NEW YORK – Exome sequencing can lead to a molecular diagnosis in 10 percent to 33 percent of people with cerebral palsy, a new analysis from researchers at Geisinger and GeneDx has found.
While cerebral palsy, a movement disorder, has often been attributed to oxygen deprivation during birth, recent studies have suggested that birth asphyxia accounts for less than 10 percent of cerebral palsy cases and that genetic variants affect disease risk.
The researchers drew on two cohorts for their retrospective, cross-sectional cohort study of cerebral palsy. For one cohort of about 1,350 largely pediatric cases, exome sequencing had a molecular diagnostic yield of nearly 33 percent, while for a cohort of about 180 mostly adult cases, it had a molecular diagnostic yield of about 10 percent. As they reported in the Journal of the American Medical Association, the researchers additionally identified genes harboring alterations in more than one individual with cerebral palsy, including ones that could influence patient care.
"Finding a genetic etiology has the potential to prompt changes in clinical management, provide an end to the diagnostic odyssey and important prognostic information for patients and families, inform recurrence risk for future children born to the same parents, and may have medicolegal implications in cases of alleged birth asphyxia," first author Andrés Moreno De Luca, a neuroradiologist and assistant professor at Geisinger's Autism & Developmental Medicine Institute, wrote in an email.
The first cohort of 1,345 individuals with cerebral palsy had a median age of 8.8 years old and underwent exome sequencing at GeneDx. The other cohort, meanwhile, included 181 individuals with cerebral palsy who were a median age of 41.9 years old and who were recruited from the DiscoverEHR project from Geisinger and the Regeneron Genetics Center. This second cohort underwent research-based exome sequencing.
For the younger cohort exome sequencing led to a positive diagnostic result for 440 patients, or 32.7 percent. Trio testing was available for a subset of that cohort, which boosted diagnostic yield from 23.3 percent for the affected individuals only to 35.4 percent in trio testing.
Meanwhile, exome sequencing led to a positive diagnostic result for 19 patients, or 10.5 percent, from the second, older cohort.
Cerebral palsy often presents with comorbidities, including intellectual disability, epilepsy, and autism spectrum disorder. The molecular diagnostic rate for patients with other conditions was higher than for patients without comorbidities: patients without other conditions had a diagnostic rate of 11.2 percent, while patients with intellectual disability, epilepsy, and autism spectrum disorder in addition to cerebral palsy had a molecular diagnostic rate of 32.9 percent.
Moreno De Luca noted that the higher diagnostic rate for the pediatric cohorts could be due to the younger cohort's more severe comorbidity profile and the availability of parental samples for trio testing, both of which boost diagnostic rate. In addition, he said that genetic testing of an adult population for a neurodevelopmental disorder is often biased toward more mild cases, as the individuals have survived to adulthood.
Additionally, he and his colleagues identified genes that harbored alterations in two or more unrelated individuals with cerebral palsy, including CTNNB1, KIF1A, GNAO1, and TUBA1A. Mutations in CTNNB1, they noted, have previously been reported in individuals with cerebral palsy and an autosomal dominant neurodevelopmental disorder marked by intellectual disability, spasticity, microcephaly, and visual defects.
Moreno De Luca added that he plans to use data from the MyCode Community Health Initiative at Geisinger to conduct even larger studies of cerebral palsy and incorporate genomic testing as a standard of care. "We are also conducting studies aimed at discovering novel genes implicated in cerebral palsy and further characterizing subgroups of cerebral palsy by genetic subtype," he said.