Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social communication and restricted and repetitive behaviors and interests. Identifying the genetic background may be one of the key features for the future diagnosis and treatment of ASD. With the tremendous development in genetic diagnosis techniques, next-generation sequencing (NGS) can be used to analyze multiple genes simultaneously with a single test in laboratory and clinical settings and is well suited for investigating autism genetics. According to previous studies, there are two types of genetic variants in ASD, rare variants and common variants, and both are important in explaining pathogenesis. In this study, NGS data from 137 participants with ASD were reviewed retrospectively with consideration for comorbid epilepsy. Diagnostic yield was 17.51% (24/137), and pathogenic/likely pathogenic variants were seen more frequently in female participants. Fourteen participants were diagnosed with comorbid epilepsy, six of them had pathogenic/likely pathogenic variants (43%). Genes with variants of unknown significance (VOUS) which have one or more evidence of pathogenicity following the American College of Medical Genetics (ACMG) criteria were also reviewed in both ASD and ASD with comorbid epilepsy groups. We found that most frequently found VOUS genes have previously been reported as genes related to ASD or other developmental disorders. These results suggest that when interpreting the NGS results in the clinical setting, careful observation of VOUS with some pathological evidence might contribute to the discovery of genetic pathogenesis of neurodevelopmental disorders such as ASD and epilepsy.

Autism Spectrum Disorder: Focus on Glutamatergic Neurotransmission

“…Interestingly, rare pathogenic deletions of the GRIN2A gene [ 137 , 138 , 139 , 140 , 141 , 142 ] and heterozygous de novo missense variants [ 143 ] have been implicated in childhood focal epilepsy. Moreover, next-generation sequencing of children with ASD has revealed variants in the GRIN2A gene with evidence that supports ASD pathogenicity [ 144 , 145 ]. Genetic studies have also found a genetic association between ASD and GRIK genes belonging to the kainate family of Glu receptors.…”

Recent Advances in the Clinical Application of Next-Generation Sequencing

“…DPS may show a wide variety of diagnostic yields depending on the disease group, the method of selecting a study subject, and the gene panel composition. In Korean patients, the diagnostic yields of DPS have been reported in disorders of sex development (29.5%) [ 4 ], syndromic growth disorder (46.2%) [ 5 ], inherited peripheral neuropathies (27.0%) [ 6 ], developmental and epileptic encephalopathy (EIEE) (37.1%) [ 7 ], intractable early onset epilepsy (37.8%) [ 8 ], developmental delay and/or intellectual disability (29%) [ 9 ], infantile nystagmus syndrome (58.3%) [ 10 ], autism spectrum disorder, and comorbid epilepsy (17.5%) [ 11 ].…”

Analysis of common genetic variation across targets of microRNAs dysregulated both in ASD and epilepsy reveals negative correlation

“…The co-occurrence of ASD and epilepsy has been well documented at the epidemiological level: between 11% and 39% of ASD patients have epilepsy ( Canitano, 2007 ; Lukmanji et al, 2019 ), while around 15%–47% of people with epilepsy also have ASD ( Clarke et al, 2005 ; Lukmanji et al, 2019 ). This comorbidity is also associated with intellectual disability and greater severity of the ASD symptomatology ( Ko et al, 2016 ; Lee et al, 2020 ). Beyond clinical comorbidity, a clear pattern of biological overlap between ASD and epilepsy has been demonstrated ( Lee et al, 2015 ).…”