Genotyping an immunodeficiency causing c.1624–11G>A ZAP70 mutation in Canadian Mennonites

Abstract

Abstract

Background Primary immunodeficiency is a life-threatening genetic disease that appeared to have an increased incidence in Manitoba Mennonites. Determining the genetic basis of this immunodeficiency was an essential step for providing early and appropriate medical intervention.

Methods Initially, DNA from probands affected with primary immunodeficiency and their family members was assessed for linkage to genes previously associated with immunodeficiency. Candidate genes were sequenced to identify the causative mutation. The frequency of the mutation among first and second degree relatives, as well as apparently unrelated community members was analyzed using a PCR-based assay.

Results A previously described c.1624–11G>A mutation in ZAP70 was identified as the causative mutation in all affected probands that were analyzed. Among 125 study participants of Mennonite descent, 79 genotyped as normal, 39 were carriers and seven were affected. None of 115 non-Mennonite random individuals carried the mutation, whereas one of ten random DNA samples from individuals who self-identified as Mennonite was a carrier.

Conclusions In collaboration with the target community, we have developed a robust screening test for determining ZAP70 genotype. Early identification of affected individuals has provided an opportunity for timely clinical intervention, while carrier identification has allowed for genetic counselling of at risk couples.