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Knome Award Winners to Apply Exome Sequencing to Study Variety of Genetic Diseases


By Julia Karow

As exome sequencing is becoming more affordable, and as initial publications have demonstrated that the technique is suited to solve the genetic underpinnings of Mendelian diseases, more and more clinical researchers are attempting to harness the new tool for their studies.

This week, three researchers — from the US, Ireland, and Israel — each won free exome sequencing and analysis services from genome analysis firm Knome, which they plan to apply to study various diseases where a single gene is likely at fault.

"We received entries from researchers all over the world, reflecting a global groundswell of interest in exome-based research," said Harvard Medical School professor George Church, a co-founder of Knome and the chair of the awards committee, in a statement from the company. Each winner will receive exome sequencing and analysis services for two human samples.

One award winner, Abhimanyu Garg, chief of the division of nutrition and metabolic diseases at the University of Texas Southwestern Medical Center, wants to use the service to find the gene that causes neonatal progeroid syndrome — also known as Wiedemann-Rautenstrauch syndrome — an autosomal recessive body fat disorder that leads to features of premature aging starting at birth.

Knowing the disease gene will allow the researchers to study it in a mouse model and to find out more about the metabolic pathway that's affected, with the hope to identify drugs or alternative diets that could interfere with the faulty pathway.

NGS is extremely rare — only 30 to 40 cases are known worldwide — and the researchers will sequence the exomes of two of those patients. It is unclear if that will be enough to identify the causal gene, but Garg told In Sequence he hopes it "will give us some leads" that can then be tested in additional patients to try and narrow down the list to a single gene — or several, because the disease is phenotypically heterogeneous and may be caused by more than one gene.

"If two people give us good leads, that's great," he said. "If they don't, naturally, we will proceed with sequencing additional patients to get us an idea."

Knome will help with the analysis and interpretation of the exome data. What will be especially helpful, Garg said, is that Knome has a proprietary database of human SNPs that are currently not listed in dbSNP or other public databases. "That information can further help us in screening and eliminating some of the genes," he said.

For Garg, this is the first time he will be using exome sequencing, though he plans to use the technique to study the causes of other types of body fat disorders, or lipodystrophies. "We really want to use this technology as much as possible," he said, adding that besides the Knome award, he has also started a collaboration with another research team that provides exome sequencing and interpretation.

Garg is currently not considering using whole-genome sequencing because exome sequencing has shown in several cases that it can identify the disease-causing gene for monogenic disorders. However, "as different investigators start using exomic sequencing, and they find that they are not getting to the bottom of the question, then I think there will be a stage where we will have to go to whole-genome sequencing," he said, because the disease-causing variant could be in non-coding regions of the genome.

Although researchers would likely not publish their unsuccessful attempts of solving monogenic disorders by exome sequencing, he said, large-scale efforts, such as those at the University of Washington, will soon determine what the limits of the approach are.

Seeking New Breast Cancer Genes

For award winner Eitan Friedman, head of the oncogenetics unit at the Sheba Medical Center near Tel Aviv, the work with Knome will also mark the first time he will use exome sequencing in his research.

Friedman wants to apply the technique to study two unrelated breast cancer patients from high-risk Ashkenazi Jewish families where no mutations in the BRCA1 and 2 genes — or in any other known breast cancer susceptibility genes — have been found. "Since the inheritance pattern looks autosomal dominant, it makes perfect sense to use two affected individuals and just sequence every exon in their genome," Eitman told In Sequence.

He expects that the analysis will come up with a long list of maybe hundreds of mutations in protein-coding genes, which he plans to study further in several hundred high-risk Ashkenazi Jewish women as well as a cohort of breast cancer patients without a family history to see what their role in breast cancer may be.


Friedman does not expect the two exomes will pinpoint a new breast cancer susceptibility gene right away, but "if my predictions are right, at least a few genes, and a few mutations, that had not been considered [previously] as valuable, will emerge." Further functional studies, for example in mouse models and cell lines, will show whether they are truly associated with cellular proliferation, specifically in breast cancer.

Knome is "providing me with tools that are hypothesis-generating," he said. "It's not a clinical tool yet, but I think in the next, let's say, two to three years, it will become clinically applicable, and when prices come down further, I intend to use this tool."

Though Friedman will be using exome sequencing for the first time in his research with Knome, he said he has several pending grant applications that involve using the technology "to be able to decipher the genetic nature of a variety of diseases, mostly — but not only — cancer-related."

What he likes about the KnomeDiscovery analysis service is that it provides him not only with sequence data but also with statistical analyses and annotations.

But exome sequencing — including the analysis — is still too expensive for him to use on a large scale. "If it were in the $500 range, I would do 1,000 [samples] with no problem," he said.

Friedman said he has also considered using whole-genome sequencing, but he reckons that the data-analysis tools, especially for mutations in "gene deserts," are currently "sub-par" and still in development.

"It's definitely better to have whole-genome sequencing than whole-exome sequencing … but if you are talking about a disease that is truly autosomal dominant — and at least in these two individuals it is — at least one of them, and hopefully both, will have intragenic mutations, and using this technique, we will be able to decipher them."

"Sure, I would love to have whole-genome sequencing of 1,000 individuals, but that's not in the cards yet," he said.

Disease and Twinning

Judith Conroy, a postdoctoral fellow at University College Dublin, wants to use her Knome award to identify the genetic cause of a form of facio-audio-symphalangism, a rare developmental syndrome, in two families, which may also shine some light on the process of twinning.

Right now, FAS patients are diagnosed by a medical examination alone. A genetic test would provide a more definite diagnosis and improve genetic counseling for families affected by the disease, Conroy told In Sequence by e-mail.

She will study the exomes of two identical twins, one from each family. Both families have triplets — identical twins and a non-identical sibling — where the twins but not their sib are also affected with FAS. "The probability of this being a chance event is extremely small," Conroy said. "Therefore, it suggests that there may be a link between FAS and twinning. Identification of a FAS gene may also help us to better understand the complex processes that result in the development of an identical twin."

Conroy said she hopes the two exomes will identify the gene involves in FAS, or "at the very least" provide a number of candidate genes.

Her team also has access to the DNA from the parents and the unaffected siblings, and sequencing parts of their DNA will help them weed out non-causative variants and "significantly reduce the number of variants to investigate further."

Also, she hopes that following publication of her results, researchers with additional cases of FAS with a similar phenotype will come forward for screening.

Depending on the mutations she finds, her group may start collaborations with other researchers to study them further.

She said most of the data analysis will be done at UCD, but she looks forward to using Knome's software, "which appears particularly user-friendly." In particular, analyzing novel variants and their potential involvement in FAS will be important, and Knome's interpretation software, KnomePathways, "may prove to be a very useful tool," she said.

The project is not Conroy's first foray into exome sequencing: she and her colleagues are currently working on two other projects using the technique in families with recessive disorders, one with four affected individuals, the other with three affected and one non-affected members.

"Although a small number of patients, nevertheless, we are making significant progress in the projects and in each case have identified a promising candidate gene for the conditions," she said.

The data for these projects was produced by German sequencing service provider GATC Biotech, although Conroy said they had also considered BGI Americas; a resequencing and genotyping service provided by the National Heart, Lung and Blood Institute; and collaborations with Irish research institutions for these projects.

Conroy said she has also considered whole-genome sequencing for her research, "but at the present time the cost is prohibitive." She added that as prices come down, "we look forward to be in a position to use this technology."

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