Objective:

Assess the diagnostic yield and clinical impact of whole genome sequencing (WGS) in children with cerebral palsy.

Approach:

• Participants and testing: Researchers recruited 86 children from five NHS specialist clinics in England. WGS was generally performed alongside sequencing of biological parents.
• Variant analysis: AI software prioritized potentially disease-causing variants, which were reviewed using broad genome analysis, targeted gene lists, and multidisciplinary interpretation.
• Prediction model: Researchers developed a machine learning model using standardized clinical descriptions to estimate the likelihood of a genetic diagnosis.

Key Findings:

• Pathogenic or likely pathogenic variants were identified in 11 children (12.8%); eight others (9.3%) had potentially relevant variants that did not establish a diagnosis.
• All 11 confirmed diagnoses influenced care or genetic counselling. Four children received tailored clinical management, while seven required additional specialist care.
• Examples included changing antiseizure medication after identifying an SCN1A variant, arranging specialist mitochondrial assessment, and introducing cardiovascular screening after detecting a COL4A1 variant.
• Intellectual disability, dystonia, and abnormalities affecting multiple body systems were associated with a greater likelihood of a genetic diagnosis.
• The machine learning model achieved an area under the curve of 0.88.
• Some diagnostic variants would have been missed if analysis had been limited to genes already associated with cerebral palsy.

Interpretation:

The authors report evidence supporting consideration of WGS in NHS cerebral palsy assessments, particularly when additional clinical features suggest an underlying genetic condition.

Limitations:

• The study included a small population of 86 children.
• The findings included potentially relevant variants that were insufficient to establish a diagnosis.
• The authors state that larger prospective studies are needed to assess diagnostic effectiveness, cost-effectiveness, and appropriate patient selection.

Conclusion:

Confirmed genetic diagnoses influenced care or genetic counselling in all 11 children with pathogenic or likely pathogenic variants.

Sources:

• The Lancet Regional Health – Europe study, as described in the supplied article context