This story was originally posted on March 24.
HINXTON, UK — Microarrays will be the technology of choice for the UK's newly launched Deciphering Developmental Disorders project.
As part of the five-year study, announced earlier this week, researchers at the Wellcome Trust Sanger Institute and the country's National Health Service will use arrays to analyze the genomes of up to 12,000 children with physical and mental developmental problems and multiple birth malformations in the hopes of developing new means to diagnose and treat these disorders.
Study leader Nigel Carter, who leads the Sanger Institute's molecular cytogenetics team, said the project will make use of Agilent Technologies comparative genomic hybridization arrays and Illumina whole-genome SNP-genotyping arrays to gather genetic information on enrolled patients.
The study will employ 2-million probe, Agilent-made CGH arrays to "identify copy number changes, deletions, and duplications in the genome," while a custom Illumina genotyping chip will allow the researchers to determine "whether those changes are inherited or not," Carter said.
He spoke with BioArray News during the Wellcome Trust's Genomic Disorders conference, held here this week.
Carter said he also anticipates using whole-exome sequencing in the project to seek out copy-number variations, exon deletions, and single base-pair changes that may be causing these developmental disorders. The approach will be adopted "according to price and as the technology develops," he said. Still, Carter noted that arrays will be the main platform used throughout the study.
"To get a comprehensive dataset, we will be fixing the microarrays that we use, and that content will be used all the way through," Carter said. "We are using state-of-the-art arrays of a higher resolution than would be used clinically," he added.
The DDD project will work with the NHS Clinical Genetics Services' 23 regional offices to collect comprehensive genomic and phenotypic data and to develop means for diagnosing the genetic causes for these developmental problems, according to a statement from the Wellcome Trust, released earlier this week.
Ultimately, researchers hope the data generated will allow clinicians to make more diagnoses and enable better treatment of children with disorders.
Helen Firth, consultant clinical geneticist at Addenbrooke's Hospital in Cambridge said in the statement that the study "could significantly improve our understanding and management of these rare conditions and provide new avenues of research into treatments for scientists to pursue."
Firth told BioArray News this week that one of the "main difficulties" geneticists currently experience is that they are unable to determine whether a genetic finding is causative of the problems the individual is experiencing. "The power of having such a big study" like DDD is that "you hope you will have multiple individuals with the same or a similar genomic finding and then you can begin to make those causal relationships," she said.
Firth said she is currently able to diagnose about a quarter of the patients that she sees. She is hoping that the results of DDD will provide a "strong uplift" of that figure. "Perhaps if we could double it, that would be fantastic," she said.
The DDD study is being financed via the Health Innovation Challenge Fund, a partnership between the UK Department of Health and the Wellcome Trust. Officially, the Department of Health has budgeted a set amount of funds towards the study, but Carter said that since much of its financing will be coming through the Wellcome Trust, and the expenses involved, such as the cost of sequencing, continue to decline, it is "very hard to put a number" on how much the project will cost by the time it is set to conclude in 2016.
As of this week, the Health Innovation Challenge Fund has not yet publicly disclosed the funding amount for the DDD project. "Advancing genetic discoveries into clinical practice" is listed as one of its main funding themes on its website.
According to Carter, the DDD project is a "natural extension" of the work the Sanger has done in the past. At the same time, he said that the project was partially inspired by the availability of new, high-resolution genomic research tools. "The changes in the technology really influence the way that we can diagnose these children," he said.
Carter will lead a team of researchers at the Sanger to analyze the individuals enrolled in the DDD project. He said that the results will be released publicly via two channels. Pertinent findings will be added to DECIPHER, the Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources, which was established in 2004. In addition, raw array and sequencing data will become through the European Genome-Phenome Archive.
"There will be two data-sharing mechanisms," said Carter. The DECIPHER database will "be the way the DDD project reports the results back to clinicians and families, upon receiving their consent to share the data," he said.
The array and sequencing data will most likely be released through EGA in tranches, he said. "We'll collect data for a few months, check the quality of it, and then we'll release it through careful control and data-access agreements," Carter said.
Carter said that the DDD project is "unique" because its participants will "feed pertinent findings back to the clinicians, who will pass those on to families under observation." To do that, "we have to be very sure what we are sharing with them," he noted. Because the results of DDD will be actionable, Carter said there are a host of ethical issues that are being debated within the project.
"We are using new technologies and we are going to find changes in the genome that we cannot interpret," he explained. "We can make guesses about what effect each of these changes will have, and so then we have a dilemma of what results to feed back to patients."
Carter said that there "aren't really any clear professional standards about what sort of information we should feed back to patients and what information we shouldn't." The DDD project therefore aims to identify which information should be shared and which information should be withheld in the future.
"We are going to ask patients and ask clinicians where they think the line should be drawn," said Carter. "We want to know what information will benefit the patient and what information will be less beneficial."
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