CALIFORNIA NEWBORN SCREENING FOR SCID. Joseph A. Church, M.D. Children s Hospital Los Angeles and Keck School of Medicine at U.S.C.
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1 CALIFORNIA NEWBORN SCREENING FOR SCID Joseph A. Church, M.D. Children s Hospital Los Angeles and Keck School of Medicine at U.S.C.
2 CELLS, DNA AND GENES
3 HOW GENES GO WRONG - MUTATIONS MONOGENIC TRAIT: Determined by a single gene (XLA) POLYGENIC TRAIT: Determined by more than one gene (asthma, most CVID) DOMINANT: an affected parent may pass a mutation to sons or daughters RECESSIVE (AUTOSOMAL) carrier parents may pass mutations in the same gene to sons or daughters X-linked recessive: Carrier mom may pass on a mutation in one of her X chromosomes: typically sons who get the X with the mutation (50%) have a medical problem; daughters (50%) will be carriers Genetic mutations are not always inherited; they may occur in a baby for the first time
4 THE IMMUNE SYSTEM The cells and the elements they produce that Together generate coordinated, controlled and normally protective responses to Factors recognized as foreign, dangerous or damaged
5 IMMUNOLOGIC BALANCE
6 ANATOMIC COMPONENTS OF THE IMMUNE SYSTEM
7 HEMATOPOIESIS - BLOOD CELLS ARE MADE IN THE BONE MARROW
8 PERIPHERAL BLOOD
9
10 BONE MARROW THYMUS LYMPH NODES Bone Marrow: Where T-cells & B-cells begin and B-cells are educated Thymus: Where T-cells are educated Lymph Nodes & Spleen: Where T-cells and B-cells interact to generate immune responses
11 CELLS AND FACTORS CELLS/FACTORS: Neutrophils/phagocytes T-cells Helper T-cells Cytotoxic T-cells (killers) B-cells/Plasma cells Natural Killer Cells Cytokines Antibodies FUNCTION: Eat (phagocytosis) bacteria, fungi and other microbes Produce cytokines that activate other cells Kill virus-infected cells Produce antibodies Control Herpes viruses and HPV Factors produced by cells that communicate signals to other cells Coat microbes (opsonization) to facilitate phagocytosis and neutralize toxins and viruses
12 T-CELL B-CELL INTERACTION
13 IMMUNE DEFICIENCY DISORDERS 1. Clinical conditions characterized by increased susceptibility to infection, malignancy, autoimmunity or autoinflammation Primary : Documented or presumed genetic mutations in immune response pathways Over 300 identified XLA, SCID, HIM, WAS, A-T
14 IMMUNE DEFICIENCY DISORDERS 2. Secondary or Acquired : Extrinsic factorinduced alterations in immune responses Infections: HIV, measles Malnutrition Iatrogenic (radiation, chemo, steroids) Natural : Normal developmental processes Immunodeficiency of immaturity newborn infants Immune attrition of aging
15 SEVERE COMBINED IMMUNE DEFICIENCY (SCID) A clinical syndrome/phenotype characterized by infections which reflect combined deficiencies/dysfunctions of T-cells and B-cells Recurrent infections and weight loss from age 2-4 months Infections with attenuated or opportunistic organisms that do not harm healthy infants Early death unless the patient is given a working immune system Incidence: 1:50,000
16 SCID: OMENN SYNDROME
17 HUMAN SCID GENES TCR Rearrangement Cytokine signaling RAG1 RAG2 DCLRE1C (Artemis) DNA ligase IV TCR Signaling subunit subunit subunit Lck (p56/ck Zap 70* CD45 Thymus Failure IL-2R (common chain) IL-7R JAK 3 STAT 5* Calcium Channel ORAI 1* STIM 1* Purine metabolism ADA NP Complete DiGeorge Syndrome COMMON FEATURE (except*): T-cells
18 BARRIERS TO EARLY SCID DIAGNOSIS Immune defects are rare Infections are common, not just in immune deficiency Family history often missed, subtle or absent Maternal IgG protects infants for their first months of life Both gene defects and environmental exposures contribute to infection risk so presentation is variable
19 SCID NEWBORN SCREENING IS JUSTIFIED SCREENING CRITERIA Disease is serious Disease is not detectable by routine exam Incidence supports screening (hypothyroidism 1:2,000, Galactosemia 1:88,000) Simple, reliable test is available Confirmation test is available Treatment alters disease Earlier treatment improves outcomes SCID MEETS CRITERIA Fatal if untreated SCID babies appear healthy at birth ~1:50,000 in California TREC Lymphocyte subset analysis BMT/HSCT cures SCID Survival improved if BMT/HSCT done before complicating infections
20 NEWBORN SCREENING FOR SCID IN THE UNITED STATES
21 CA SCID NEWBORN SCREENING PROGRAM Consent not required All newborns screened Screening done at NBS regional laboratories TREC quantification by PCR Abnormal screens Peripheral blood collected and sent to Central Lab for confirmatory CBC+diff and lymphocyte subset analysis by flow cytometry
22 T-CELL RECEPTOR EXCISION CIRCLES (TREC) 1. Small circles of DNA By-products of T-cell receptor (TCR) gene rearrangement during generation of antigen specific TCR in the thymus Stable, detectable and quantifiable TREC T-cells
23 T-CELL RECEPTOR EXCISION CIRCLES (TREC) 2.
24 GUTHRIE CARD BLOOD SAMPLING
25 TREC DRIED BLOOD SPOT ASSAY 50 ul blood/drop Guthrie Card 3 mm hole punched from blood spot ~3 ul blood Extract DNA Measure TRECs by PCR
26 TREC CORRESPOND TO T-CELL NUMBER y = 0.224x r 2 =.9744 Graded numbers of T-cells added back to T-depleted blood. T-cells per 3-mm punch corresponds to 3 ul of blood.
27
28 T-CELL SUBSET ANALYSIS Hematopoietic cells, including T-cells, B-cells and NKcells display specific proteins ( antigens ) on surfaces Nomenclature for these proteins use cluster of differentiation (CD) designations CD3+ = T-cell CD19+ = B-cell CD3+ CD4+ = helper T-cell Specific CD s are readily measured with flow cytometry and antigen-specific monoclonal antibodies
29 FLUORESCENT LABELING OF LYMPHOCYTES
30 FLOW CYTOMETRY
31 EXAMPLE OF LYMPHOCYTE SUBSET REPORT
32 California SCID Screening--6.5 Years Dried blood spot 3,252,156 infants screened Neonatal intensive care unit (NICU) 9% Regular nursery 91% Liquid blood sample 562 infants required flow cytometry (1/6,000 births) 52% 48 % 212 infants had T-cell lymphopenia (1/15,000) Positive predictive value of low TRECs for T-cells <1,500/uL = 38% 54% 46 % 50 SCID Cases, 1/65,000
33 Genotypes of Typical and Leaky SCID Reports from Transplant Centers, no Screening RAG2 1% DCLRE1C 5% RMRP 1% TTC7A 1% Duke University, European centers (estimates) ADA 14% Unknown 3% IL7R 10% IL2RG 50% California, with TREC Screening 6.5 years, infants, 50 SCID cases Unknown 10% BCL11B RMRP RAG2 6% JAK3 6% IL7R 12% RAG1 IL2RG ADA RAG1 1% Overall Survival ~74% Overall Survival 96%
34 SECONDARY TARGETS OF TREC SCREENING: CONDITIONS WITH LOW T-CELLS (CALIFORNIA) Syndromes with T-cell impairment DiGeorge syndrome Trisomy 21 / Down syndrome Ataxia Telangiectasia CHARGE Secondary T-cell lymphopenia Congenital heart disease Gastrointestinal malformations Hydrops, loss into third space Preterm birth alone Microarray or exome sequencing may reveal an underlying genetic cause
35 BABY BOY SCID #904 a. 38 wga, 3230 gmbw Uncomplicated pregnancy, labor and delivery Normal exam at birth SCID screen positive TREC = 1/mcL (normal >18) ACTIN = 1670/mcL Hemoglobin screen HgbC/Beta thalassemia
36 BABY BOY SCID #904 b. AGE (WEEKS) 2 2+ WBC/mL ALC/mL CD3+ % (#) 0 (0) <1 (1) CD3+4+% (#) 0 (0) <1 (<1) CD3+8+% (#) 0 (0) <1 (1) CD19+% (#) 86 (518) 83 (572) NK% (#) 4 (24) 8 (57) Diagnosis: SCID + Hemoglobinopathy Focused Exome: pathogenic variant IL2RG (c. 711G>A, p. Trp237*) Therapy: Stem cell transplant (haploidentical from parent) OR gene therapy
37 PRIMARY IMMUNODEFICIENCIES NOT DEFECTED WITH TREC SCREENING Defects occur after TCR recombination in thymus Hyper-IgM syndrome Zap-70 deficiency MHC II deficiency Others Syndromes with variable T-cell deficiency DiGeorge syndrome Ataxia telangiectasia Late onset ADA deficiency (presumed maternal neutralization of metabolic defect) PIDs not involving T-cells at birth XLA CVID CGD
38
39 BABY GIRL SCID #946 a. 39 wga, 3332 gmbw Uncomplicated pregnancy, labor and delivery Normal physical examination SCID screen positive TREC = 13/mcL (normal >18) ACTIN: 3790/mcL
40 BABY GIRL SCID #946 b. Age (days) 6 11 WBC/mcL ALC/mcL CD3+ % (#) 49 (1025) 50 (962) CD3+4+% (#) 33 (687) 37 (699) CD3+8+% (#) 15 (324) 12 (226) CD19+% (#) 29 (599) 27 (507) NK% (#) 17 (362) 26 (416) Diagnosis: T lymphopenia of unknown etiology Microarray: Deletion 22q11.2 (DiGeorge Syndrome- partial ) Therapy: Proactive assessments, anticipatory monitoring, genetic counseling
41 DIGEORGE SYNDROME/ANOMALY Embryologic developmental field defect of 3 rd & 4 th pharyngeal pouches Associated with del22q11.2 Variable spectrum of organ system involvement Craniofacial: dysmorphisms, development Cardiovascular: conotruncal malformations Parathyroid: hypocalcemia Thymic: T-cell deficiency Immunologic phenotypes Complete Partial
42 BABY GIRL SCID #127 a. 40 wga, 3500 gmbw, NVD Normal exam at birth SCID Screen positive (After 2 DAF) TREC 4 copies/mcl (normal >22) ACTIN 10,000 copies/mcl
43 BABY GIRL SCID # 127 b. Age (Months) CD3 (+ % (#) 27 (1093) 31 (615) 41 (432) CD (724) 22 (502) 22 (238) CD (267)_ 7 (172) 10 (107) CD ) 4 (84) 5 (56) CD (294) 45 (605) 52 (542) IgG (mg/dl) (on SC lg) IgA (mg/dl) <7 <7 <7 IgM (mg/dl) Tetanus Ab (>0.1 IV/ml) 0.07 Hib Ab (>1.0mg/ml) <0.15
44 BABY GIRL SCID # 127 c. Diagnosis: Combined Immune Deficiency Exome sequencing: compound heterozygous mutations in ATM Genetic diagnosis: Ataxia telangiectasia Therapy: Ig Infusions
45 ATAXIA TELANGIECTASIA Autosomal recessive disorder due to mutations in ATM Chromosomal instability due to inefficient dsdna break repair Ataxia, telangiectasias Variable combined immunodeficiency ~25%lifetime risk of cancer
46 BABY BOY SCID #210 a. 40 wga, 2860 gmbw CSF noted with prenatal ultrasound 1 month age dx d hydrocephalus V-P shunt 1 month age noted developmental delay SCID screen positive TREC 12 copies/mcl Actin 19,800 copies/mcl
47 BABY BOY SCID #210 b. Diagnosis: Syndromic combined immunodeficiency Exome sequencing: Compound heterozygous mutations in NBN Genetic diagnosis: Nijmegen Breakage syndrome Therapy: Stem cell transplant
48 NIJMEGEN BREAKAGE SYNDROME Autosomal recessive disorder due to mutation in NBN/NBS Chromosomal instability due to inefficient dsdna break repair Intellectual disability, short stature, microcephaly, recurrent infections Variable combined immunodeficiency Malignancy in 40% by 21 y/o
49 BABY GIRL SCID #502 a. 39 wga, 3870 gmbw, C-section Normal exam at birth SCID screen positive TREC = 13 copies/mcl (normal >22) ACTIN = 3500 copies/mcl
50 BABY GIRL SCID #502 b. AGE (MONTHS 1 4 & 5 12 WBC ALC CD3+ %(#) 59 (244) 60 (240) 38 (99) CD (213) 55 (221) 30 (79) CD (15) 4 (17) 5 (14) CD (127) 34 (138) 46 (120) CD (28) 4 (16) 13 (33) IgG mg/dl IgA <7 47 IgM 8 56 Tetanus Ab units > Hib Ab units > PMN chemotaxis normal PMN DHR (fmlp & PMA) normal
51 BABY GIRL SCID #502 c. Diagnosis: Combine Immunodeficiency Exome Sequencing: De novo hemizygous mutation in Rac2 Therapy: Stem cell transplant
52 RAS-RELATED C3 BOTULINUM TOXIN SUBSTRATE 2 (RAC2) Ras superfamily, Rho subfamily of small GTPases Hematopoietic-specific Neutrophils Chemotaxis 1 granule exocytosis Actin cytoskeleton regulation Extracellular traps (nets) Interacts with NCF2(p67) to regulate phagocyte NADPH oxidase T-cells Distribution and chemotaxis TH1 activation Required in DC's for T-cell priming B-cells Development Signaling
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