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Neurodevelopmental Disorders Involving Epilepsy Include Some Distinct De Novo Variants

NEW YORK (GenomeWeb) – Members of an international team led by investigators at the University of Leipzig Hospitals and Clinics have started characterizing the distinct de novo variants (DNVs) involved in neurodevelopmental disorders (NDDs) that cause epilepsy symptoms.

Using the DNV profiles of the members of 6,753 parent-child trios affected by diverse NDDs, the researchers narrowed in on almost three dozen genes with higher-than-usual DNV burdens in the subset of NDD cases that included epilepsy. Along with the insights it offered into de novo variation in known NDD-related genes, the study — which appeared online today in Nature Genetics — also led to a new NDD candidate gene called CACNA1A.

"Comparing NDDs with and without epilepsy, we found missense DNVs, DNVs in specific genes, age of recruitment, and severity of intellectual disability to be associated with epilepsy," senior and corresponding author Johannes Lemke, head of the Leipzig University Hospital Institute of Human Genetics, and his colleagues wrote.

For the analysis, the researchers and their collaborators used Illumina instruments to sequence protein-coding portions of the genome for the parent-child trios, who were enrolled through eight prior studies. They included 1,942 cases with epilepsy, 529 of whom had epilepsy syndromes termed epileptic encephalopathies (EE), while the remaining 1,413 of whom were classified as NDD with unspecified epilepsy.

With these exome sequences — together with sequencing for 1,911 unaffected siblings of children with autism spectrum disorder — the researchers searched for DNVs that corresponded to NDD with or without these types of epilepsy.

"We compared the rates of DNVs among EE, NDDs with unspecified epilepsies, and NDDs without epilepsy to identify genetic differences among these phenotypic groups," the authors explained. "We further investigated the potential implications of our findings for the design of genetic testing approached and assessed the extent of therapeutically relevant diagnoses."

The team noted that epilepsy was more common within groups of patients who had more severe forms of NDD. Likewise, DNVs in a set of 50 genes previously implicated in EE appeared more common in individuals with NDD who either had EE or unspecified epilepsy than in the epilepsy-free NDD cases.

"In NDDs with epilepsy, we could scarcely distinguish individuals ascertained to have EE and NDDs with unspecified epilepsy on a genetic level," the authors reported. "Thus, we conclude that these phenotypic groups share a spectrum of disease-associated genes predominately including genes initially reported as EE-associated genes."

Across the wider exomes, meanwhile, the researchers saw an uptick in missense DNVs in the cases with both forms of epilepsy compared with those without, while highlighting 33 genes that were particularly prone to such alterations in the epilepsy-affected groups. That set included genes such KCNQ2, SCN2A, and SCN1A.

When analyzing the full collection of NDD cases together, they flagged 101 DNV-prone genes, including 62 gene sets that had more missense DNVs in the NDD cases with epilepsy compared with the other NDDs. In a series of follow-up analyses, the team took a closer look at the 33 genes with excess DNVs in the epilepsy-NDD cases, as well as the genes impacted by DNVs within the broader NDD cohorts.

Using expression data from the Allen Institute for Brain Science's BrainSpan atlas of developing human brains, the group saw hints that the DNV-affected genes implicated in NDD with epilepsy tend to show enhanced expression in the infant brain. And according to analyses done with the help of Centre for Evidence-Based Medicine criteria, at least five of the 33 genes have potential treatment implications.

Even so, the authors noted that a little more than half of the DNVs in those genes would be picked up using two dozen available diagnostic sequencing panels for EE or other forms of epilepsy. Such data "provide grounds for replacing genes with limited evidence with genes with higher evidence in the design of gene panels for NDDs with epilepsy," they wrote.