Whole-genome sequencing for optimized patient management

MN Bainbridge, W Wiszniewski, DR Murdock… - Science translational …, 2011 - science.org
MN Bainbridge, W Wiszniewski, DR Murdock, J Friedman, C Gonzaga-Jauregui, I Newsham…
Science translational medicine, 2011science.org
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 …
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.
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