Therapeutic implications of etiology-specific diagnosis of early-onset developmental and epileptic encephalopathies (EO-DEEs): A nationwide Turkish cohort study

Abstract

ObjectiveTo evaluate the etiology-specific diagnosis of early-onset developmental epileptic encephalopathies (EO-DEEs) in a nationwide Turkish cohort to determine the implications for therapeutic management. MethodsThe cohort comprised 1450 patients who underwent EO-DEE. The utility of genetic testing was assessed with respect to the initial phases of next generation sequencing (NGS) (2005–2013) and the current NGS era (2014–2022). A predefined four-stepwise diagnostic model was evaluated using cost-effectiveness analysis. The diagnostic and potential therapeutic yields of the genetic tests were subsequently determined. ResultsGene-related EO-DEEs were identified in 48.3% (n=701) of the cohort: non-structural genetic (62.6%), metabolic genetic (15.1%), and structural genetic (14.1%). The most common nonstructural genetic variants were SCN1A (n=132, 18.8%), CDKL5 (n=30, 4.2%), STXBP1 (n=21, 2.9%), KCNQ2 (n=21, 2.9%), and PCDH19 (n=17, 2.4%). The rate of ultra-rare variants (< 0.5%) was higher in the NGS era (52%) than that in the initial phase (36%). The potential therapeutic yields with precision therapy and antiseizure drug modification were defined in 34.5% and 56.2% in genetic-EO-DEEs, respectively. The diagnostic model provided an etiology-specific diagnosis at a rate of 78.7%: structural (nongenetic) (31.4%), genetic (38.5%), metabolic (6.1%), and immune-infectious (2.8%). Based on a cost-effectiveness analysis, the presented diagnostic model indicated the early implementation of whole-exome sequencing for EO-DEEs. SignificanceIn the present cohort, the higher rate (48.3%) of gene-related EO-DEE diagnoses in the NGS era provides a potential therapeutic management plan for more patients.