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.

Disease gene identification strategies for exome sequencing

“…8 This reduces the amount of variants from 3 to 4 million to o25 000 for follow-up. [20][21][22][23][24] Because whole genome sequencing is still limited in throughput and too costly to be applied as the main tool for disease gene discovery, different capturing approaches have been developed to enrich the exome before NGS. 25 The advantage of this enrichment is that many more exomes than genomes can be sequenced per NGS system per run, and despite the additional enrichment, costs are lower by a factor of 5-10.…”

The future of DNA sequencing

“…Analyses of the resulting sequences can reveal the disease-causing mutations in around 30% of such cases 5,6 -a figure that will only rise as the ability to interpret the data matures. In some instances, the resulting diagnoses have led to dramatic improvements in clinical management 7,8 . More typically, they benefit both families and physicians by ending a diagnostic odyssey and providing clinical clarity.…”

Naked bodies, naked genomes: the special (but not exceptional) nature of genomic information

“…1 Human genomic data are regularly used in research and clinical applications are beginning to emerge. 2,3 Medical geneticists, counselors, and investigators see the great promise in these developments. Nonetheless, patients and the public have expressed special fears about the privacy of genetic information.…”