perkin Elmer staff testing CA NBS specimens at Genetic Disease Laboratory facility (lab within a lab concept).  September 2010  TREC Cut-off dropped from 60 to 25.  January 2011  Actin assay refined and nursery (ie regular nursery vs. NICU) evaluation added to flow chart. California’s Laboratory Experience History and Current Status

16 California’s Laboratory Experience Results of Testing (August 16 – December 31, 2010) Number Screened: 217,515 (initial NBS specimen) –Positive*: 12 (.01%) SCID4 DiGeorge Syndrome 1 Non-SCID T Cell Lymphopenia1 Negative Flow Cytometry3 Expired3 –Inconclusive Results: 229 (.11%) Positive*10 Inconclusive* 3 Negative127 Expired23 Lost to Follow-up7 * Positives and inconclusives on 2nd heelstick go on to Flow Cytometry

17 California’s Laboratory Experience Results of Testing (August 16 – December 31, 2010) From Second Heelstick - Positive:10 DiGeorge Syndrome 1 Non-SCID T Cell Lymphopenia1 Negative Flow Cytometry4 Expired1 Pending 3 - Inconclusive3 SCID *1 Negative Flow Cytometry2

18 217,515 initial specimens 157 Second Heelsticks (Total 217,672) 26 Referred for Flow Cytometry SCID5 Di George Syndrome2 Non-SCID T Cell Lymphopenia2 Negative10 Expired4 Pending3 California’s Laboratory Experience Evaluation of Screened Positive Infants (August 16 – December 31, 2010)

19 Funding and Support Jeffrey Modell Foundation National Institutes of Health

20 DBS Reference Materials Available for the TREC Assay Screen Normal Cord Blood Pools: Highest, Lower, Lowest Individual Cord Bloods (~50) Screen Positive Two Pools Indeterminate Two Pools ~ 4000 DBS in each category

21 CDC Model Performance Evaluation Survey (Pilot Proficiency Testing) Wisconsin NBS Massachusetts NBS California NBS New York NBS University of California San Francisco PerkinElmer Genetics PerkinElmer Life & Analytical Sciences  Monthly Sendouts  Five Blinded Reference DBS  Additional Prototype DBS  Seven enrolled Participants

22 Publications Identification of an infant with severe combined immunodeficiency by newborn screening. Hale JE, Bonilla FA, Pai SY, Gerstel-Thompson JL, Notarangelo LD, Eaton RB, Comeau AM. J Allergy Clin Immunol. 2010 Nov;126(5):1073-4. Epub 2010 Oct 8. A multiplex immunoassay using the Guthrie specimen to detect T-cell deficiencies including severe combined immunodeficiency disease. Janik DK, Lindau-Shepard B, Comeau AM, Pass KA. Clin Chem. 2010 Sep;56(9):1460-5. Epub 2010 Jul 21. High-throughput multiplexed T-cell-receptor excision circle quantitative PCR assay with internal controls for detection of severe combined immunodeficiency in population-based newborn screening. Gerstel-Thompson JL, Wilkey JF, Baptiste JC, Navas JS, Pai SY, Pass KA, Eaton RB, Comeau AM. Clin Chem. 2010 Sep;56(9):1466-74. Epub 2010 Jul 21. Guidelines for implementation of population-based newborn screening for severe combined immunodeficiency. Comeau AM, Hale JE, Pai SY, Bonilla FA, Notarangelo LD, Pasternack MS, Meissner HC, Cooper ER, DeMaria A, Sahai I, Eaton RB. J Inherit Metab Dis. 2010 Oct;33(Suppl 2):S273-81. Epub 2010 May 20.

23 Publications Development of a routine newborn screening protocol for severe combined immunodeficiency. Baker MW, Grossman WJ, Laessig RH, Hoffman GL, Brokopp CD, Kurtycz DF, Cogley MF, Litsheim TJ, Katcher ML, Routes JM. J Allergy Clin Immunol. 2009 Sep;124(3):522-7. Epub 2009 May 31. Statewide newborn screening for severe T-cell lymphopenia. Routes JM, Grossman WJ, Verbsky J, Laessig RH, Hoffman GL, Brokopp CD, Baker MW. JAMA. 2009 Dec 9;302(22):2465-70. Implementing routine testing for severe combined immunodeficiency within Wisconsin's newborn screening program. Baker MW, Laessig RH, Katcher ML, Routes JM, Grossman WJ, Verbsky J, Kurtycz DF, Brokopp CD. Public Health Rep. 2010 May-Jun;125 Suppl 2:88-95.

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