MG-107 Congenital sucrase-isomaltase deficiency: Identification of the common inuit founder mutation

Objective Congenital sucrase-isomaltase deficiency (CSID) is a rare hereditary cause of chronic diarrhoea in children. Persons with CSID lack the intestinal brush-border enzyme required for digestion of di- and oligosaccharides, including sucrose and isomaltose. Malabsorption results in abdominal pain, distention, copious diarrhoea, and failure to thrive. If recognised, dietary avoidance of the offending carbohydrates is highly effective. Although CSID is known to be highly prevalent (˜5–10%) in several Inuit populations, the genetic basis for this condition has not been described. Methods We sequenced the sucrase-isomaltase gene, SI, in a single Inuit CSID proband with severe fermentative diarrhoea and failure to thrive. We then genotyped a further 128 anonymized Inuit control individuals from a variety of circumpolar locales to assess for a possible founder effect. Results We identified a novel, homozygous frameshift mutation, c.273_274delAG (p. Gly92Leufs*8) in exon 4 of SI in the proband, that is predicted to result in complete absence of functional protein product. This change is indeed very common among Inuit control specimens, with an observed allele frequency of 0.17 (95% confidence interval 0.13–0.22). The predicted Hardy-Weinberg prevalence of CSID in the Inuit, based on this single founder allele is ˜3% (95% confidence interval 1.6–5.0%), comparable with previous estimates. Interpretation Targeted mutation testing for the c.273_274delAG allele should afford a simple and minimally invasive means of diagnosing CSID in persons of Inuit descent. Because CSID is a readily treatable disorder, such testing should be considered at an early stage in the assessment of Inuit patients with chronic diarrhoea.