Early Genetic Testing Considerations in Suspected CDKL5 Deficiency Disorder

CDKL5 deficiency disorder (CDD) is a rare, X-linked developmental and epileptic encephalopathy caused by pathogenic variants in the CDKL5 gene.¹ The condition is estimated to occur in approximately 1 in 40,000 to 60,000 live births and is more commonly observed in girls.² Clinically, CDD is characterized by early-onset, often treatment-resistant seizures, severe developmental impairment, and a range of associated neurologic and systemic features.³ Given its early presentation and phenotypic overlap with other infantile-onset epilepsies, timely recognition and appropriate use of genetic testing may be critical for accurate diagnosis and management.

In the first episode of this NeurologyLive® Insights video program, Raj Rajaraman, MD, MS, the director of the UCLA CDKL5 Center of Excellence, expanded on the clinical presentation of CDD, emphasizing that it most often manifests with seizures in the first 2 to 3 months of life. He noted that the condition predominantly affects girls because of its X-linked inheritance pattern and may involve seizure types such as tonic or focal tonic events that can evolve into epileptic spasms. He explained that a normal MRI may further point toward an underlying genetic etiology. These features were described as key indicators that should prompt consideration of CDD and further diagnostic evaluation.

Raj also discussed evolving approaches to genetic testing in early-onset epilepsy. He highlighted a shift from traditional multigene epilepsy panels toward more comprehensive strategies, including whole exome and whole genome sequencing. He emphasized the value of trio testing to help clarify variants of uncertain significance and improve diagnostic interpretation. Although he noted that decisions around testing are often influenced by factors such as insurance coverage and turnaround time, he underscored that early genetic testing in some form remains an important component of timely and accurate diagnosis.