Combined newborn screening for familial hemophagocytic lymphohistiocytosis and severe T- and B-cell immunodeficiencies Stephan Borte, MD, Marie Meeths,

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Presentation transcript:

Combined newborn screening for familial hemophagocytic lymphohistiocytosis and severe T- and B-cell immunodeficiencies Stephan Borte, MD, Marie Meeths, MD, PhD, Ines Liebscher, MD, Kerstin Krist, Magnus Nordenskjöld, MD, PhD, Lennart Hammarström, MD, PhD, Ulrika von Döbeln, MD, PhD, Jan-Inge Henter, MD, PhD, Yenan T. Bryceson, PhD Journal of Allergy and Clinical Immunology Volume 134, Issue 1, Pages 226-228.e7 (July 2014) DOI: 10.1016/j.jaci.2014.04.026 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Quantification of UNC13Dwt (A) and TREC and KREC (B) copy numbers in DBSS from patients with FHL, carriers, anonymous newborns, and PID patients with SCID or XLA. The arbitrary cutoff for UNC13Dwt copies is depicted as a dashed line. Abnormal (“positive”) screening results were defined as less than 8 TRECs/μL and less than 6 KRECs/μL of dried blood, according to current prospective screening trials in Sweden and Germany. inv, Inversion; wt, wild type; XLA, X-linked agammaglobulinemia. Journal of Allergy and Clinical Immunology 2014 134, 226-228.e7DOI: (10.1016/j.jaci.2014.04.026) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Schematic illustration of UNC13D wild-type (wt) and inversion (inv) alleles adapted from Meeths et al.6 A, The breakpoints (BP) are located in Alu elements containing an identical sequence of 25 bp. Two elements, AluSc8 and AluSx1 (yellow, orange), are located on the reverse strand in intron 30 of UNC13D, and an AluY (red) element is located 253 kb upstream of UNC13D on the forward strand. B, Position of primers and hydrolysis probes for the detection of UNC13Dwt copy numbers. In the qPCR screening assay, the primers do not amplify the UNC13Dinv allele. C, Position of primers used in the multiplex PCR analysis step for the amplification of both the UNC13Dwt and the UNC13Dinv allele. Journal of Allergy and Clinical Immunology 2014 134, 226-228.e7DOI: (10.1016/j.jaci.2014.04.026) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 qPCR amplification plots for the UNC13Dwt hydrolysis probes targeting either genotype A only (A), or genotype A and B (B) of the polymorphic probe hybridization site. inv, Inversion; wt, wild type. Journal of Allergy and Clinical Immunology 2014 134, 226-228.e7DOI: (10.1016/j.jaci.2014.04.026) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Flow chart of the TREC-KREC-UNC13Dwt qPCR dried blood spot screening assay and the multiplex PCR analysis step. wt, Wild type. Journal of Allergy and Clinical Immunology 2014 134, 226-228.e7DOI: (10.1016/j.jaci.2014.04.026) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 A, Comparison of ACTB and UNC13Dwt copy numbers in incomplete samples on initial screen, patients with FHL and carriers, patients with PID with SCID or XLA, and anonymous newborns. Correlation analysis of TREC copy numbers (B) or KREC copy numbers (C) measured by triplex qPCR with either ACTB or UNC13Dwt probes. XLA, X-Linked agammaglobulinemia; wt, wild type. Journal of Allergy and Clinical Immunology 2014 134, 226-228.e7DOI: (10.1016/j.jaci.2014.04.026) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Product analysis of the multiplex PCR for the detection of UNC13Dwt and UNC13Dinv alleles with DNA samples from peripheral blood or DBSS eluates. “Normal” and “positive” screening results from the second-tier multiplex PCR indicated below the lanes. inv, Inversion; wt, wild type. Journal of Allergy and Clinical Immunology 2014 134, 226-228.e7DOI: (10.1016/j.jaci.2014.04.026) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions