KCNQ2 variants causing benign neonatal epilepsy or developmental and epileptic encephalopathy.
There are several genetic epilepsies in which a mutation in the same gene can cause a wide range of outcomes. This is the case with KCNQ2, which can result in benign neonatal epilepsy (B(F)NE, in which seizures resolve and there is limited long term effect), or KCNQ2 developmental and epileptic encephalopathy (DEE). Scientists previously discovered that DEE occurred when the particular variant of KCNQ2 mutation had a dominant-negative impact on the potassium channel function, meaning, that if any one of the four subunits comprising the channel had the mutation, the channel would not function properly.
The authors of this study used existing databases of known KCNQ2 variants and the associated patient outcomes, alongside genetic data from unaffected individuals, to test various algorithms to predict which variants might be more severe. This analysis identified “hot spots”, in which more severe variants occur and an algorithm to evaluate specific nucleotide substitutions, that could be helpful in evaluating novel variants to determine the severity of outcome.
The goal of the study was to better understand KCNQ2 variants which lead to severe outcomes in patients by analyzing a large number of variants collected as part of a Japanese study of KCNQ2 cases, the Chinese EpilepsyGene database (led by Dr. JinYu Wu of Wenzhou Medical University), and from the RIKEE database (developed by Dr. Edward Cooper, at Baylor College), and comparing these to data from public datasets of unaffected individuals.
The KCNQ2 variant data from the various sources was aggregated. The data was analyzed using several different prediction algorithms. This process evaluated genetic differences between more severe, DEE KCNQ2 cases, B(F)NE cases, and unaffected individuals. The analysis also took into account whether the variants were missense mutations (a substitution of an incorrect nucleotide into the sequence, deletions (a nucleotide missing from within the sequence), or a truncating variant (a sequence missing nucleotides from the end).
• Patient characteristics: There were a total of 259 KCNQ2 cases that were used in the evaluation. Of these cases, 148 (57%) were characterized as benign neonatal epilepsy (BFNE, either inherited or de novo) and 111 (43%) as developmental and epileptic encephalopathy (DEE). There were 216 different variants, with 139 B(F)NE and 77 DEE.
The types of variants were seen to impact the outcome. The B(F)NE cases were 59% truncations, 38% missense mutations, 3% deletions. The DEE cases were 98% missense and 2% deletions.
Of the B(F)NE cases, 6% were de novo (not inherited) while 83% of the DEE cases were de novo.
• Location of mutations: The study evaluated whether the mutations occur consistently throughout the KCNQ2 gene sequence, or are located mostly in specific areas. They found that the truncating variants (mostly associated with B(F)NE), appeared evenly distributed. However, the missense mutations (which cause almost all of the DEE cases) seemed to be located in specific regions in the KCNQ2 gene sequence.
Because some missense variants cause B(F)NE and some cause DEE, the investigators analyzed the locations of the missense variants in these two populations, and found that the location of the missense variant impacts the severity of the outcome. They then evaluated different prediction algorithms and found that some could be used to predict the severity of missense mutations based on the location.
• Type of substitution: The investigators further evaluated if the specific substitution (which amino acid took the place of which) affects the severity of the disease. The specific amino acid substitution only appeared to really make a difference in two regions of the gene, while in others it did not appear to have an impact on severity.
This study demonstrated that there are particular “hot spots” in the potassium channel. In technical terms, these regions are located at the region starting from S1 to the proximity of helix A and the region from helix B to helix D. The first of these two regions includes all of the membrane-spanning segments, S1-S6. “Specifically, the region from S2 to S3 had more B(F)NE related variants ad the regions to the ion pore to S6 to the proximity of helix A had more DEE related variants.” These are the areas of the KCNQ2 gene sequence that code for the portion of the potassium channel with the most important function, such that these mutations cause more severe outcomes.
However, the algorithms based on the location of the missense mutation alone could not completely predict whether a variant will be severely pathogenic. Depending on the location, a further algorithm, which analyzes the extent to which the specific nucleotide substitution changes the protein product, is able to improve the prediction.
The investigators concluded that an analysis of the type of mutation (missense, deletion, truncation), the location of the missense mutations, and the specific nucleotide substitution, along with the patients EEG findings, could be useful in predicting the severity of the outcome for a patient.
Ayako Goto, Atsushi Ishii, Mami Shibata, Yukiko Ihara, Edward C. Cooper, Shinichi Hirose Characteristics of KCNQ2 variants causing either benign neonatal epilepsy or developmental and epileptic encephalopathy. Epilepsia. 2019 Sep;60(9):1870-1880. doi: 10.1111/epi.16314. Epub 2019 Aug 16.