Genetic diagnostic yield by MRI pattern in children with cerebral palsy: a population-based study

Area of Science:

• Genetics
• Neuroscience
• Pediatrics

Background:

• Cerebral palsy (CP) affects 80-86% of individuals with neuroimaging abnormalities.
• Lesional white matter (WMI) or grey matter injuries (GMI) are common in CP, often attributed to environmental factors.
• Genetic causes are hypothesized for non-lesional CP and normal neuroimaging, but this requires validation.

Purpose of the Study:

• To evaluate the hypothesis that genetic etiologies are more prevalent in non-lesional cerebral palsy (CP).
• To determine the diagnostic yield of genomic testing across different neuroimaging classifications in CP.
• To assess the role of neuroimaging in guiding genetic testing decisions for CP.

Main Methods:

• A population-based study of 331 children with CP (born 1986-2018) from the Australian CP biobank.
• Genomic DNA sequencing, variant filtering, and classification using ACMG-AMP criteria.
• Neuroimaging (MRI, CT, ultrasound) coded using the Magnetic Resonance Imaging Classification System (MRICS).

Main Results:

• A genetic etiology was identified in 24% of children with CP.
• Genetic diagnoses were more frequent in children with maldevelopments (41%), miscellaneous findings (48%), and normal neuroimaging (39%) compared to those with WMI (19%) or GMI (10%).
• Relative risk ratios indicated significantly higher genetic resolution in non-lesional CP categories compared to lesional injuries.

Conclusions:

• Findings support the hypothesis that genetic causes are more common in non-lesional CP.
• Genetic diagnoses were identified across all neuroimaging categories, including 17% of lesional brain injuries.
• Neuroimaging should guide, not exclude, genomic testing in cerebral palsy evaluations.