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UK's Deciphering Developmental Disorders Study Yields Diagnoses in Quarter of First 1,133 Children

NEW YORK (GenomeWeb) – The UK's Deciphering Developmental Disorders project has provided diagnoses to more than a quarter of 1,133 children with previously undiagnosed developmental disorders and plans to recruit additional families until next April.

The DDD study, launched in 2011, is a collaboration between the Wellcome Trust Sanger Institute, the UK Department of Health, and 24 regional genetics services of the UK's National Health Service and Ireland. Using genome-wide microarrays and exome sequencing, the study aims to analyze up to 12,000 children with developmental disorders and provide them with molecular diagnoses while minimizing incidental findings.

According to the Sanger Institute, the DDD study will continue to recruit families until next April, and the researchers hope the workflow they developed will serve as a prototype for the clinical implementation of diagnostic genome sequencing for other rare diseases.

First results from the study, which involved 1,133 children, appeared in The Lancet today. "By pulling together 24 regional genetics services and more than 180 clinical geneticists, we've implemented one single exome sequence diagnostic pipeline for children across the country," Caroline Wright, program manager of the DDD project and the lead author of the study, said in a statement.

For the project, the regional genetics services recruited undiagnosed patients with severe neurodevelopmental disorders, congenital anomalies, abnormal growth, dysmorphic features, or unusual behaviors and recorded their clinical information and phenotypes through a web portal in the DECIPHER database, which supports the clinical interpretation of genetic variations. Over three years, they recruited more than 8,000 families.

Researchers at the Sanger Institute analyzed their DNA using Agilent array CGH and Illumina SNP genotyping arrays to identify copy number variants in the patients, and performed exome sequencing with the Illumina HiSeq in patient-parent trios to find single nucleotide variants, small insertions and deletions, and CNVs in coding regions.

After filtering out common variants, they identified about 400 rare and protein-changing variants per patient. Running these against the Developmental Disorders Genotype-to-Phenotype database, DDG2P, which contains more than 1,100 genes previously implicated in specific phenotypes or syndromes, reduced the number of variants to 30 per patient. They also looked for large and rare CNVs that overlapped non-DDG2P genes.

Further filtering based on DDG2P categories decreased the number of variants to 10, and when the researchers took parental data into account for filtering, they were able to whittle the number down to a median of one variant per patient.

Candidate variants were manually reviewed in light of the patients' phenotypes and clinical history in meetings that involved clinical geneticists and scientists, and those likely to be causative were forwarded to the regional genetics service, where they were validated in a diagnostic laboratory and reported to families.

The manual review was "the most human-intensive step of the workflow, but was essential for validation and improvement of the automated filtering and prevention of likely non-pathogenic and incidental findings from being reported," the authors noted. Overall, it took 75 hours of meetings that were attended by up to eight people.

While they plan to automate the clinical reporting process further, "we expect that some variants will always need expert gene-specific clinical and scientific interpretation," they wrote.

Overall, the researchers reviewed 1,696 candidate variants in 1,133 family trios and reported 317 likely diagnostic SNVs, indels, and CNVs, as well as six cases of uniparental disomy, where both copies of a chromosome came from one parent, and five large mosaic chromosomal rearrangements . In total, 311 children obtained a likely diagnostic variant, translating to a diagnostic rate of 27 percent.

De novo variants accounted for 65 percent of diagnoses, and pathogenic mutations were found in 146 DDG2P genes.

Five children had mutations in DDG2P genes associated with errors in metabolism that can potentially be treated, and they might benefit from dietary restriction, supplements, or drug therapy.

No incidental findings were reported as part of the study. "At the outset of DDD, we could not be confident that actively screening for additional incidental findings unrelated to the child's developmental disorder would be in the best interest of the patients and families within DDD," the authors wrote, in particular because the "true significance" of such findings in persons with no symptoms or family history of the disease is unknown, and because reporting them might "undermine established clinical practice with respect to screening of children for adult-onset conditions."

While they confined their analysis to DDG2P genes that were known to be involved in developmental disorders, whole-genome or exome sequencing still has advantages over targeted gene panels, they wrote, because it allows for re-analysis of the data in light of new research.

About 20 new genes on average are added to DDG2P every month, they said, making reviews of the results "essential to maximize the diagnostic benefit."

Many of the patients in the cohort had already received genetic testing and "introduction of exome sequencing early in the diagnostic pathway could substantially reduce costs and increase diagnostic yields," the authors wrote.

On the other hand, they said, the infrastructure for the workflow of the project "is considerable," involving "hundreds of individuals" to process and analyze the data as well as access to a high-performance computing cluster.

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