AGL mutation underlies glycogen storage disease in Inuits

Last Updated: 2015-01-20

By Will Boggs MD

NEW YORK (Reuters Health) - A homozygous frameshift mutation in the AGL gene underlies glycogen storage disease type IIIa in Inuits, according to results of whole-exome sequencing of five affected children.

"Given the failure of our earlier efforts to find this mutation, modern genetic techniques are extremely helpful when searching for genetic mutations in monogenic diseases," Dr. Celia Rodd, of the Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada, told Reuters Health by email.

"We were also motivated by families of the affected children, who were keen to pursue all avenues, including whole exome sequencing," she added.

Earlier, targeted genetic analysis failed to identify a suspected mutation in the AGL gene in 4 Inuit children with putative glycogen storage disease type III.

Dr. Rodd's team used exome sequencing, which examines all protein-encoding DNA sequences (exons), in their effort to identify the genetic cause of this disease in the Inuit population of Nunavik on the eastern coast of Hudson Bay.

Two of five affected children underwent whole-exome sequencing, and all five children and their available family members underwent confirmation of the identified mutation by conventional Sanger sequencing, according to the January 19 CMAJ online report.

The researchers identified a single-base homozygous deletion of a thymine residue (c.4456delT) that resulted in a homozygous frameshift deletion at location NM000_642 of exon 33 of AGL.

This homozygous deletion was present in all of the children with glycogen storage disease type IIIa; one sibling and four parents were heterozygous for the same mutation; and two siblings had normal AGL sequences.

"The major implications revolve mostly around the possibility of genetic counseling and screening for these Inuit communities, where the carrier state is at least as common as cystic fibrosis (the most common lethal genetic defect)," Dr. Rodd explained.

"Our findings confirm that this genetic defect shows clinical heterogeneity, with considerable variation in the severity of clinical features and outcomes. Some of this may be related to age of diagnosis, adherence to diet, or other individual genetic factors," she continued.

"Our work also shows how genetic defects can be missed in conventional Sanger analysis, as was the case when we first examined these kids a decade ago," Dr. Rodd said. "As you can imagine, a single missing T in a 'sea of Ts' (a polyT region) is easy to miss, though we were able to confirm the deletion by Sanger sequencing once we had the results of the whole-exome sequencing. I think there's a lesson there about persistence."

She added, "This mutation probably arose de novo in this population at a 'hot spot,' a region of DNA that is particularly prone to mutations. That would explain why an unrelated African population has the same defect."

SOURCE: http://bit.ly/15tofy0

CMAJ 2015.