A novel de novo variant of CDKL5 in an Iranian child with infantile-onset refractory epilepsy.

backgroundEpilepsy is defined as a long-term brain disease with recurrent and spontaneous seizures that often begin in childhood and encompass a wide range of etiologies, including genetic factors. This study aimed to identify and characterize the genetic cause underlying developmental delay and refractory epilepsy in an Iranian patient.

methodsWe performed a prospective evaluation of an Iranian girl presenting with developmental delay, refractory seizures, and hypotonia. The case was referred to the Genetic Research Center, Meybod,, Iran. Whole exome sequencing and Sanger sequencing were performed to identify the disease-causing variant and validate it, respectively. Also, bioinformatic analyses were used to evaluate the predicted pathogenicity and structural consequences of the variants.

resultsA novel de novo frameshift variant in CDKL5 gene (c.1037_1038delTCinsCAGATCTAA, p.Ile346Thrfs*14) was identified and classified as pathogenic based on ACMG criteria. The variant is predicted to engender a premature stop codon, leading to extensive shortening of the protein and loss of essential functional domains. Additionally, Valproate-Lamotrigine combination therapy resulted in significant clinical effects, such as a considerable reduction in the number of seizures.

conclusionThe present study can expand the mutational spectrum of CDKL5 and highlight the clinical advantage of sequencing-based genetic testing for early diagnosis and personalized therapeutic management of refractory epilepsy.