A Happy Sequencing Ending

Genome sequencing finds the cause of and identifies treatment for twins' health problems.

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This is one of the rare

This is one of the rare examples of where whole genome-wide DNA sequencing is reported to provide vital clues as to the underlying nature of an illness that afflicted children. It's actually old news and was previously covered by Richard Knox at the NPR Shots (http://www.npr.org/blogs/health/2011/06/18/137204964/genome-maps-solve-m...) and The Daily Scan (http://www.genomeweb.com/blog/nancy-drew-and-mystery-whole-genome). It appears that Dr. Topol's NBC interview is aimed to drum up support for a research project called IDIOM at Scripps Health, which seeks to use genome sequencing to help determine the causes of idiopathic disease, or rare conditions that are unresponsive to regular treatment.

The problem with this example, which I previously commented upon in the first Daily Scan report, is that it is unclear that genome-wide DNA sequencing of these twins, their parents and grandparents was even necessary in this case if the treating clinicians had a better understanding of basic biochemistry. The Beery twins were already known to have low levels of dopamine, and tests should have been performed to assess the levels of other neurotransmitters that share overlapping metabolic pathways. In many cases of dystonia that are DOPA-responsive, it is well known that these can arise from sepiapterin reductase (SPR) deficiency (DRDSPRD) [MIM:612716]. The disease has been well described to be due to severe dopamine and serotonin deficiencies in the central nervous system caused by a defect in the synthesis of 5,6,7,8-tetrahydrobiopterin (BH4) catalyzed by SPR.

Noradrenaline is produced from dopamine so the inclusion of L-dopa would have resulted in normalization of the noradrenaline levels in these patients. However, serotonin is produced from 5-hydroxytryptophan by aromatic amino acid decarboxylase, which is the same enzyme that produces dopamine from L-dopa. BH4 is a cofactor required for the enzymatic activity of aromatic amino acid decarboxylase. Supplementation with higher levels of L-dopa may have been able to overcome deficiencies in the enzymatic activity of aromatic amino acid decarboxylase. However, substrate competition may have well led to a further reduction in serotonin levels in the twins. The attending physicians should have performed obvious tests for serotonin levels in the Beery twins in the first place.

to S. Pelech: Great comment.

to S. Pelech:
Great comment. While genome sequencing is a remarkable technology it is important that it is not used unnecessarily. We don't want another blow-out of pathology testing budgets.
Scientists must refrain from over-hyping the benefits of the technology. There will be cases where genome sequencing will not provide answers that clinicians seek.

This is also a one-off

This is also a one-off example of where whole genome sequencing may have been useful, I don't think it provides support for routine genome sequencing.

What would provide sufficient

What would provide sufficient support for routine individual genome sequencing?