Whole-genome sequencing for optimized patient management.

Abstract

Whole-genome sequencing of patient DNA can facilitate diagnosis of a disease, but its potential for guiding treatment has been under-realized. We interrogated the complete genome sequences of a 14-year-old fraternal twin pair diagnosed with dopa (3,4-dihydroxyphenylalanine)-responsive dystonia (DRD; Mendelian Inheritance in Man #128230). DRD is a genetically heterogeneous and clinically complex movement disorder that is usually treated with l-dopa, a precursor of the neurotransmitter dopamine. Whole-genome sequencing identified compound heterozygous mutations in the SPR gene encoding sepiapterin reductase. Disruption of SPR causes a decrease in tetrahydrobiopterin, a cofactor required for the hydroxylase enzymes that synthesize the neurotransmitters dopamine and serotonin. Supplementation of l-dopa therapy with 5-hydroxytryptophan, a serotonin precursor, resulted in clinical improvements in both twins.

• Authors: Matthew N Bainbridge, Wojciech Wiszniewski, David R Murdock, Jennifer Friedman, Claudia Gonzaga-Jauregui, Irene Newsham, Jeffrey G Reid, John K Fink, Margaret B Morgan, Marie-Claude Gingras, Donna M Muzny, Linh D Hoang, Shahed Yousaf, James R Lupski, Richard A Gibbs
• Journal: Science translational medicine (Sci Transl Med) Vol. 3 Issue 87 Pg. 87re3 (Jun 15 2011) ISSN: 1946-6242 [Electronic] United States
• PMID: 21677200 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Levodopa

Topics

• Adolescent
• Decision Making
• Dystonic Disorders (drug therapy, genetics)
• Female
• Genome, Human
• Humans
• Levodopa (therapeutic use)
• Male
• Patient Care
• Pedigree
• Sequence Analysis, DNA
• Treatment Outcome
• Twins, Dizygotic (genetics)