Development of a Population-Based Newborn Screening Method for Severe Combined Immunodeficiency in Manitoba, Canada

Abstract

Abstract:The incidence of Severe Combined Immunodeficiency (SCID) in Manitoba, (1/15,000), is at least three to four times higher than the national average and that reported from other jurisdictions. It is overrepresented in two population groups: Mennonites (ZAP70 founder mutation) and First Nations of Northern Cree ancestry (IKBKB founder mutation). We have previously demonstrated that in these two populations the most widely utilized T-cell receptor excision circle (TREC) assay is an ineffective newborn screening test to detect SCID as these patients have normal numbers of mature T-cells. We have developed a semi-automated, closed tube, high resolution DNA melting procedure to simultaneously genotype both of these mutations from the same newborn blood spot DNA extract used for the TREC assay. Parallel analysis of all newborn screening specimens utilizing both TREC analysis and the high-resolution DNA procedure should provide as complete ascertainment as possible of SCID in the Manitoba population.

Social determinants of health and primary immunodeficiency

“…In this way, CD18 deficiency, the cause for leukocyte adhesion defect(LAD) type I, and IL12B defect, which causes Mendelian susceptibility to mycobacterial disease, are both common in North Africa. 55,56 Other examples include SLC35C1, the cause of LAD type II in Israeli Arabs, 62 NCF1 mutations causing chronic granulomatous disease among Kavkazi Jews, 63 NSB1 mutations causing Nijmegen breakage syndrome in people of Slavonic origin, 64 RAB27A mutations causing Griscelli type II syndrome in Qatar, 65 Bloom syndrome among Ashkenazi Jews, 66 adenosine deaminase deficiency in Somalians, 67 ZAP70 in Mennonites, 68 IKBKB mutations among First Nation of Northern Cree ancestry, 68 and pathogenic variants in RMRP, the cause of cartilage−hair hypoplasia among Finns and Old Order Amish in the United States. 69 This partial list emphasizes the need for the immunologist and geneticist caring for patients with immunodeficiency to be aware of the conditions associated with ethnic and cultural background of every patient.…”

“…The need for early diagnosis of SCID is further emphasized by the routine protocol for early BCG vaccination in many countries, which may adversely affect undiagnosed patients with SCID. 16,18 Many IEI, including combined immunodeficiencies, 68,75 and non −T-cell defects are not detected by NBS using TREC. Population-specific NBS programs have been proven effective in regions with known founder effects.…”

“…Such is the case for next generation-based screening of 202 pathogenic variants among old order Amish and Mennonites in Pennsylvania, 76 screening for ZAP70 among Canadian Mennonites and for IKBKB among First Nations of Northern Cree ancestry in Manitoba, Canada. 68 Premarital and preconception genetic counseling are important ways to reduce genetic diseases, including IEI. Prophylactic measures include prevention of at-risk marriages, pregestation diagnosis (PGD), or prenatal diagnosis (PND) by amniocentesis or chorionic villous sampling.…”