Neonatal screening for PID. T cell defects (SCID) B cell defects (XLA) Phagocytic disorders (CGD) Complement defects (C2, P)

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1 Lennart Hammarström Stephan Borte Ulrika von Döbeln Clinical Immunology Karolinska Institutet at KUS Huddinge γc JAK 3 Pro NK Periphery NK Common lymphoid progenitors Haematopoetic stem cells γc JAK 3 IL 7 Rα RAG 1,2 Pro T Rag 1,2 Artemis γδ αβ Zap 70 Tap 1,2 HLA γδ CD8 CD4 Myeloid cells THYMUS RAG 1,2 BTK Zap 70 B Pro B Pre B μ Igα/β λ5 BLNK Immature B Ig switched B CD40L AID Neonatal screening for PID T cell defects (SCID) B cell defects (XLA) Phagocytic disorders (CGD) Complement defects (C2, P) 1

2 Genetic causes of SCID IL2RG IL7RA JAK3 PTPRC RAG1/2 Artemis CORO1A PRKDC ADA AK2 Neonatal screening for PID S (Puck et al 2005)* S (Nakagawa et al 2011) * T cell lymphopenia Rearrangement of T cell receptor genes 2

3 s represent newly formed T cells screening (for PID) Wisconsin 2008* Massachusetts 2009 Louisiana 2009 New York 2009 California 2010 Puerto Rico 2010 Texas 2010 Pennsylvania 2010 * Routes and Verbsky USA update children screened (0.04 %) FACS referrals 52 children with SCID (1/58 000) 92 % survival after therapy No SCID patient missed 460 additional positive samples Kwan et al, JAMA

4 Neonatal screening for PID T cell defects (SCID) B cell defects (XLA) Phagocytic disorders (CGD) Complement defects (C2, P) Neonatal screening for PID S (Puck et al 2005) S (Nakagawa et al 2011)* * B cell lymphopenia Formation of the B cell receptor (BCR) 4

5 s represent newly formed B cells Neonatal screening for PID S (Puck et al 2005) S (Nakagawa et al 2011) -actin Borte et al, Blood 2012 Proof of principle (retrospective) Borte et al, Ann NY Acad Sci

6 Neonatal screening in Sweden Time schedule (Sweden) 2010 (2 500 anonymous samples) 2011 (2 500 anonymous samples) 2012 (5 000 anonymous samples) ( samples) ( samples) ( samples) 2016 national implementation (?) Prospective NBS screening (Sweden) Newborns first sample Normal 334 Abnormal ACTB 1000 copies/µl blood 156 Inconclusive ACTB 1000 copies/µl blood 15 Abnormal and 60 Abnormal 259 Abnormal 9 Inadequate samples new sample request 12 Normal and 50 Normal 222 Normal 144 Normal on repeat testing 3 Abnormal on repeat testing 9 Normal on second sample 1 Recall 1 Recall and 1 Recall 10 Recalls 37 Recalls 1 Recall 2 Recall 53 Recalls Normal 2 True positive 51 Add. positive 6

7 USA update (non-scid T cell lymphopenia) 29 Prematurity (only) 58 DiGeorge 21 Trisomy 21 4 AT 1 Nijmegen Breakage Syndrome 117 Secondary T-cell impairment 230 Other Kwan et al, JAMA 2014 Additional positive samples - prematurity Borte et al, Ann NY Acad Sci 2013 USA update (non-scid T cell lymphopenia) 29 Prematurity (only) 58 DiGeorge 21 Trisomy 21 4 AT 1 Nijmegen Breakage Syndrome 117 Secondary T-cell impairment 230 Other Kwan et al, JAMA

8 Additional positive samples - DiGeorge Lingman-Framme et al, JoCI 2014 USA update (non-scid T cell lymphopenia) 29 Prematurity (only) 58 DiGeorge 21 Trisomy 21 4 AT 1 Nijmegen Breakage Syndrome 117 Secondary T-cell impairment 230 Other Kwan et al, JAMA 2014 Additional positive samples - Trisomy 21 Verstegen et al, JACI

9 Prospective NBS screening (Sweden) Newborns first sample Normal 334 Abnormal ACTB 1000 copies/µl blood 156 Inconclusive ACTB 1000 copies/µl blood 15 Abnormal and 60 Abnormal 259 Abnormal 9 Inadequate samples new sample request 12 Normal and 50 Normal 222 Normal 144 Normal on repeat testing 3 Abnormal on repeat testing 9 Normal on second sample 1 Recall 1 Recall and 1 Recall 10 Recalls 37 Recalls 1 Recall 2 Recall 53 Recalls Normal 2 True positive 51 Add. positive Clinical follow up Doctors visit Clinical chemistry FACS(EuroFlow) Genetic testing PID screening panel (219 genes, 2800 exons) Exome sequencing Whole genome sequencing Future NBS challenges Normal / SCIDs Improved assay performance Cut-offs for / Granulocyte deficiencies Complement deficiencies 9

10 Unknown SCID Borte et al, unpublished Future NBS challenges Normal / SCIDs Improved assay performance Cut-offs for / Granulocyte deficiencies Complement deficiencies Towards neonatal complement screening C2 deficient patients Non-deficient controls Luminex based assay Hamsten et al, J Proteomics

11 Acknowledgements Patient referrals Anders Fasth, Jacek Winiarski, Nicholas Brodszki, Solveig Oskarsdottir, Jenny Lingman Framme, Esther de Vries, Ruud Verstegen assay Jack Routes, James Verbsky, Jennifer Puck Complement assay Lennart Truedsson, Lillemor Skattum, Peter Nilsson, Maja Neiman Acknowledgements 11