Abstracts

#67 Presymptomatic Newborn Detection of IKBKB Severe Combined Immune Deficiency Mutations in Manitoba: a Pilot Project


Herman Tam, University of Manitoba; Cheryl Rockman-Greenberg, University of Manitoba; J. Robert Thompson, Cadham Provincial Laboratory; Paul Van Casseele, University of Manitoba; Marlis L. Schroeder, University of Manitoba; Tamar Rubin, University of Manitoba


Introduction

Severe combined immune deficiency (SCID) is the most profound form of primary immune deficiency, and is usually fatal within the first year of life without treatment. Newborn screening for SCID, with presymptomatic detection and early treatment, has dramatically changed the natural history of this disorder. The gold standard for SCID newborn screening worldwide uses quantitative analysis of T-cell receptor excision circles (TRECs) as SCID babies typically do not make TRECs. IKBKB deficiency is a rare form of SCID, overrepresented in our Manitoba population, where T cells can develop normally. TRECs analysis is expected to be normal in this condition and would not identify these cases. The objective of our study is to determine the feasibility of targeted genetic newborn testing for IKBKB deficiency.


Methods

We implemented a pilot project for prospective targeted genetic testing of a previously described IKBKB mutation in newborns from 2 small northern Manitoba communities. Between 2013 and 2017, DNA was extracted from dried blood spots of 663 newborns from these communities, and targeted Sanger sequencing of the mutation-harbouring IKBKB exon was performed.


Results

All 663 infants born in in the 2 selected communities underwent testing. Forty-nine (1/14 or 7%) were found to be heterozygous carriers. One affected infant was identified (consistent with the predicted homozygosity for this mutation 1/14 X 1/14 = 1/784 births), and underwent hematopoietic stem cell transplantation.


Conclusion

We demonstrated that targeted newborn testing for IKBKB deficiency was feasible, and provided the first prospective estimate of the IKBKB mutation carrier frequency in select Manitoba northern Cree populations. We suggest that if we are to capture all babies with SCID in Manitoba, that future newborn screening should be universal and include both TRECs and direct mutation testing for population-specific mutations, including the First Nations IKBKB mutation.