Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A
Cambridge, United Kingdom – 3rd December, 2019 – Congenica Ltd, a digital health company enabling rapid analysis of complex genomic data to improve disease characterization and diagnosis, has announced the publication of a new study on the re-annotation of developmental and epileptic encephalopathy-associated genes with significant clinical implications.
Developmental and epileptic encephalopathies are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60–65% of patients without a molecular diagnosis.
Recent advances in genomic medicine indicate that up to 40% of individuals with early-onset epileptic encephalopathy have an underlying causative pathogenic variant in many different genes, which lead to significant homeostatic disruption across a wide range of brain pathways. However, up to now, the unresolved aetiology of devastating brain dysfunction in other patients has been a source of frustration to the medical community.
This study from a team of international collaborators led by Dr Charles Steward, Clinical Domain Lead for Epilepsy at Congenica, illustrates the potential gains of thorough gene annotation in improving diagnostic yields and patient outcomes in neurodevelopmental genetic disorders.
The findings demonstrate how a new class of ‘poison exons’, within previously unannotated regions of the SCN1A gene, may be disrupted and lead to reduced levels of critical proteins within the central nervous system resulting in devastating brain dysfunction and seizures. Additionally, the study identifies many previously unannotated exons in other epilepsy-associated genes, including CDKL5, SCN2A and SCN8A.
This new data is now available in the Congenica® clinical decision support platform, enabling clinicians to identify mutations caused by poison exons in the selected epilepsy gene. Alongside the recently announced exome capture kit, ExomeCG, which contains these exons, Congenica empowers healthcare professionals with a greater opportunity for finding causative variants in epilepsy-associated genes and successfully making life-changing diagnoses.
Professor Norman Delanty, Consultant Neurologist and Associate Professor at the FutureNeuro Research Centre, Dublin: “This important study by Steward et al highlights the evolving complexity of the genetic architecture of severe disabling brain disease causing life-threatening epilepsy and associated cognitive decline.
“The work here is evidence that more hidden regions of the genome are important in human disease and may be amenable to new therapies underscoring the fact that we have truly entered the era of genomic medicine and precision therapies”.
Dr Nick Lench, Chief Scientific Officer, Congenica: “Establishing a genetic cause for epilepsy in patients is a key step in clinical management. It provides an explanation, ends the diagnostic odyssey and informs treatment options and prognostication. We are pleased to offer the new annotations from this study within Congenica software, helping healthcare professionals to better understand, identify and resolve the underlying genetic causes of these disorders and improve outcomes for patients and their families.”
The Steward et al study (DOI: 10.1038/s41525-019-0106-7) is available as an open access paper in npj Genomic Medicine: https://www.nature.com/articles/s41525-019-0106-7
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