First whole-genome sequencing for rare genetic diseases

14 March 2010

This week, the first findings from whole-genome sequencing of people with rare genetic diseases have been released. Hitherto performed for only a few healthy individuals, researchers have now used high-throughput genomic sequencing of DNA from two families with different inherited disorders.
Reporting in The New England Journal of Medicine, Lupski et al. present whole genome sequencing of a person with Charcot-Marie-Tooth disease (CMT), in whom a causative mutation had not previously been identified. Investigation of functional variants in a total of 40 genes known to be involved in other neurological diseases identified a number of candidate variants, which were then genotyped in other family members [Lupski JR et al. N Engl J Med. 2010, DOI: 10.1056/NEJMoa0908094]. Two mutations (one of them novel) were identified in the SH3TC2 gene; each of four affected siblings possessed both mutations, whereas the four healthy siblings and parents had no more than one of the mutations each. Investigations showed that each mutation was associated with different physiological effects.
A second paper in Science reports whole-genome sequencing of a healthy couple and their two children, each with two different genetic diseases, Miller syndrome and primary ciliary dyskinesia [Roach JC et al. Science. 2010, DOI: 10.1126/science.1186802]. Comparing the genome sequences of the parents and children made it easier to identify possible disease-associated mutations because it was possible to identify matching familial (inherited) regions and exclude these from consideration as possible mutations, effectively reducing the number of candidate disease genes from 34 to just four.
Of these, one (in the DNAH5 gene) had previously been identified as a cause of primary ciliary dyskinesia and was assumed to be causative in this case, whilst separate (earlier) exome sequencing – that is, sequencing only exons, which is quicker and cheaper than the full genome – identified a mutation in the DHODH gene as the most probable cause of Miller syndrome in the children [Ng SB et al. (2010) Nat Genet. 42(1):30-5].
Both papers conclude that the rapidly falling costs of whole-genome sequencing make it increasingly feasible that clinical geneticists will use family genome analysis to investigate families with rare inherited disorders, to obtain precise diagnoses and hopefully, improved information about the probable clinical features and course of the disease in each patient based on the underlying mutation/s.
Comment: In the excitement over the mid- to long-term prospects for generalised improvements in disease prediction and prevention that are likely to arise from affordable, rapid whole genome-sequencing, we have perhaps been inclined to overlook the potential impact on families with rare genetic diseases. It is often very difficult for clinical geneticists to precisely identify causative mutations and to give any idea of the prognosis, since many genetic diseases have very variable symptoms. These first demonstrations of how the short-term future may look for medical genetics are very promising.

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