Epilepsy phenotype and developmental outcome in girls with mosaicism in X-linked neurodevelopmental disorders

CDKL5 deficiency disorder (CDD) and SMC1A-related epilepsy are X-linked neurodevelopmental disorders characterized by early-onset, mostly intractable epilepsy and severe intellectual disability. While recent advances in next-generation sequencing improved diagnostic yields, detecting low-frequency mosaicism remains challenging. We retrospectively analyzed the epilepsy and developmental phenotype of four female patients with mosaic CDKL5 or SMC1A variants. Clinical data, including seizure types, electroencephalographic findings, neurodevelopmental milestones, and genetic analyses, were reviewed. The two girls with CDKL5 mosaicism presented at 5 and 6 weeks with tonic seizures, rapidly developing hypermotor-tonic-spasms sequence seizures. Both achieved independent walking by age two and developed speech by 3 years. The two girls with SMC1A mosaicism presented clusters of focal impaired awareness, myoclonic, and tonic-clonic seizures at 19 and 20 months of age. They demonstrated milder intellectual disabilities, with one achieving normal speech and the other speaking over 100 words by age four. Both achieved independent walking, which is uncommon in germline patients. Girls with mosaic CDKL5 and SMC1A variants share the same epilepsy phenotype as the germline females but have milder intellectual and motor disabilities compared to germline patients. Recognizing specific seizure patterns may direct genetic testing, enabling earlier diagnosis and access to precision treatment.