A founder AGL mutation causing glycogen storage disease type IIIa in Inuit identified through whole-exome sequencing: a case series.

BACKGROUND: Glycogen 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. METHODS: Five 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. RESULTS: We 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. INTERPRETATION: Our detection of a homozygous frameshift mutation in 5 Inuit children determines the cause of glycogen storage disease type IIIa and confirms a founder effect.

Molecular analysis of the AGL gene: heterogeneity of mutations in patients with glycogen storage disease type III from Germany, Canada, Afghanistan, Iran, and Turkey.

Glycogen storage disease type III (GSD III) is an autosomal recessive disorder characterized by excessive accumulation of abnormal glycogen in the liver and/or muscles and caused by deficiency in the glycogen debranching enzyme (AGL). Previous studies have revealed that the spectrum of AGL mutations in GSD III patients depends on ethnic grouping. We investigated nine GSD III patients from Germany, Canada, Afghanistan, Iran, and Turkey and identified six novel AGL mutations: one nonsense (W255X), three deletions (1019delA, 3202-3203delTA, and 1859-1869del11-bp), and two splicing mutations (IVS7 + 5G > A and IVS21 + 5insA), together with three previously reported ones (R864X, W1327X, and IVS21 + 1G > A). All mutations are predicted to lead to premature termination, which abolishes enzyme activity. Our molecular study on GSD III patients of different ethnic ancestry showed allelic heterogeneity of AGL mutations. This is the first AGL mutation report for German, Canadian, Afghan, Iranian and Turkish populations.

Glycogen storage disease type III in Inuit children.

Glycogen storage disease type III (GSD III) was diagnosed in 4 Inuit children (3 confirmed, 1 suspected case) at our institution over the last decade. This rare autosomal recessive disease, which results from a deficiency of the debranching enzyme required for complete degradation of the glycogen molecule, has not been previously described in this population. The possible clinical presentations are heterogeneous, as is the spectrum of severity of this disease. The long-term sequelae can be severe, including recurrent hypoglycemia, hepatic cirrhosis and progressive muscle weakness. These 4 cases would suggest an increased prevalence of GSD III in the Inuit population. Therefore, it is important for health care providers caring for this population to consider and recognize this rare but serious disease.