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Researchers Report on Use of Whole-Genome Sequencing to Help Diagnose, Treat Rare Disease

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – In a study appearing online today in Science Translational Medicine, researchers described how they used whole-genome sequencing to improve diagnosis and treatment for a pair of non-identical twins with a condition called dopa-responsive dystonia (DRD).

The twins, one male and one female, had been diagnosed with the movement disorder, which involves involuntary muscle contractions and spasms, several years earlier and were already being treated with L-dopa, a pre-cursor in the production of the neurotransmitter dopamine. But the newly generated genome information showed that the twins had also inherited mutations in the sepiapterin reductase gene SPR, which codes for a co-factor in a pathway used to produce dopamine as well as another neurotransmitter, serotonin.

The mutations seemed to explain some symptoms that persisted in the twin even with L-dopa treatment — a recognition that prompted doctors to supplement their L-dopa treatment with a serotonin pre-cursor called 5-hydroxytryptophan (5-HTP).

"This work is a pivotal example of how genomics will revolutionize medicine by improving diagnostics and ultimately helping physicians optimize care for their patients," lead author Matthew Bainbridge, who was a graduate student in Richard Gibbs' Baylor College of Medicine lab when the study was conducted, said in a statement.

Although they do not carry mutations in two genes that are typically tested for mutations in DRD, L-dopa treatment had been used to ease many of the 14-year-old twins' DRD symptoms. Relatively recently, though, one of the twins began experiencing more pronounced respiratory problems.

Because DRD can stem from a range of known and unknown genetic glitches, the research team — which included BCM geneticist James Lupski, whose own genome sequence helped track down mutations behind his Charcot-Marie-Tooth disease — decided to do whole-genome sequencing on the twin pair.

Using the SOLiD 4 sequencing platform, they sequenced the twins' genomes to 29 and 30 times coverage. They also used Agilent 1M oligonucleotide arrays to look for copy number alterations by high resolution oligonucleotide array comparative genomic hybridization in the twins and sex-matched controls.

In addition, researchers obtained DNA samples from the other members of the family, including the twins' unaffected brother, mother, and father, Life Technologies Chief Information Officer Joseph Beery.

After comparing the twins' genome sequences to the human reference genome and tossing out apparently harmless genetic variants found in the dbSNP, 1000 Genomes Project, and other databases, the researchers were left with potential disease-related mutations in three genes, including SPR, which has been linked to DRD in the Mendelian Inheritance in Man disease database.

When the team scrutinized the mutated region of the gene in the twins' family members, they found that the children's mother has nonsense mutation in SPR that leads to a truncated version of the resulting protein while their father carries a missense mutation that changes its amino acid sequence.

Together, findings from the genome sequences and follow-up experiments showed that the twins had inherited both mutant alleles, while their unaffected sibling had inherited neither mutation.

Because SPR mutations curb the production of a co-factor used by enzymes involved in dopamine and serotonin production, the researchers explained, DRD patients with disruptions in the gene are typically treated with both dopamine and serotonin pre-cursors.

Indeed, when the twins' doctor tweaked their treatment to include the serotonin pre-cursor 5-HTP, both showed improvements in their DRD symptoms.

"The involvement of SPR was unexpected in the twin pair given their clinical symptoms including the lack of intellectual disability, their sustained response to monotherapy with L-dopa, and a family history of neurological disorders that complicated the interpretation of the potential inheritance pattern," the study authors wrote.

"Our observations highlight both the challenge of clinical phenotyping for rare diseases by non-specialists, and the ability of whole-genome sequencing to identify susceptibility variants," they added, "especially when initial candidate genes have been eliminated by more traditional locus-specific gene testing."

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