International consensus establishes cytogenetic testing as gold standard for ring chromosome 20 syndrome diagnosis

Original abstract

OBJECTIVE: This study was undertaken to establish expert consensus clinical and diagnostic criteria for ring chromosome 20 syndrome using a modified electronic Delphi process. METHODS: In this modified two-round electronic Delphi consensus study, international experts rated candidate statements using a 9-point Likert scale. Consensus was predefined as at least 70% agreement. A disagreement index assessing rating dispersion was calculated for each statement. The international expert consensus study was conducted remotely using Research Electronic Data Capture. Thirteen international experts with clinical and/or research expertise in ring chromosome 20 syndrome were invited; 12 completed Round 1, and 11 completed Round 2. Experts evaluated statements developed by a steering committee across clinical and diagnostic domains, including age at onset, seizure phenotype, comorbidities, treatment response, laboratory testing, neuroimaging, electroencephalographic findings, and genetic/genomic testing. Statements not reaching consensus after Round 1 were revised and redistributed in Round 2. Proportion of statements achieving consensus agreement was determined, and high-agreement statements were synthesized into key diagnostic criteria. RESULTS: Consensus was achieved for 25 clinical statements and 19 diagnostic statements, with agreement ranging from 73% to 100%. Clinical consensus emphasized normal early development before seizure onset, seizure onset most commonly between ages 4 and 8 years in mosaic cases, rapid progression to drug resistance, and recurrent nonconvulsive status epilepticus with fluctuating cognitive impairment. Diagnostic consensus highlighted the limited utility of routine laboratory testing and neuroimaging, while strongly endorsing a characteristic electroencephalographic pattern of prolonged rhythmic theta activity over frontal and temporal regions. Participants unanimously agreed that karyotype analysis is required for diagnosis and that next generation sequencing modalities cannot reliably establish diagnosis in mosaic cases. SIGNIFICANCE: This study establishes the first internationally accepted consensus clinical and diagnostic criteria for ring chromosome 20 syndrome. These criteria provide a framework to improve recognition of this underdiagnosed epilepsy syndrome and reinforce the continued importance of cytogenetic testing in childhood onset drug-resistant epilepsy.