title: 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.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Bainbridge
authors.forename: Wojciech
authors.initials: W
authors.lastname: Wiszniewski
authors.forename: David R
authors.initials: DR
authors.lastname: Murdock
authors.forename: Jennifer
authors.initials: J
authors.lastname: Friedman
authors.forename: Claudia
authors.initials: C
authors.lastname: Gonzaga-Jauregui
authors.forename: Irene
authors.initials: I
authors.lastname: Newsham
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Reid
authors.forename: John K
authors.initials: JK
authors.lastname: Fink
authors.forename: Margaret B
authors.initials: MB
authors.lastname: Morgan
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gingras
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.forename: Linh D
authors.initials: LD
authors.lastname: Hoang
authors.forename: Shahed
authors.initials: S
authors.lastname: Yousaf
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
mesh_terms: D000293:Adolescent; D003657:Decision Making; D020821:Dystonic Disorders / Q000188:drug therapy / Q000235:genetics; D005260:Female; D015894:Genome, Human; D006801:Humans; D007980:Levodopa / Q000627:therapeutic use; D008297:Male; D005791:Patient Care; D010375:Pedigree; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D014429:Twins, Dizygotic / Q000235:genetics
chemical_list: D007980:Levodopa