Objective:

To describe a nationwide cohort of patients with disease-causing genotypes in genes associated with developmental and epileptic encephalopathies (DEEs).

Background:

DEEs are conditions characterized by seizures and developmental delay. Increasingly, genotype drives diagnosis, treatment, and clinical trial options.

Design/Methods:

Retrospective chart review of patients with disease-causing genotypes in DEE-associated genes referred to a nationwide telehealth genetic counseling practice.

Results:

Between 2019 and 2025, 269 patients with disease-causing genotypes in 66 DEE genes were referred. Most patients were children (190/269, 70.6%) at the time of visit, and 54.6% (147/269) were female. The median age was 3 for children (IQR 1-7) and 38 for adults (IQR 27.5-39). Patients resided in 46 states, most frequently Texas (27/269, 10.0%), California (23/269, 8.6%), and Florida (19/269, 7.1%). Variants occurred most frequently in SCN1A (27/269, 10.0%), CACNA1A (16/269, 5.9%), and TSC2 (15/269, 5.6%). Among those with parental genetic testing, 61.5% (40/65) had a de novo variant. The inheritance pattern was autosomal dominant (226/269, 84.0%), X-linked (33/269, 12.3%), autosomal dominant/recessive (8/269, 3.0%), and autosomal recessive (2/269, 0.7%). Data on DEE features were extracted from clinic notes if available: 86.3% (169/196) had known or suspected seizures, 72.1% (127/176) had developmental delay, 62.8% (27/43) had intellectual disabilities, and 23% (20/85) had structural brain abnormalities. The age of first seizure was under 1 year for 55.6% of patients with seizures (65/117). Median time from first seizure to molecular diagnosis was 1 year (IQR 0-6).

Conclusions:

This nationwide cohort highlights the clinical and genetic heterogeneity of DEEs, underscoring the value of genotype-driven care and the broad geographic reach of telehealth genetics.