Genome sequencing identified diagnoses in 15% of individuals with unsolved developmental and epileptic encephalopathiesGenome sequencing finds diagnoses in 15% of unsolved epilepsy cases

medRxiv Published April 29, 2026 Study authors: Munro, J. E.; Thiyagarajah, H.; Bennett, M. F.; Chiu, A. T. G.; Schneider, A. L.; Bennett, C. A.; Li… DOI ↗ Editorial oversight: Dr. Julia Lee, PhD · Oncology, Genomics & Drug Development

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Key Takeaway

Consider genome sequencing for unsolved developmental and epileptic encephalopathies after negative prior genetic testing.

This cohort study evaluated 242 individuals with unsolved developmental and epileptic encephalopathies (DEEs) who had previously tested negative on genetic testing. The population consisted of patients with unsolved cases where standard exome or gene panel analysis had failed to identify a cause.

The intervention involved performing genome sequencing along with enhanced variant analyses outside of coding regions. This approach was compared against the baseline of prior genetic testing, which included exome or gene panel analysis. The primary outcome measured was the achievement of a molecular diagnosis.

Results showed that 36 of 242 participants, or 15%, received a molecular diagnosis through this enhanced genomic approach. The absolute diagnostic yield was 15% when comparing the new sequencing strategy to the prior testing methods. No specific adverse events, serious adverse events, discontinuations, or tolerability data were reported in the study.

The study design was observational, and the findings reflect associations rather than causal effects. Limitations regarding the generalizability of these results to other clinical settings or populations were not detailed in the provided data. The certainty of these findings is constrained by the observational nature of the cohort design and the specific context of unsolved DEEs.

A large group study looked at individuals with developmental and epileptic encephalopathies who had not received a diagnosis after standard genetic testing. The researchers examined 242 participants who had previously tested negative using exome or gene panel analysis. They added genome sequencing along with enhanced variant analyses that look outside of coding regions to their testing process. This approach helped find a molecular diagnosis for 36 of the 242 participants, which is 15% of the group. The study used a cohort design to compare these new results against the earlier negative findings. No safety concerns were reported in the study data provided. This type of testing may help explain conditions that were previously considered unsolved. Readers should note that this is a cohort study and the results reflect a specific group of patients. While the findings are promising, they apply to people with unsolved cases who have already had negative standard tests. The main takeaway is that expanded genetic testing can find answers in a meaningful portion of difficult cases.

What this means for you:

Expanded genome sequencing found diagnoses in 15% of unsolved epilepsy cases with prior negative tests.

Study Details

Study typeCohort

Sample sizen = 242

EvidenceLevel 3

PublishedApr 2026

View Original Abstract ↓

Purpose: Although most developmental and epileptic encephalopathies (DEEs) have a monogenic aetiology, routine clinical genetic testing is negative for 50% of patients. We hypothesized that the diagnostic yield could be increased in a large cohort of individuals with unsolved DEEs by applying genome sequencing along with enhanced variant analyses outside of coding regions. Methods: We performed genome sequencing for 242 participants with DEEs negative on prior genetic testing. We interrogated single nucleotide variants (SNVs), indels, and structural variants in both established and candidate DEE genes. All variants of interest were reviewed, classified, and validated by a multidisciplinary team. Results: A molecular diagnosis was discovered for 36/242 (15%) participants. The pathogenic or likely pathogenic variants comprised 26 SNVs and indels within coding regions, 9 structural variants, and 5 SNVs and indels in introns or non-coding genes. Variants of uncertain significance were detected in a further 10/242 (4%) participants. Conclusion: Genetic diagnostic yield for individuals with unsolved DEEs improves with genome sequencing analysis. This increase reflects both the identification of structural and non-coding variants not detectable on exome or gene panel analysis, and the detection of variants in genes newly associated with DEEs.

Genome sequencing identified diagnoses in 15% of individuals with unsolved developmental and epileptic encephalopathiesGenome sequencing finds diagnoses in 15% of unsolved epilepsy cases

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Genome sequencing identified diagnoses in 15% of individuals with unsolved developmental and epileptic encephalopathiesGenome sequencing finds diagnoses in 15% of unsolved epilepsy cases

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