Genetic Diagnosis in Children with Epilepsy and Developmental Delay/Mental Retardation Using Targeted Gene Panel Analysis

Purpose Epileptic encephalopathies (EEs) are the severe form of childhood epilepsy and phenotypically heterogeneous disorders with different underlying genetic defects. EEs are always accompanied with developmental delay/mental retardation and behavior problems. Finding the genetic basis of epileptic encephalopathies with developmental delay/mental retardation can be valuable not only for diagnosis but also for guiding treatment and providing disease prognosis. Methods and Results A customized panel of 90 genes related to epileptic encephalopathies was utilized to screen for potential genetic variants via targeted next generation sequencing (NGS). A total of 78 children with epilepsy and developmental delay/mental retardation were analyzed with an average read depth of 265.3 ± 68.3X. Mutations were found in 23 (9 boys and 14 girls) probands, and the overall mutation identification rate was 29.5% (25.0% for males and 33.3% for females). Fifteen (65.2%) mutations involve ion channels, including SCN1A, KCNT1, SCN2A, SCN8, KCNB1 and KCNQ2. The other (34.8%) mutations involve CDKL5, ALG13, GFAP, SNAP25, STXBP1 and SYNGAP1. Sixteen (69.6%) of the identified mutations were confirmed to be de novo and one (4.3%) was found to be paternal mosaicism. Channelopathies were found to be the major cause of both early onset (≤6 months) and later onset of unclassified EE as well as febrile seizure cases. On the contrary, patients with infantile spasms or West syndrome were mainly caused by mutations in non-ion channel proteins, whereas patients of epilepsy with developmental delays and/or mental retardation were caused by mutations in both channel and non-channel genes. Conclusion NGS is a valuable and reliable diagnostic tool to detect the gene mutation in epileptic children with developmental delay/mental retardation. This cost-effective method shortens the course from seizure onset to genetic diagnosis. By understanding the gene mutations and genotypephenotype correlation better, clinical practitioners could provide the optimal anticonvulsant and treatment.