Children with suspected hereditary spastic paraplegia clearly benefit from whole exome analysis.

backgroundEstablish a genetic diagnosis in patients referred for clinical suspicion of hereditary spastic paraplegia (HSP). The cohort of 134 paediatric patients was divided into three groups according to age at symptom onset: group A (0–5 years, n = 82), group B (5–10 years, n = 32), and group C (10–18 years, n = 20). Exome sequencing was followed by virtual panel evaluation of HSP associated genes. In patients with a negative result, full exome evaluation was subsequently performed.

resultsWe established the genetic diagnosis in 31% of patients across all the groups, representing 41 index patients from 41 unrelated families. In the group A, the diagnostic yield increased by up to one-third when panel analysis was followed by full exome analysis, reaching 37%. In group B, 18% of patients were diagnosed using either a virtual panel or a combination of virtual panel and exome analysis. In group C, panel testing alone provided a 25% yield, with no additional benefit from exome evaluation. We confirmed 10 de novo variants comprising 19% of all detected variants, and except for one, all were detected in the group A. In the majority of solved patients, the diagnosis of HSP was confirmed by the detection of a pathogenic variant in an HSP-associated gene. However, in 32% of cases, the final diagnosis corresponded to a different rare neurological disorder, caused by a pathogenic variant in a gene associated with a condition other than HSP. Among the genetically solved patients with HSP our data suggest that autosomal dominant forms (82%) may be more common than autosomal recessive forms (18%) in paediatric patients in the Czech Republic.

conclusionWe have demonstrated that exome sequencing with virtual panel evaluation, followed by analysis of the full exome data according to HPO terms, is the most suitable approach, particularly for young paediatric patients.