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Gene Maps to Spot Disease


Senior Member
Just saw this article online, and find the implications fascinating for all of us. Okay, selfishly specific for my family.

Several of my cousins have autoimmune disorders, and I've always wondered if we'd ever know if my cfids and their issues are hereditary. Throw in XMRV and it gets even more interesting.

I wonder if this will affect the HERV genetic study some of us are in? (probably still too expensive)




Hi Shelley,

Medpage has an article on it too that intrigued me with its possibilities.

My favourite excerpt (below) implies we may all be getting this someday.
In his NEJM editorial, Lifton noted that there may be other ways to accelerate the use of genomic tools in clinical applications as well as research.

"Large cost reductions can be achieved by shrinking the target for sequencing," he wrote.

Lifton pointed out that the "exome" -- those sections of DNA that code for proteins -- is about 1% of the entire genome but contains "about 90% of all mutations with large effects."

He indicated that sequencing methods focusing on the exome are now available at a cost of about $4,000 per individual.

The notes for GPs include:
* Explain to interested patients that determining the entire sequence of a person's DNA could be useful in diagnosing and managing genetically-based disorders, but the cost has been prohibitive until now.

* Explain that the cost of sequencing in these studies was still too high to be performed routinely, in the tens of thousands of dollars, but it is much lower than previously, suggesting that such analyses may soon be clinically feasible.

Whole Genome Sequencing Nears Clinic

By John Gever, Senior Editor, MedPage Today
Published: March 10, 2010
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Two reports this week suggested that whole-genome sequencing may soon become clinically useful, not just a research tool.

In one, appearing online in the New England Journal of Medicine, researchers told of locating the exact genetic sources of a patient's inherited neuropathy by sequencing his entire genome.

The other, published online in Science by another group of investigators, described how whole-genome sequencing explained why two phenotypically healthy parents gave birth to children with two very different genetic diseases.

Neither accomplishment will benefit the patients or their families directly, except perhaps to give them some insight into their situations. But the findings show how much the field of whole-genome sequencing has advanced in recent years, to the point where clinicians may now envision how they might use it for disease diagnosis and management.

In an editorial accompanying the NEJM report, geneticist Richard P. Lifton, MD, PhD, of Yale University, said that whole-genome sequencing could sweep away the problems now facing clinicians trying to diagnose what appear to be inherited diseases.

"Traditionally, the genetic diagnosis of a Mendelian disorder relied on the establishment of a clinical diagnosis followed by the sequencing of previously implicated genes," he wrote.

"Practical limitations of this approach include frequent diagnostic uncertainties, which thwart efforts to define a short list of genes for sequencing. Similar limitations arise for diseases in which mutations in many genes can cause the same disease."

Lifton noted that sequencing genes individually "is cumbersome and limits the number that can be efficiently examined."

In contrast, he wrote, "supplanting this approach with routine sequencing of all the genes is consequently attractive and, more importantly, scalable."

The NEJM report focused on a patient with Charcot-Marie-Tooth syndrome, who also happened to be the lead author, James Lupski, MD, PhD, a geneticist at Baylor College of Medicine in Houston.

Lupski and three of his seven siblings have the condition, in which nerve function in the extremities is impaired and muscles are weak and wasted. Past research, including some by Lupski's group, had identified 39 genetic loci at which copy number variants or single nucleotide polymorphisms were associated with Charcot-Marie-Tooth syndrome and other inherited peripheral neuropathies. But none of these were present in Lupski's family.

For what Lupski and colleagues estimated would now cost about $50,000, though it was more at the time, they sequenced his entire genome using the so-called shotgun method. Samples of his DNA were broken up into relatively short pieces for rapid sequencing, performed multiple times (each base was sequenced an average of 30 times). These overlapping short sequences were then patched together to provide a sequence for the whole genome.

Comparing Lupski's sequence to the reference genome developed in the federal government's Human Genome Project revealed two mutations in the SH3TC2 gene.

This gene was one of those previously implicated in Charcot-Marie-Tooth syndrome but the particular mutations had not. The gene's role in humans remains uncertain; its cousin in mice is believed to help regulate nerve myelination and/or axon-glial cell interactions.

With these mutations localized in Lupski, his team sequenced this gene in his parents and siblings, including those without Charcot-Marie-Tooth syndrome.

Comparing their sequences at this locus with their outward health status showed that one of the mutations -- an SNP -- was associated with Charcot-Marie-Tooth syndrome. This SNP had not been identified as a cause for the syndrome in previous studies.

The other variant, a nonsense mutation that prevented any protein from being expressed, appeared to promote carpal tunnel syndrome in family members whether or not they had Charcot-Marie-Tooth syndrome.

The Science report, led by David Galas, PhD, of the Institute for Systems Biology in Seattle, described an investigation of how two siblings inherited both Miller's syndrome and primary ciliary dyskinesia from healthy parents.

Both conditions are extremely rare. The odds that a person would develop both were estimated at more than 10 billion to one.

Miller's syndrome involves morphological defects in the face and limbs. In primary ciliary dyskinesia, airway cilia that move mucus and aspirated foreign matter out of the lungs fail to work.

The gene mutations responsible for these disorders had previously been identified, with each condition arising from a combination of four mutations. Whole-genome sequencing of the two parents and their children confirmed that they were present in this family as well, and confirmed that one particular gene, DHODH, is primarily responsible for Miller's syndrome.

What wasn't known was the probability that a child would inherit these mutations. The inheritance is not strictly Mendelian because of sequence changes that occur spontaneously during the generation of eggs and sperm. As a result, children may have gene sequences not present in either parent.

The whole-genome sequencing of these two generations within a family allowed Galas and colleagues to estimate directly this intergenerational mutation rate.

After adjusting for errors in sequencing -- base pairs may be sequenced 30 times in the shotgun method, but with more than 3 billion in the genome, mistakes still occur -- the researchers came up with a figure of 70 new mutations arising with each act of human reproduction.

This estimate is similar to those obtained indirectly by comparing differences in the human versus chimpanzee genomes and the number of generations ensuing since these species diverged some five million years ago.

Galas and colleagues suggested that whole-genome sequencing of families could become increasingly important for identifying disease-causing genes. As the cost of sequencing falls, it may supplant the traditional approach of sequencing selected genes in large numbers of people, they argued, as it becomes more economical to sequence the entire genomes of a small number of families.

"As our knowledge of gene function increases, we will be able to use the power of family genome analysis rapidly to identify disease-gene candidates," Galas and colleagues predicted. "These data, along with relevant environmental and medical information, will characterize the integrated medical records of the future."

In his NEJM editorial, Lifton noted that there may be other ways to accelerate the use of genomic tools in clinical applications as well as research.

"Large cost reductions can be achieved by shrinking the target for sequencing," he wrote.

Lifton pointed out that the "exome" -- those sections of DNA that code for proteins -- is about 1% of the entire genome but contains "about 90% of all mutations with large effects."

He indicated that sequencing methods focusing on the exome are now available at a cost of about $4,000 per individual.

"Notably, this approach could have led to the same conclusion [that Lupski and colleagues found] far less expensively," Lifton wrote.

The NEJM study was partly funded by the National Human Genome Research Institute and the National Institute of Neurological Disorders and Stroke.

The Science study was funded by the National Institutes of Health and internal funds from authors' institutions.

Several authors of the NEJM study reported relationships including employment with Life Technologies (formerly Applied Biosystems and Invitrogen) which produces sequencing instruments. One co-author also reported relationships with Ion Torrents Systems, Athena Diagnostics, and 23andMe.

Most authors of the Science study were employees of the Institute for Systems Biology. One was an employee of Complete Genomics. No other potential conflicts of interest were reported.

Lifton declared he had no potential conflicts of interest.

Primary source: New England Journal of Medicine
Source reference:
Lupski J, et al "Whole-genome sequencing in a patients with Charcot-Marie-Tooth neuropathy" N Engl J Med 2010; DOI:10.1056/NEJMoa0908094.

Additional source: New England Journal of Medicine
Source reference:
Lifton R, "Individual genomes on the horizon" N Engl J Med 2010; DOI:10.1056/NEJMe1001090.

Additional source: Science
Source reference:
Roach J, et al "Analysis of genetic inheritance in a family quartet by whole-genome sequencing" Science 2010; DOI:10.1126/science.1186802.