Genetic diagnoses in pediatric patients with epilepsy and comorbid intellectual disability

•The diagnostic yield appeared to correlate positively with ID severity and negatively with age of seizure onset.•The diagnostic yield of SNVs was higher than that of CNVs in patients with seizure onset in the first year of life but lower than CNVs in patients with childhood-onset epilepsy.•Both CMA and WES are advantageous as unbiased approaches for a genetically heterogeneous condition.•For patients with seizure onset in the first year of life, WES is recommended as the first-tier test. However, for patients with childhood-onset epilepsy, SNP array should be considered for the first-tier test. The aim of this retrospective study is to investigate the genetic etiology and propose a diagnostic strategy for pediatric patients with epilepsy and comorbid intellectual disability (ID). From September 2014 to May 2020, a total of 102 pediatric patients diagnosed with epilepsy with co-morbid ID with unknown causes were included in this study. All patients underwent tests of single nucleotide polymorphism (SNP) array for chromosomal abnormalities. Whole exome sequencing (WES) was consecutively performed in patients without diagnostic copy number variants (CNVs) (n = 85) for single nucleotide variants (SNVs). Subgroup analyses based on the age of seizure onset and ID severity were done. The overall diagnostic yield of genetic aberrations was 33.3 % (34/102), which comprised 50.0 % with diagnostic CNVs and 50.0 % with diagnostic SNVs. The yield nominally increased with ID severity and decreased with age of seizure onset, though this result was not statistically significant. The diagnostic yield of SNVs in patients with seizure onset in the first year of life (25.0 % (11/44)) was significantly higher than those with childhood-onset epilepsy (10.3 % (6/58)) (p = 0.049), however, the diagnostic yield of CNVs in patients with childhood-onset epilepsy (17.2 % (10/58) was higher than the diagnostic yield of SNVs (10.3 % (6/58)). The most frequently syndromic epilepsy detected by SNP array was Angelman syndrome (n=4), including one confirmed with paternal uniparental disomy. Meanwhile, the most frequent SNVs were mutations of MECP2 (n=2) and IQSEC2 (n = 2) in sporadic cases. Both CMA and WES are advantageous as unbiased approaches for a genetically heterogeneous condition. We proposed an effective diagnostic strategy for pediatric patients with epilepsy. For patients with seizure onset in the first year of life, WES is recommended as the first-tier test. However, for patie