Infantile Spasm Syndrome In The Genomic Era: Etiologic Trends and The Yields of Genetic Test

Objective. To define the etiologic trend in infantile spasm syndrome (ISS) in the genomic era with a step-based approach in a large cohort. Methods. The study cohort consisted of 314 patients with ISS from Ege University between 2005 and 2021. The most likely specific etiologies were coded by two independent reviewers based on a step-based approachment: step I (clinical phenomenology), step II (magnetic resonance imaging), step III (metabolic screening), and step IV (genetic tests). A specific etiologic diagnosis was defined according to the ILAE classification: structural, metabolic, genetic, immune-infectious, unknown. Precision therapy was considered positive if the genetic test result influenced the treatment choice (e.g., levetiracetam and STXBP1). Results: Etiologic diagnosis was established in 70.4% of patients (221/314): structural, 40.8% (n:128); genetic, 17.2% (n:54); metabolic, 8.2% (n:26); immune-infectious, 4.1 (n:13) (Table I). The combined use of the first three steps (I-III) provides a specific diagnosis in 77.8% of children presenting with infantile spasms (Table II). Further genetic studies (step IV) revealed an additional etiologic diagnosis in 22.2% of the cohort. Since 2014, with the advent of next-generation sequencing, the diagnostic yield of genetic tests has reached 38.3% with the dynamic use of genetic counseling and the precision therapy rate was 27.7%. Conclusion In this study, we propose a step-based approach for the etiologic diagnosis in children with ISS. Dynamic use of genetic tests in step IV might provide more diagnostic yield and precision therapy.