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Advancing Cerebral Palsy Diagnosis Through Genomic Sequencing

Cerebral palsy (CP) is one of the most common motor conditions in children and is an umbrella term for a group of conditions affecting movement and posture that can be accompanied by comorbidities such as intellectual disability, epilepsy, or sensory impairments.  

While CP might be caused by brain trauma before or during birth, in other cases it may be the result of genetic changes that impact brain development. Risk factors for CP include prematurity, low birth weight, complicated birth, and infection1. It is diagnosed clinically, often without a clear understanding of the underlying etiology. This uncertainty can leave families without answers and clinicians without the information they need to guide short- and long-term care.  

At Baylor Genetics, we are committed to closing this diagnostic gap through comprehensive genomic testing. While a genetic diagnosis does not change the clinical definition of CP, it can help guide care and inform critical decision-making for healthcare providers and families. 

Understanding the Genetic Complexity of Cerebral Palsy

Today, studies suggest that up to 35% of individuals with CP may have an identifiable genetic etiology 2, 3. This changes the traditional paradigm assuming that CP is largely the result of perinatal injury and has led to greater utilization of genetic testing in clinical care. 

Importantly, CP often overlaps with other neurodevelopmental disorders. Roughly half of all patients with CP have intellectual disability, ~30% have epilepsy, and ~9% are diagnosed with autism spectrum disorder 4, 5. 

As a result, critical questions arise: Which patients should be considered for genetic testing and what does a genetic diagnosis mean for their care? 

What the Evidence Says: Diagnostic Yield of Genomic Testing for Patients with Cerebral Palsy

Published studies report diagnostic yields by whole genome sequencing (WGS) or whole exome sequencing (WES) ranging from 7% to 35%, depending on cohort selection.  

  • A meta-analysis of 15 study cohorts involving 2,419 individuals with CP found an overall diagnostic rate of 23% using WES. The diagnostic yield rose to 35% in patients with CP and no known risk factors compared to just 7% in those with risk factors. Clinical referral cohorts that include patients with additional neurodevelopmental features also report high diagnostic rates. In contrast, population-wide cohorts tend to show lower yields2. 
  • Another meta-analysis published in JAMA Pediatrics, which evaluated over 2,600 individuals with CP across 13 studies, reported an average diagnostic yield of 31.1% using WGS or WES6. This rate is comparable to other neurodevelopmental disorders such as developmental delay, intellectual disability, and autism spectrum disorder, where WGS and WES are already recommended as first-tier testing by the American College of Medical Genetics and Genomics (ACMG) 7. 
  • In a npj Genomic Medicine of 150 children with cerebral palsy, WGS identified pathogenic or likely pathogenic variants in 24.7% of participants—revealing unexpected diagnoses and uncovering familial risks 8. 
  • A March 2024 Nature Genetics study used WGS to evaluate the genetic underpinnings of CP in 327 children and their biological parents. Pathogenic or likely pathogenic (P/LP) variants were identified in 11.3% of participants, with almost half having copy number variants and variants within the mitochondrial genome (1.5%). In addition, the study also detected short tandem repeat (STR) expansions in both known and candidate CP-associated genes 4.  

At Baylor Genetics, we offer WGS which includes coverage of the mitochondrial genome as well as 29 STR expansion disorders, flexible sample types, and a 3-week turnaround time. RNA sequencing is also available as a reflex test when a qualifying variant is identified through WGS, helping clarify uncertain results and provide additional insights through functional evidence. 

For critically ill babies or those in acute care settings, our rapid WGS delivers written results in as few as 5 days.  

Clinical Implications of Genetic Testing

Genomic testing enhances diagnostic accuracy by identifying underlying genetic causes, especially in patients with complex or atypical phenotypes. This information supports targeted treatment strategies and prompts referrals to specialists. 

Approximately half of patients tested by WGS are predicted to benefit from changes in clinical management or access to targeted therapies 8. This underscores the actionable nature of genomic testing, particularly WGS, in CP.   

By revealing underlying genetic causes, WGS empowers healthcare teams to tailor treatment strategies, make informed referrals, and optimize care plans based on precise molecular diagnoses. Additionally, the results provide essential information on recurrence risks, supporting reproductive counseling and family planning decisions. Even when just variants of uncertain significance are identified, these might lead to future diagnoses as our understanding of genetics and genomics continues to improve. 

Overall, genomic testing streamlines the diagnostic process, reduces the burden of extensive evaluations, and facilitates timely, personalized care — improving outcomes for patients and families alike.  

Watch the video below to learn how WGS can impact care in CP. 

Patient Case: How Baylor Genetics’ WGS Uncovered a Dual Diagnosis in a Child with CP 

A 9-year-old boy presented with CP, spasticity, dystonic posturing, scoliosis, hemiparesis, and other neuromuscular findings. 

With no prior genetic testing, his care team turned to Proband WGS, understanding that CP can often have a genetic basis. WGS revealed a dual diagnosis that explained his complex presentation: 

  • A heterozygous pathogenic repeat expansion in ATXN8OS, confirming spinocerebellar ataxia type 8 (SCA8) 
  • A likely pathogenic variant in GCH1, consistent with dopa-responsive dystonia 

These insights directly impacted his care. He became eligible for SCA8 clinical trials, and his provider-initiated levodopa therapy, a well-established treatment for dopa-responsive dystonia that may prevent or even reverse symptoms. 

WGS was the right test at the right time—detecting both sequence variants and STR expansions in a single analysis. These findings, especially the STR expansion, would likely have been missed by traditional gene panels. 

Advancing Care with Baylor Genetics

Genomic testing is reshaping how we diagnose and understand CP, ultimately enabling a molecular diagnosis that supports personalized medical management, surveillance, and patient advocacy. 

At Baylor Genetics, we equip clinicians with the industry’s most comprehensive WGS, featuring integrated RNA sequencing, mitochondrial genome analysis, and STR expansion testing—capabilities unmatched by other labs. This powerful combination delivers faster, more precise diagnoses, empowering healthcare teams to uncover the full genetic complexity behind CP. With these insights, providers can make informed, personalized care decisions that truly transform patient outcomes.  

For more information on how we can help you advance the diagnosis of cerebral palsy, visit [Whole Genome Sequencing Test | Baylor Genetics].  

Supported by our comprehensive portfolio—including our metabolomic Global MAPS® test—and dedicated clinical teams, Baylor Genetics stands as your partner in delivering precision diagnostics tailored to every patient’s unique needs. 

Reach out to us today to learn how we can support your practice and improve patient outcomes. 

References 

  1. National Institute of Neurological Disorders and Stroke. (n.d.). Cerebral palsy. https://www.ninds.nih.gov/health-information/disorders/cerebral-palsy 
  2. Srivastava, S., Lewis, S. A., Cohen, J. S., et al. (2022). Molecular diagnostic yield of exome sequencing and chromosomal microarray in cerebral palsy: A systematic review and meta-analysis. JAMA Neurology, 79(12), 1287–1295. https://doi.org/10.1001/jamaneurol.2022.3549 
  3. Weinberg Family Cerebral Palsy Center. (n.d.). New study highlights the potential of genetic testing in cerebral palsy care. New Study Highlights the Potential of Genetic Testing in Cerebral Palsy Care | Weinberg Family Cerebral Palsy Center 
  4. Fehlings, D. L., Zarrei, M., Engchuan, W., et al. (2024). Comprehensive whole-genome sequence analyses provide insights into the genomic architecture of cerebral palsy. Nature Genetics, 56, 585–594. https://doi.org/10.1038/s41588-024-01686-x 
  5. van Eyk, C. L., Fahey, M. C., & Gecz, J. (2023). Redefining cerebral palsies as a diverse group of neurodevelopmental disorders with genetic aetiology. Nature Reviews Neurology, 19(9), 542–555. https://doi.org/10.1038/s41582-023-00847-6 
  6. Gonzalez-Mantilla, P. J., Hu, Y., Myers, S. M., et al. (2023). Diagnostic yield of exome sequencing in cerebral palsy and implications for genetic testing guidelines: A systematic review and meta-analysis. JAMA Pediatrics, 177(5), 472–478. https://doi.org/10.1001/jamapediatrics.2023.0008 
  7. Manickam, K., McClain, M. R., Demmer, L. A., et al. (2021). Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: An evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genetics in Medicine, 23(11), 2029–2037. https://doi.org/10.1038/s41436-021-01242-6 
  8. van Eyk, C. L., Webber, D. L., Minoche, A. E., et al. (2021). Yield of clinically reportable genetic variants in unselected cerebral palsy by whole genome sequencing. NPJ Genomic Medicine, 6, 74. https://doi.org/10.1038/s41525-021-00238-0