Genomic sequencing study boosts rare disease diagnosis

Philippa Brice

18 December 2014

The Deciphering Developmental Disorders (DDD) project based at the Wellcome Trust Sanger Institute near Cambridge and funded jointly by the Wellcome Trust and the Department of Health is an important step towards genomic medicine.

Recruitment of children with severe developmental disorders for which no underlying cause has been identified and their families to the DDD project began in 2011. The aim was to use genome-wide microarray and whole exome sequencing and analysis to attempt to find a genetic diagnosis in children from 12,000 families. Besides being of immediate importance to the families involved, the project is also a flagship demonstration of the potential value of large-scale DNA sequencing and analysis as diagnostic tools in healthcare. It also has the backing of the current national network of 24 regional genetics laboratories.

The value of a diagnosis

Finding a cause for developmental disorders is desirable for family members, for a number of reasons. It can in some cases help inform medical care and prognosis, for example by suggesting other complications that may be present. In many cases it allows clinical geneticists to evaluate the risk that future siblings might also be affected, important information for parents considering whether to have more children. Perhaps most compellingly, it can ‘end the diagnostic odyssey’ – ongoing medical investigations, some potentially quite invasive, to attempt to make a diagnosis. Removing the need for further testing may therefore remove a significant burden from patients, families and indeed health services. Finally, some families find psychological relief just in having a cause of their child’s condition identified; it may also be useful in accessing appropriate social care and educational support services.

Improving diagnostic rates

The first results from the project have now been published in The Lancet, the findings from 1,133 families based on genome-wide microarray analysis focused on 1,100 genes previously linked with developmental disorders, as well as whole exome sequencing and careful description of the observed clinical symptoms in each patient. Typically, around 80,000 genomic variants of potential interest were initially identified, of which a few hundred were rare and expected to have a functional effect. The geneticists were able to identify a genetic cause of disease in 27% of cases, mostly new mutations not previously associated with disease. The expectation is that this diagnostic rate will rise further as more and more new variants are identified in patients as potentially or definitely causing disease (pathogenic).

Implications for genomic medicine

The DDD project is immensely valuable in having created and tested a viable, cost-effective pipeline for genome-wide sequencing, analysis and investigation and feedback of results. Sequencing parents as well as affected children in rare disease investigation proved a good approach, reducing the number of sequence variants requiring appraisal for potential pathogenicity ten-fold compared with sequencing the children alone.

The workflow process developed for the project is said to be scalable (ie. transferrable to large-scale use) and clinically useful, with the authors stating that ‘we hope that it will act as a prototype for the translation of diagnostic genome sequencing into the clinic for a range of rare diseases’. Importantly, the system can be used to reanalyse patient data, potentially yielding more diagnoses later on as knowledge expands – information that should be of significant interest for the 100,000 Genomes Project, a research initiative that is intended to create the basis for genomic medicine within the NHS in England.

Lead author Dr Caroline Wright said: “The project has shown that large-scale genome-wide testing, which brings enormous benefits to patients and families, is both effective and affordable”.

The issue of incidental findings

An additional area explored by the DDD project, which will continue to recruit patients and families until April next year, is that of unexpected or incidental findings (IFs) – significant health-related information unrelated to the condition under investigation, for example a BRCA1/2 mutation associated with hereditary breast ovarian cancer syndrome. It was decided that IFs would not be returned to families by the clinicians who discussed diagnostic results with them.

However, a linked project also examined views on the sharing of incidental findings, using an online survey to gather information from nearly 7,000 people (public, health and genetics professionals) from 75 different countries on their expectations. It was reported that the vast majority of respondents felt that IFs should be made available to research participants – but not actively sought.

Although this was in the context of a research projec t, the distinction between research and clinical spheres is likely to remain blurred in genomics for some years to come. It is therefore relevant to note that the survey conclusions is not contrast markedly to the policy adopted by US genetic health professionals who favour active, opportunistic screening for unrelated but medically significant variants in the context of genome sequencing, whilst being consistent with that recently recommended by the PHG Foundation Realising Genomics project. Will the 100,000 Genomes Project adopt a similar line, likely to be backed by NHS professionals – or opt for a novel, US-led approach instead?