An in-depth phenotype analysis, led by researchers at the Children’s Hospital of Philadelphia, including more than 400 people with a neurological disorder caused by variants in the SCN2A gene, could help improve diagnosis and treatment for carriers of these variants in the future.
SCN2A encodes a sodium channel protein present in neurons. Disease-causing variants in this gene are one of the most common causes of developmental and epileptic encephalopathies – a group of childhood epilepsies also linked to autism.
SCN2A-related conditions are often diagnosed in the first year of life and can have widely variable symptoms. While the genetics of SCN2A has been well characterized, the phenotypes associated with these variants had not been systematically recorded or analyzed in depth until recently.
To try and improve diagnosis and treatment options for these children, Ingo Helbig, M.D., a pediatric neurologist at the Children’s Hospital of Philadelphia, and colleagues carried out an in-depth phenotype analysis in 413 unrelated individuals with SCN2A mutations with the aim of better linking genotypes and phenotypes.
The Human Phenotype Ontology (HPO) database was set up to standardize terms used by clinicians to describe symptoms to allow much more widespread comparisons and more accurate scientific studies. Helbig and team used the HPO terms and found 10,860 phenotypes in the cohort. Of these, 562 were not previously recorded.
“Based on our previous work with HPO, we knew we had the opportunity to provide the research and clinical community with the full phenotypic landscape of SCN2A-related disorders,” said Helbig, who is lead author of the article describing the work, which is published in the journal Genetics in Medicine.
“Individuals with variants of SCN2A present with a wide variety of clinical features, some of which have been difficult to easily categorize prior to our study.”
Among many other findings, Helbig and team observed that protein shortening variants were linked with autism and behavioral abnormalities. Missense variants, which cause different amino acids to be encoded in resultant proteins, were associated with early onset of seizures and epileptic spasms.
Using principal components analysis, the researchers found that most phenotypes fell into three distinct groups, which could be helpful for designing treatments or interventions for these patients and also for predicting future prognosis for children with certain genotypes.
“Our findings help define subclasses within SCN2A-related disorders that could pave the way for future precision medicine approaches to help these individuals,” noted Helbig.
“This work, built upon our previous studies, now provides a framework on how HPO terminology can map complex clinical data in a variety of rare disorders to get to answers about clinical features, natural history, and outcomes that we do not have yet.”