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HudsonAlpha Sequencing 500 Trio Exomes to Elucidate Rare Genetic Disorders under CSER Grant

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This is the third article in a series of profiles of centers awarded grants under NHGRI's Clinical Sequencing Exploratory Research program this year. Click here and here for the first and second article.

The HudsonAlpha Institute for Biotechnology has embarked on a research project to analyze the genomes of 500 children with unexplained genetic disorders and their parents in order to provide at least some families with a molecular diagnosis.

The project, funded with up to $7.6 million over four years, is one of four that received a total of up to $27 million this summer under the National Human Genome Research Institute's Clinical Sequencing Exploratory Research, or CSER, program. In late 2011, NHGRI awarded the first six CSER grants (CSN 12/7/2011).

The study, a collaboration between researchers at HudsonAlpha, based in Huntsville, Ala.; the University of Alabama at Birmingham Medical School; and the University of Louisville; is recruiting about 500 children and their families from North Alabama Children's Specialists, a clinic in Huntsville that is affiliated with UAB.

These children – many of whom are adults now – each suffer from a rare congenital disorder, but the genetic cause of their problem is unknown. Most of them show signs of intellectual delay, and many have physical abnormalities as well, according to Rick Myers, HudsonAlpha's president and director and the principal investigator on the project.

"The families go through what they call a 'genetic odyssey,' they go from one physician or clinic to the next," Myers said. "Even when you don't know what you can do about it, the parents really want to know what the cause of this is. It's a big relief, often, to know it's not because of the way you raised your child, or something you did during pregnancy, it's because they are born with this. It's nobody's fault."

Once doctors see mutations in the same gene in different patients, they can learn about how these mutations affect phenotype and disease progression, benefiting future patients. And in some cases, knowledge of the mutation might point to a treatment to alleviate some of the symptoms, for example if there is a defect in a metabolic enzyme.

For the project, HudsonAlpha researchers will sequence the exomes of each patient and both parents on the Illumina HiSeq 2500 to an average depth of 100x, deep enough to be able to call heterozygous variants. The reason for analyzing parent-child trios is that many of the causative variants are expected to be de novo mutations, so they should occur in the child but not the parents.

For any child where they do not find a potentially causative mutation in the exome, the researchers will also sequence 48 megabases of DNA in regions of the genome that are associated with copy number variations. Greg Cooper, a HudsonAlpha researcher, identified those regions several years ago as a postdoc, and they are likely to contain genes associated with a disorder, Myers explained.

A new set of algorithms called CADD for Combined Annotation Dependent Depletion, developed by Cooper and Jay Shendure at the University of Washington, will help the researchers prioritize which variants are likely pathogenic.

All potentially causative mutations are confirmed by Sanger sequencing in a CLIA lab, currently an external contract laboratory but in the future probably at HudsonAlpha. A 'variant review committee' that includes physicians, geneticists, genetic counselors, and an external bioethicist then analyzes the results and decides which should be returned to treating physicians and participants.

According to Greg Barsh, one of the study investigators, clearly deleterious variants, for example in the p53 gene, would be reported even if they had not been seen in humans before and therefore be classified as variants of unknown significance by a clinical lab. However, variants that the committee deems to be "truly of unknown significance," such as novel synonymous mutations in p53, would not be returned.

Families meet with a HudsonAlpha genetic counselor for an hour prior to signing the consent form and having their blood drawn. During that session, they learn about incidental findings and their choices to receive them. They can choose to obtain broad categories of incidental findings, such as for heart disease, cancer, or neurodegenerative disease, or they can choose to not receive any.

To receive the results, families meet several months later with the counselor, as well as a medical geneticist and Martina Bebin, a pediatric neurologist who is the lead clinician on the study.

About a week after receiving the findings, families will get a set of questionnaires to assess the impact of the test results, and a subset of families will have structured interviews about a month after obtaining the results.

One aim of the study is to investigate the best way for delivering information about the test, and the results – including incidental findings – to physicians and families, and different approaches will be studied in a randomized trial. Half the families will receive extensive education about genetics and incidental findings before their results are returned; the other half will receive the standard of care, which is a discussion of incidental findings during the informed consent session and questions about which results they want to learn during the second visit.

Generally speaking, families are eager to participate in the study and "very motivated to help, even when it's not going to help their child," Myers said.

The CSER grant provides sufficient funding to analyze the genomes of 500 patients and their parents, but the clinic has several hundred more families with that could benefit, so HudsonAlpha is raising additional funding from sources other than the NIH to expand the project.

"It's going to be a numbers game: the more [patients] you have, the more you will learn, and if you see the same disorder multiple times, that’s where the value in terms of being able to interpret it and making clinical predictions will come from," Myers said.

That additional knowledge will be needed before exome sequencing might become a routine diagnostic tool for rare genetic disorders, he said. "Insurance companies are not going to pay to have it done unless they see that it actually saves them money overall," he said.

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