Epileptic encephalopathies are severe epilepsy disorders with strong genetic bases. We performed targeted next-generation sequencing (NGS) in 70 patients with epileptic encephalopathies. The likely pathogenicity of variants in candidate genes was evaluated by American College of Medical Genetics and Genomics (ACMG) scoring taken together with the accepted clinical presentation. Thirty-three candidate variants were detected after population filtration and computational prediction. According to ACMG, 21 candidate variants, including 18 de novo variants, were assessed to be pathogenic/likely pathogenic with clinical concordance. Twelve variants were initially assessed as uncertain significance by ACMG, among which 3 were considered causative and 3 others were considered possibly causative after analysis of clinical concordance. In total, 24 variants were identified as putatively causative, among which 19 were novel findings. SCN1A mutations were identified in 50% of patients with Dravet syndrome. TSC1/TSC2 mutations were detected in 66.7% of patients with tuberous sclerosis. STXBP1 mutations were the main findings in patients with West syndrome. Mutations in SCN2A, KCNT1, KCNQ2 and CLCN4 were identified in patients with epileptic infantile with migrating focal seizures; among them, KCNQ2 and CLCN4 were first identified as potential causative genes. Only one CHD2 mutation was detected in patients with Lennox-Gastaut syndrome. This study highlighted the utility of targeted NGS in genetic diagnoses of epileptic encephalopathies and a comprehensive evaluation of the pathogenicity of variants based on ACMG scoring and assessment of clinical concordance. Epileptic encephalopathies differ in genetic causes, and the genotype-phenotype correlations would provide insights into the underlying pathogenic mechanisms.
We have cloned the junction region of the previously characterized Yunnanese (Agammadeltabeta)0-thalassemia deletion and the normal DNA region surrounding its 3' breakpoint. The sequence of 1138 bp of the 3'-flanking region and 555 bp of the normal region surrounding the 3' breakpoint was determined. The 5' breakpoint of the deletion is positioned between 116 and 117 bp upstream of the Agamma-globin gene, and the 3' breakpoint at 34 bp downstream of the BglII site that lies approximately 12.7 kb upstream of the 3' deletion breakpoint of Chinese (Agammadeltabeta)0-thalassemia. There is no significant homology between the normal DNAs flanking the 5' and 3' breakpoints, except 2-bp (TG) identity and two pairs of short direct repeats at the deletion junction. The 3' breakpoint is within an L1 family sequence that normally occurs about 66 kb downstream of the beta-globin gene in 11p15. This L1 element is partially in reversed orientation at the 5' side and is therefore, presumably, an inactive element. This type of junction indicates illegitimate DNA breakage and end-joining involving the L1 sequence. Similar to many other deletions in the beta-globin locus, the Yunnanese (Agammadeltabeta)0-thalassemia deletion lacks a sequence characteristic of defined recombination factors near the deletion junction, suggesting that chromatin configuration and other locus-specific features are important. Computer-aided analysis revealed that several transcriptional factors could bind to putative motifs present in the 3'-flanking sequence. It is possible that binding features of the distal L1 element are required to generate a suitable chromatin configuration for the recombination event in Yunnanese (Agammadeltabeta)0-thalassemia. This may also be related to the reactivation of the Ggamma-globin gene in adults with the Yunnanese (Agammadeltabeta)0-thalassemia mutation.
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