Sequencing a patient's entire genome to discover the source of his or
her disease is not routine -- yet. But geneticists are getting close.
A case report, published this week in the American Journal of Human Genetics,
shows how researchers can combine a simple blood test with an
"executive summary" scan of the genome to diagnose a type of severe
metabolic disease.
Researchers at Emory University School of Medicine and
Sanford-Burnham Medical Research Institute used "whole-exome sequencing"
to find the mutations causing a glycosylation disorder in a boy born in
2004. Mutations in the gene (called DDOST) that is responsible for the
boy's disease had not been previously seen in other cases of
glycosylation disorders.
Whole-exome sequencing is a cheaper, faster, but still efficient
strategy for reading the parts of the genome scientists believe are the
most important for diagnosing disease. The report illustrates how
whole-exome sequencing, which was first offered commercially for
clinical diagnosis in 2011, is entering medical practice. Emory Genetics
Laboratory is now gearing up to start offering whole exome sequencing
as a clinical diagnostic service.
It is estimated that most disease-causing mutations (around 85
percent) are found within the regions of the genome that encode
proteins, the workhorse machinery of the cell. Whole-exome sequencing
reads only the parts of the human genome that encode proteins, leaving
the other 99 percent of the genome unread.
The boy in the case report was identified by Hudson Freeze, PhD and
his colleagues. Freeze is director of the Genetic Disease Program at
Sanford-Burnham Medical Research Institute. A team led by Madhuri Hegde,
PhD, associate professor of human genetics at Emory University School
of Medicine and director of the Emory Genetics Laboratory, identified
the gene responsible. Postdoctoral fellow Melanie Jones is the first
author of the paper.
"This is part of an ongoing effort to develop diagnostic strategies
for congenital disorders of glycosylation," Hegde says. "We have a
collaboration with Dr. Freeze to identify new mutations."
Glycosylation is the process of attaching sugar molecules to proteins
that appear on the outside of the cell. Defects in glycosylation can be
identified through a relatively simple blood test that detects
abnormalities in blood proteins. The sugars are important for cells to
send signals and stick to each other properly. Patients with inherited
defects in glycosylation have a broad spectrum of medical issues, such
as developmental delay, digestive and liver problems and blood clotting
defects.
The boy in this case report was developmentally delayed and had
digestive problems, vision problems, tremors and blood clotting
deficiencies. He did not walk until age 3 and cannot use language. The
researchers showed that he had inherited a gene deletion from the father
and a genetic misspelling from the mother. "Over the years, we've come
to know many families and their kids with glycosylation disorders. Here
we can tell them their boy is a true 'trail-blazer' for this new
disease," Freeze said. "Their smiles -- that's our bonus checks."
The researchers went on to show that introducing the healthy version
of the DDOST gene into the patient's cells in the laboratory could
restore normal protein glycosylation. Thus, restoring normal function by
gene therapy is conceivable, if still experimental. However,
restoration of normal glycosylation would be extremely difficult to
achieve for most of the existing cells in the body.
The research was supported by the National Institutes of Health and by the Rocket Fund.
Journal Reference:
- Melanie A. Jones, Bobby G. Ng, Shruti Bhide, Ephrem Chin, Devin Rhodenizer, Ping He, Marie-Estelle Losfeld, Miao He, Kimiyo Raymond, Gerard Berry, Hudson H. Freeze, Madhuri R. Hegde. DDOST Mutations Identified by Whole-Exome Sequencing Are Implicated in Congenital Disorders of Glycosylation. The American Journal of Human Genetics, 2012; DOI: 10.1016/j.ajhg.2011.12.024
Courtesy: ScienceDaily
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