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Exome Sequencing for Cerebral Palsy Has Sufficient Diagnostic Yield for First-Tier Test

NEW YORK – By digging into data from published studies, a team led by researchers at Geisinger has found that cerebral palsy diagnoses could be improved with routine exome sequencing.

"Data from this meta-analysis provide evidence to support the inclusion of cerebral palsy in the current recommendation of exome sequencing in the diagnostic evaluation of individuals with neurodevelopmental disorders," senior and corresponding author Andres Moreno-De-Luca, a researcher affiliated with Geisinger's developmental medicine, radiology, and diagnostic medicine institutes, and his colleagues wrote in JAMA Pediatrics on Monday.

Although individuals with neurodevelopmental disorders (NDD) such as intellectual disability (ID), developmental delay (DD), or autism spectrum disorder (ASD) routinely receive exome sequencing as a first-tier genetic test, the authors explained, such clinical diagnostic testing is not currently recommended for individuals with cerebral palsy.

While birth complications such as asphyxia appear to explain a relatively small subset of cases, studies have also found rare genetic variants contributing to cerebral palsy, pointing to the potential for uncovering additional risk factors through genetic testing.

To explore that possibility and assess the diagnostic yield of exome or genome sequencing, the researchers sifted through almost 150 papers published between 2013 and 2022, narrowing in on 13 articles meeting their inclusion criteria. They focused on studies that involved exome or genome sequencing on at least 10 cerebral palsy patients, while weeding out smaller studies or papers that relied on variant detection by gene panel sequencing, chromosomal microarrays, or other genetic testing methods.

Based on data for 2,612 individuals with cerebral palsy who were tested by exome or genome sequencing for the 13 papers, the team saw a diagnostic yield of just over 31 — on par with the diagnostic yield that has been reported for other neurodevelopmental conditions. Moreover, the yield appeared to be higher in pediatric than in adult cases, and in analyses that relied on strict patient selection criteria.

Consequently, the researchers argued that exome sequencing should be used as a first-tier diagnostic test in individuals with cerebral palsy, even in the absence of other neurodevelopmental conditions where exome sequencing is already recommended.

"Waiting for an additional NDD diagnosis to consider genetic testing in [cerebral palsy] is a missed opportunity to improve clinical outcomes," the authors suggested, "as [cerebral palsy] can be diagnosed earlier than ID or ASD and testing sooner could result in a more timely genetic diagnosis allowing early interventions with the potential to have a positive impact on health outcomes."

In addition, the investigators noted that studies that validate or expand the collection of rare variants contributing to cerebral palsy may ultimately provide a better understanding of the condition, while bolstering the diagnostic yield of sequencing-based genetic tests.

"We expect that continued identification of monogenic forms of [cerebral palsy] will drive the understanding of its pathophysiology and that ongoing validation studies of rare genomic variants will further increase the current diagnostic yield," they concluded.

In a related editorial, investigators from the University of Adelaide and the Women's and Children's Hospital suggested that findings from the study "provide sufficient evidence to support the inclusion of genomic sequencing as a first-tier test for individuals with cerebral palsy, regardless of their comorbidities and risk factors."

Still, the authors of the commentary cautioned that while new genetic information unearthed by genomic testing may lead to additional explanations or interventions for individuals with cerebral palsy, the new data should not change patients' existing clinical diagnoses.

"Cerebral palsy is a diagnosis made on clinical criteria and not genetic [testing] or brain imaging," they reasoned. "Inappropriately changing the clinical diagnosis can disenfranchise the child from financial and medical support resources specific for cerebral palsy, such as hip subluxation surveillance, and would undermine cerebral palsy registries and their important role in monitoring cerebral palsy incidence and the demographic characteristics of individuals with cerebral palsy."