• Isabelle Rousseau-Nepton, Minoru Okubo, Rosemarie Grabs, FORGE Canada Consortium, John Mitchell, Constantin Polychronakos, and Celia Rodd.
• Department of Pediatrics (Rousseau-Nepton, Mitchell, Polychronakos), Montreal Children's Hospital, Montréal, Que.; Okinaka Memorial Institute for Medical Research (Okubo), Tokyo, Japan; Endocrine Genetics Laboratory (Grabs), Montreal Children's Hospital, McGill University Health Centre, Montréal, Que.; Department of Pediatrics and Child Health (Rodd), Winnipeg, Man.
• CMAJ. 2015 Feb 3;187(2):E68-73.

BackgroundGlycogen storage disease type III is caused by mutations in both alleles of the AGL gene, which leads to reduced activity of glycogen-debranching enzyme. The clinical picture encompasses hypoglycemia, with glycogen accumulation leading to hepatomegaly and muscle involvement (skeletal and cardiac). We sought to identify the genetic cause of this disease within the Inuit community of Nunavik, in whom previous DNA sequencing had not identified such mutations.MethodsFive Inuit children with a clinical and biochemical diagnosis of glycogen storage disease type IIIa were recruited to undergo genetic testing: 2 underwent whole-exome sequencing and all 5 underwent Sanger sequencing to confirm the identified mutation. Selected DNA regions near the AGL gene were also sequenced to identify a potential founder effect in the community. In addition, control samples from 4 adults of European descent and 7 family members of the affected children were analyzed for the specific mutation by Sanger sequencing.ResultsWe identified a homozygous frame-shift deletion, c.4456delT, in exon 33 of the AGL gene in 2 children by whole-exome sequencing. Confirmation by Sanger sequencing showed the same mutation in all 5 patients, and 5 family members were found to be carriers. With the identification of this mutation in 5 probands, the estimated prevalence of genetically confirmed glycogen storage disease type IIIa in this region is among the highest worldwide (1:2500). Despite identical mutations, we saw variations in clinical features of the disease.InterpretationOur detection of a homozygous frameshift mutation in 5 Inuit children determines the cause of glycogen storage disease type IIIa and confirms a founder effect.© 2015 Canadian Medical Association or its licensors.

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