The genetic landscape of intellectual disability and epilepsy in adults and the elderly: a systematic genetic work-up of 150 individuals
Pia Zacher, Thomas Mayer, Frank Brandhoff, Tobias Bartolomaeus, Diana Le Duc, Martin Finzel, Anja Heinze, Susanne Horn, Chiara Klöckner, Gudrun Körber, Julia Hentschel, Malgorzata Kalita, Ilona Krey, Marina Nastainczyk-Wulf, Konrad Platzer, Johannes Rebstock, Bernt Popp, Mathias Stiller, Anne‐Christin Teichmann, Rami Abou Jamra, Johannes R. Lemke
Abstract
PURPOSE: Genetic diagnostics of neurodevelopmental disorders with epilepsy (NDDE) are predominantly applied in children, thus limited information is available regarding adults or elderly. METHODS: = 24). RESULTS: We identified (likely) pathogenic variants in 71 cases (47.3%) comprising fragile X syndrome (n = 1), disease-causing copy number (n = 23), and single-nucleotide variants (n = 49). Seven individuals displayed multiple independent genetic diagnoses. The diagnostic yield correlated with the severity of intellectual disability. Individuals with anecdotal evidence of exogenic early-life events (e.g., nuchal cord, complications at delivery) with alleged/unproven association to the disorder had a particularly high yield of 58.3%. Screening for disease-specific comorbidities was indicated in 45.1% and direct treatment consequences arose in 11.8% of diagnosed individuals. CONCLUSION: Panel/exome sequencing displayed the highest yield and should be considered as first-tier diagnostics in NDDE. This high yield and the numerous indications for additional screening or treatment modifications arising from genetic diagnoses indicate a current medical undersupply of genetically undiagnosed adult/elderly individuals with NDDE. Moreover, knowledge of the course of elderly individuals will ultimately help in counseling newly diagnosed individuals with NDDE.