Researchers from the Children’s Hospital of Philadelphia (CHOP) linked to the CHOP Neurogenetics Epilepsy Initiative (ENGIN) have genetically and clinically analyzed more than 400 people with SCN2A-related disorders, which have been linked to a variety of neurodevelopmental disorders, including epilepsy and autism. By linking clinical features to genetic disorders in a routine format, the researchers hope that their findings will lead to better identification and clinical intervention.
The study was published online by the journal Genetics in Medicine.
Pathogenic changes in the SCN2A gene can lead to a wide range of clinical features – or phenotypes – associated with neurodevelopmental disorders. Several studies have described the genetic information collected about individuals with disease changes in this gene. However, although genetic information is collected in a routine manner, data on phenotypes are not regulated, and prior to this study, the available data on the clinical characteristics of these patients were not analyzed in detail. , meaning that there were few correlations between genotypes and phenotypes of these patients was often newsworthy.
To correctly link genetic and phenotypic data, researchers from CHOP Ontology Human Phenotype (HPO) used a method that measures patient clinical characteristics and allows those data to be translated similar to genetic data.
Based on our previous work with HPO, we knew we had the opportunity to bring a fully phenotypic landscape of SCN2A-related problems to the research and clinical community. Individuals with modifications of SCN2A present with a wide variety of clinical features, some of which were difficult to easily classify prior to our study. “
Ingo Helbig, MD, serves as ENGIN’s genomic and data science physician and director and chief investigator of the study
The researchers extracted phenotypic information from SCN2A-related disorders published over nearly two decades, including all descriptions of the disease in medical literature between 2001 and 2019, as well as patients with ENGIN afterwards. Over 413 unrelated individuals, the study team received a total of 10,860 clinical notes in HPO terms, with a total of 562 unique terms. This allowed researchers to link clinical traits to specific genetic changes.
For example, protein-truncating mutations, which are genetic modifications that shorten the gene coding sequence, were associated with autism and behavioral disorders. Missense differences, or changes in the genetic code leading to amino acid production were different than would normally be expected, associated with neonatal epileptic spasms and seizures. Using key-component analysis to simplify the complexity of the data, the researchers found that three key components accounted for one-third of the phenotypic variability in their data set, confirming, despite the complexity of the data, informative clinical groups can be extracted.
“The disorders associated with SCN2A are the group of situations where such systematic mapping has been performed to computable phenotypes. Our findings help to define subclasses of the side. within SCN2A-related disorders that may be a way for future detailed treatments to help these people, ”Helbig said. “This work, built on our previous studies, now provides a framework on how HPO terminology can map complex clinical data into a number of rare disorders to access responses to clinical features, natural history, and outcomes not yet available. “
Source:
Philadelphia Children ‘s Hospital
Magazine Reference:
Crawford, K., et al. (2021) Computational analysis of 10,860 phenotypic pounds in individuals with SCN2A-related disorders. Genetics in Medicine. doi.org/10.1038/s41436-021-01120-1.