In Congenica’s latest publication, we describe the importance of how genomic annotation might influence pathogenic variant identification in the review article “Genome annotation for clinical genomic diagnostics: strengths and weaknesses”. This article was published online in Genome Medicine on May the 30th 2017 and is freely available here.

As an introduction to the review, lead author Dr Charles Steward of Congenica says: “With science and medicine becoming ever more intertwined, clinicians’ ability to interpret and apply clinical genomics data becomes ever more important. Using illustrations, and examples from both common and rarer neurological disorders, we introduce subjects that are important to consider in clinical genomics interpretation but might not be obvious to clinicians who haven’t yet had much exposure to this field. For example, why, after whole-exome sequencing, does the genetic basis for a particular phenotype remain unclear in a considerable proportion of patientsWhy should a clinician be interested in regions of the genome where there are no protein-coding genes? Why should a clinician consider large numbers of transcripts for a gene when a single “canonical” transcript is much simpler to interpret? These are just some of the important questions which we answer.”

The authors discuss approaches used for the annotation and classification of important elements of protein-coding genes, other genomic elements such as pseudogenes and the non-coding genome, comparative-genomic approaches for confirming gene function, new technologies for aiding genome annotation, and how this might influence pathogenic variant identification, as a practical guide for clinicians.

Co-author, Dr Alasdair Parker, Consultant Paediatric Neurologist at Addenbrooke’s Hospital in Cambridge and Cambridge University explains: “This is an exciting, but daunting time for clinicians working with families affected by genetic diseases. With modern genomic techniques, the yield of investigation has increased dramatically, as have the challenges. We hope this paper will be used as a resource for the clinician trying to understand the strengths and weaknesses of current techniques, and the likely innovations that will improve the yield over the next decade.”

The review also considers why current genome technology can fail to identify the pathogenic basis of a patient’s disorder, or produce an incorrect result where the wrong variant is labelled as causative.

Co-author, Professor Berge Minassian from the Department of Pediatric Neurology, University of Texas Southwestern, USA, and The Hospital for Sick Children, Toronto, Canada, takes a philosophical view: “‘Idiopathic’ is Greek for ‘a disease onto itself’, although most people think it means ‘of unknown cause’. In a great way, this is now changed.  Since humans are primarily the unfolding of their genomic programs, our ability to sequence and analyse the genome means that we are now able to know, when it is in the genome, the actual cause of disease.  Knowledge of root causes places us on solid paths to direct therapy (correction of the causal defect) and proper understanding of pathogenesis for additional means to intervene.”

This is pertinent because, in the context of genome analysis, the absence of evidence is not necessarily evidence of absence because the causative variant may not be identifiable using current genomic techniques. For example, it is now known that genes might only be expressed in certain tissue types and, even more confusingly, only at certain developmental stages so that an exon that is not expressed in the disease tissue or at the right developmental stage is unlikely to be associated with the disease phenotype, which is an important consideration for pharmacogenomics.

Co-author, Professor Sanjay Sisodiya from UCL Institute of Neurology, London and the Epilepsy Society says: “Even whilst we are still learning more and more about the genome, sequencing data will become ever more available and present in clinical practice, and will take on an increasingly important role as another tool in the toolbox of clinical investigations, providing insights about possible causation, drug responses and outcomes. It is therefore important that clinicians become familiar with the interpretation of sequence data, and this study is one of many steps to be taken in that journey“.

For these reasons, the authors believe it is important to re-analyse unresolved cases as newer technology and software improves gene and genome annotation. It should also encourage clinicians to request a referral for disease modification when therapy becomes available for a clinical disease caused by specific genomic alterations. The authors conclude that such genomic advances will begin to address some of the controversies and challenges that these rapid advances in genomics create for clinicians. Accordingly, a deeper understanding of this will help clinicians explain the advantages and limitations of genomics to families and healthcare professionals when caring for their patients.