Population-specific genetic variants and related health outcomes in a cohort of Inuit children in Nunavut

Like all populations, Inuit children experience rare genetic conditions. Awareness of the unique Inuit genetic architecture allows the identification of specific variants associated with autosomal recessive conditions affecting child health across the Arctic. As a priority, the impact of the IFNAR2 c.157T>C variant causing IFNAR2 Deficiency, DNAH11 c.4095+2C>A causing Primary Ciliary Dyskinesia, and SI c.273_274delAG causing Congenital Sucrase-Isomaltase Deficiency (CSID), along with other disease-causing variants were assessed to determine the potential health outcomes on infant and child health in Nunavut. With the direction of Nunavut Tunngavik Incorporated and the Government of Nunavut Department of Health a research group was established utilizing local and national expertise. Newborn dried screening blood spots of a 4-year cohort of infants born to residents of Nunavut between January 1st, 2010, and December 31st, 2013, were genotyped ( n =2947) followed by linkage of a subset of the cohort to a database with demographic and health information collected from records spanning from birth to 5 years ( n =2206 Inuit children). Live birth prevalence (LBP) of cases and carrier frequencies were first estimated for the full cohort and recalculated for the subset with linked data. Health visit information was reviewed for phenotype features consistent with the conditions of interest. In addition, baseline characteristics, and health visits for CSID cases were compared to those without the variant. LBP of cases due to homozygosity of the DNAH11 , IFNAR2 and SI variants were 1/1474, 1/737 and 1/28; carrier frequency was 1/13, 1/18 and 1/4, respectively. Four children with IFNAR2 , one with DNAH11 , and 83 with SI homozygosity were linked to health data, confirming phenotypes consistent with the conditions. CSID was associated with significant increased health care utilization for gastrointestinal illness visits before age two (OR=1.9, 95% CI 1.2–3.0). However, breastfeeding for up to six months was found to be protective, with a reduced number of health care visits (OR=0.80, 95% CI 0.63–1.0). We describe the presence and health impact of three autosomal recessive conditions in a Canadian Inuit population. Genetic testing, practitioner education, and Inuit-informed management strategies are urgently needed to address these conditions and improve outcomes.