A Novel Epilepsy Phenotype in a Young Girl With a Pathogenic SETD5 Gene Variant

Recent studies suggest a possible association between variants in SETD5 and epilepsy, particularly in individuals with intellectual disability and developmental delay. However, the current understanding of SETD5 function in epilepsy is limited. We describe a 6-year-old girl harboring a pathogenic SETD5 gene variant, disclosed in early infancy by whole exome sequencing that was performed for global developmental delay. Her neurologic phenotype evolved during follow-up to include focal and generalized seizures as well as an overt neurodevelopmental disorder, characterized by receptive-expressive language difficulties with speech disorder and mild cognitive impairment. Her clinical picture was also characterized by recurrent urinary tract infections in a duplex collecting system due to a concomitant and unrelated GREB1L gene variant. Our findings confirm that epilepsy may arise after SETD5 variants, with subtle clinical manifestations that may overlap with behavioral phenomena in children who also exhibit cognitive and behavioral comorbidities.