Is cerebral palsy (CP) hereditary?

Cerebral Palsy Has a Significant Genetic Component

Cerebral palsy is not purely hereditary, but recent evidence shows that genetic factors play a substantial role in approximately 31% of cases, with genetic diagnostic yield similar to other neurodevelopmental disorders for which genetic testing is now recommended as standard of care. 1

Genetic Contribution to Cerebral Palsy

Cerebral palsy (CP) has traditionally been attributed to non-progressive disturbances in the developing fetal or infant brain, with environmental factors such as birth complications often considered the primary cause. However, recent evidence has significantly changed our understanding of CP etiology:

• The complete causal pathway to CP remains unclear in approximately 80% of cases 1
• Recent evidence suggests that 14% of CP cases have a genetic component according to earlier studies 1
• A 2023 systematic review and meta-analysis found genetic diagnostic yield of 31.1% (95% CI, 24.2%-38.6%) in CP patients who underwent exome or genome sequencing 1
• Birth asphyxia, historically considered the leading cause, accounts for less than 10% of CP cases 1

Types of Genetic Contributions

The genetic contribution to CP takes several forms:

• Single gene variants: Pathogenic or likely pathogenic variants detected through exome sequencing or genome sequencing in 31.1% of cases 1
• Copy number variants (CNVs): Identified in 10% to 31% of cases using chromosomal microarray analysis 1
• Complex inheritance patterns: CP typically exhibits multifactorial inheritance with genetic heterogeneity and complex interactions with environmental factors 2

Factors Affecting Genetic Diagnostic Yield

The likelihood of identifying a genetic cause varies based on several factors:

• Age: Higher diagnostic yield in pediatric populations (34.8%) compared to adult populations (26.9%) 1
• Patient selection: Higher yield in studies that used exclusion criteria (42.1%) versus unselected cohorts (20.7%) 1
• Presence of comorbidities: Even in CP patients without intellectual disability/developmental delay, genetic causes were found in 17.6% of cases 1
• Presence of risk factors: Genetic causes were found in 8-16% of individuals with risk factors (prematurity, low birth weight, perinatal asphyxia) and 14-48% in those without risk factors 1

Clinical Implications

The recognition of genetic factors in CP has important implications:

• Diagnostic approach: Exome sequencing should be considered in the diagnostic evaluation of individuals with CP, similar to recommendations for other neurodevelopmental disorders 1
• Family planning: Identifying genetic causes provides accurate recurrence risk information 1
• Precision medicine: 36.8% of individuals with pathogenic/likely pathogenic variants benefited from genomic-informed changes in clinical management 1
• Early intervention: Early genetic diagnosis allows timely interventions that may positively impact health outcomes 1

Common Pitfalls in CP Diagnosis and Management

Several pitfalls should be avoided:

1. Assuming environmental causation: Not investigating genetic causes due to the presence of risk factors like prematurity or birth asphyxia misses genetic diagnoses in a significant proportion of cases 1

2. Waiting for comorbidities: Delaying genetic testing until additional neurodevelopmental disorders emerge misses the opportunity for early diagnosis and intervention 1

3. Incomplete genetic evaluation: Not performing comprehensive genetic testing (including CNV analysis and trio analysis when possible) may underestimate genetic contributions 1

4. Overlooking mild presentations: Even patients without intellectual disability may have genetic forms of CP 1

CP should be viewed as a clinical syndrome with multiple potential etiologies, including significant genetic contributions. Current evidence supports including CP in recommendations for genetic testing that already exist for other neurodevelopmental disorders, with potential benefits for diagnosis, management, and family counseling.