Advancing Diagnosis of Rare Neurological Disorders in Pediatrics Through Clinical Genome Sequencing-VCBeat

Deep Analysis of Medical Evidence: DeepEvidence Supports Your Decision-MakingRare genetic diseases affect approximately 3.5% to 8% of the global population, with about 90% of rare pediatric diseases exhibiting significant neurological manifestations. These patients often endure a prolonged and complex “diagnostic odyssey,” involving repeated clinical evaluations, imaging studies, and laboratory tests, which not only delays appropriate clinical management but also imposes substantial psychological and economic burdens. Traditional stepwise genetic testing strategies typically begin with chromosomal microarray analysis, progressing to targeted gene panels or exome sequencing; however, this approach is costly, time-consuming, and yields an overall diagnostic rate of less than 50%. In recent years, clinical genome sequencing has emerged as a promising alternative due to its comprehensive coverage and ability to detect diverse variant types. This study aims to evaluate the diagnostic utility of clinical genome sequencing in a cohort of undiagnosed pediatric patients with complex neurological rare diseases within the Italian National Health Service.Conducted between 2018 and 2022 at three medical genetics centers in Turin, Trieste, and Pavia, Italy, in collaboration with Illumina’s charitable iHope program, this study provided trio-based clinical genome sequencing to 64 undiagnosed pediatric patients with complex conditions. Inclusion criteria comprised: clinical presentations suggestive of ultra-rare monogenic disorders, negative results from at least one first-tier genetic test, availability of DNA samples from the patient and both parents (trio), and lack of insurance or private funding coverage for sequencing costs. All patients had previously undergone chromosomal microarray analysis with negative results, and part