Reanalysis of whole exome sequencing data in patients with epilepsy and intellectual disability/mental retardation

Abstract To evaluate the additional diagnostic yield of whole exome sequencing (WES) reanalysis in patients with epilepsy and intellectual disability/mental retardation, we reanalyzed raw WES data and clinical information for 76 patient trios whose initial reports returned negative results. Eight patients (10.5%, 8/76) had positive genetic diagnoses finally, including six novel mutations in five genes. The reasons for the previous false-negative reports were divided into four categories: specific gene–disease associations had not been established at the time of the initial report; the disease database of the genetic test center had not been updated in a timely manner; the patient's clinical phenotype had not been carefully or correctly collected, submitted and reviewed when applicating genetic test and analyzing the variants; and the first round of data analysis missed a synonymous variant that affected splicing. Therefore, physicians should not give up the discovery of disease-causing mutations before re-examining the WES data and clinical phenotype by themselves or by collaborating with bioinformatic experts in the genetic test centers, especially for patients with strongly suspected genetic disease whose initial WES result was “negative”. The suitable time points for reanalysis might be the 6–12 months after initial report.