Abstract
Severe combined immunodeficiency (SCID) and other T cell lymphopenias can be detected during newborn screening (NBS) by measuring T cell receptor excision circles (TRECs) in dried blood spot (DBS) DNA. Second tier next generation sequencing (NGS) with an amplicon based targeted gene panel using the same DBS DNA was introduced as part of our prospective pilot research project in 2015. With written parental consent, 21 000 newborns were TREC-tested in the pilot. Three newborns were identified with SCID, and disease-causing variants in IL2RG, RAG2, and RMRP were confirmed by NGS on the initial DBS DNA. The molecular findings directed follow-up and therapy: the IL2RG-SCID underwent early hematopoietic stem cell transplantation (HSCT) without any complications; the leaky RAG2-SCID received prophylactic antibiotics, antifungals, and immunoglobulin infusions, and underwent HSCT at 1 year of age. The child with RMRP-SCID had complete Hirschsprung disease and died at 1 month of age. Since January 2018, all newborns in Norway have been offered NBS for SCID using 1st tier TRECs and 2nd tier gene panel NGS on DBS DNA. During the first 20 months of nationwide SCID screening an additional 88 000 newborns were TREC tested, and four new SCID cases were identified. Disease-causing variants in DCLRE1C, JAK3, NBN, and IL2RG were molecularly confirmed on day 8, 15, 8 and 6, respectively after birth, using the initial NBS blood spot. Targeted gene panel NGS integrated into the NBS algorithm rapidly delineated the specific molecular diagnoses and provided information useful for management, targeted therapy and follow-up i.e., X rays and CT scans were avoided in the radiosensitive SCID. Second tier targeted NGS on the same DBS DNA as the TREC test provided instant confirmation or exclusion of SCID, and made it possible to use a less stringent TREC cut-off value. This allowed for the detection of leaky SCIDs, and simultaneously reduced the number of control samples, recalls and false positives. Mothers were instructed to stop breastfeeding until maternal cytomegalovirus (CMV) status was determined. Our limited data suggest that shorter time-interval from birth to intervention, may prevent breast milk transmitted CMV infection in classical SCID.
Highlights
Diagnosis is important in severe combined immunodeficiency (SCID)
We have explored the utility of rapid NGS integrated in the Newborn screening (NBS) laboratory algorithm for SCID
Out of the 21,232 samples tested in the prospective pilot project, three individuals were identified with SCID: on day 16, 13, and 11 after birth, respectively; one IL2RG, one RAG2, and one RMPR related SCID (Table 1 and Figure 1A)
Summary
Diagnosis is important in severe combined immunodeficiency (SCID). Targeted treatment, molecularly adjusted preconditioning, as well as avoiding infections such as cytomegalovirus (CMV) before undergoing hematopoietic stem cell transplantation (HSCT), improves overall prognosis [1,2,3,4]. Newborn screening (NBS) for SCID was first introduced in the United States in 20081. SCID became part of the US core recommended uniform screening panel (RUSP) in 2010, and since December 2018 all US states have implemented SCID screening as part of their NBS program. Nationwide SCID screening was implemented in Taiwan 2012 [5, 6], and Israel Oct 2015 [6, 7]. In Europe, universal SCID screening started in the region of Catalonia in Spain (Jan 2017) [8], Iceland (2017), Switzerland (Jan 2019), Sweden and Germany (Aug 2019) proceeded by pilots [9,10,11]3, and Denmark (Feb 2020) [12]. Hospital pilots have been performed [13], or are ongoing in European countries and regions such as France [14], Finland, Poland, Italy, and the Netherlands [15, 16]
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