Abstracts

Rationale: Patients with rare genetic neurodevelopmental and epilepsy conditions such as SLC6A1-related disorders often undergo lengthy diagnostic journeys, which may include multiple genetic tests. However, little is known about the genetic testing patterns that culminate in diagnosis.

Methods: We utilized a real-world data platform developed by AllStripes Research to collect and digitize medical records from patients with SLC6A1-related disorders and confirm diagnoses as defined by the identification of a likely pathogenic or pathogenic variant in SLC6A1. We then reviewed patients’ records to assess genetic testing and clinical history including age at seizure onset. Written informed consent was provided for all patients.

Results: Genetic testing histories were collected for 28 patients with confirmed diagnoses, including 18 females (64%) and 10 males (36%) with an age range of 16 months to 22 years. 18 patients (64%) were diagnosed via exome sequencing and 10 (36%) with multi-gene panels (Figure 1). Patients underwent an average of 2.8 genetic tests, not including biochemical screening (range 1-7 genetic tests). Five (18%) were diagnosed with their first genetic test, which was a panel for all five patients. Those diagnosed via panel had fewer genetic tests on average (mean=1.7) than those diagnosed via exome sequencing, some of whom also had prior non-diagnostic panels (mean=3.4) (p=0.001). Other correlates with fewer genetic tests include seizure manifestation prior to the first genetic test (mean=2.6) versus those without seizures prior to first genetic test (mean=3.1) (p=0.14) and being born after SLC6A1 was associated with a neurodevelopmental phenotype in 2015 (mean=2.4) versus prior (mean=3.1) (p=0.19). The most common non-diagnostic genetic test was microarray (21/28; 75%), followed by genetic tests for Rett (7/28; 25%), Angelman (5/28; 18%), and Fragile X (5/28; 18%) syndromes (Figure 2).

Conclusions: Most patients underwent multiple genetic tests prior to diagnosis, drawing out diagnostic journeys and potentially delaying interventions. Diagnosis via panel was associated with undergoing fewer genetic tests, which may be related to differences in ease of access and insurance coverage between panels and exome. Interestingly, patients born since SLC6A1 was associated with a phenotype did not undergo significantly fewer genetic tests than those born prior, perhaps due to improved access to genetic testing over time. Most patients had microarrays performed, including the majority of those with seizure onset prior to genetic testing and despite evidence of higher diagnostic yields for epilepsy patients with broad sequencing-based tests. This suggests a need for further discourse surrounding diagnostic approaches. Larger cohorts could also help clarify the impact of gene discovery and increasing genetic testing access on diagnostic journeys.

Funding: Please list any funding that was received in support of this abstract.: Fully funded by AllStripes Research.