NEW YORK (GenomeWeb) – Using gene panel sequencing data generated by commercial diagnostic companies, a team from the US, Germany, and Italy has attempted to focus in on the genes that are most prone to risky, ultrarare de novo variants in individuals with neurodevelopmental disorder with epilepsy (NDD+E).
As they reported online yesterday in Genetics in Medicine, the researchers used available epilepsy gene panel sequencing data — produced between 2013 and 2017 by the Massachusetts-based company Courtagen (which discontinued its genetic testing business in 2017) andCeGaT in Tubingen, Germany — to look at de novo variants in up to 645 suspected epilepsy genes in almost 7,000 patients with NDD+E.
By comparing the de novo variants found in these cases with targeted sequence or exome data for unaffected control individuals and thousands more NDD+E patients profiled for past studies, they were able to start tallying the genes that were recurrently altered by rare, de novo mutations in the NDD+E patients, and the frequency with which those variants turned up.
"We show that improvement of panel design increased diagnostic yield over time, but panels still display genes with low or no diagnostic yield," co-corresponding and senior author Johannes Lemke, a human genetic researcher at the University of Leipzig Medical Center, and his colleagues wrote.
A significant subset of the de novo variants being detected in genes implicated in NDD+E may lend themselves to targeted treatment, the team explained. Even so, the extent of de novo mutation in NDD+E-associated genes remains poorly understood, and the genes included in epilepsy panels often vary between diagnostic companies and over time as new genes are linked to epilepsy, prompting the current analysis.
"To increase yield in diagnostic sequencing panels, it is essential to consider genes with proven disease association as well as a reasonable frequency of pathogenic variants among affected individuals," the authors explained.
The investigators analyzed targeted sequence data for 6,994 NDD+E patients with suspected monogenic conditions assessed at Courtagen and CeGaT using gene panels that included up to 645 genes. They noted that sequence data was available for at least 2,000 patients — and a median of 4,870 individuals — for each gene included in the analysis.
The team set data on ultrarare de novo variants found in those sequences alongside targeted sequences for up to 645 genes in 10,937 unaffected controls, as well as sequences for 8,565 previously reported NDD+E cases profiled across 70 genes and more than 1,900 exome-sequenced patients reported in another past study.
Consistent with past studies, the researchers saw recurrent, ultrarare de novo variants in genes such as SCN1A, KCNQ2, SCN2A, CDKL5, SCN8A, and STXBP1. On the other hand, their results suggest that ultrarare de novo variants in genes such as CACNB4, CLCN2, EFHC1, GABRD, MAGI2, and SRPX2 turned up as often in the unaffected controls as they did in the NDD+E patients.
The team noted that several other genes with ties to NDD+E in prior exome sequencing-based analyses — including ARID1B, ASXL3, EEF1A2, and SLC6A1 — were not included in the gene panels used for the cases and controls profiled at Courtagen and CeGaT.
Still other genes appeared prone to rare, de novo mutations in gene panel sequence data but not in previous parent-child exome-based analyses, the researchers reported, hinting that they may have stemmed from inheritance rather than appearing anew in affected individuals. Their data also suggested that risky de novo variants tended to turn up more often in genes with autosomal recessive inheritance than in those with autosomal dominant or X-linked inheritance models.
"With our data, we hope to improve current diagnostic NDD+E panel design and provide a resource of ultrarare variants in individuals with NDD+E to the community," the authors wrote.