Molecular Diagnostic Yield of Exome Sequencing in Patients With Cerebral Palsy

Abstract

Importance: Cerebral palsy is a common neurodevelopmental disorder affecting movement and posture that often co-occurs with other neurodevelopmental disorders. Individual cases of cerebral palsy are often attributed to birth asphyxia; however, recent studies indicate that asphyxia accounts for less than 10% of cerebral palsy cases.

Objective: To determine the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) in individuals with cerebral palsy.

Design, setting, and participants: A retrospective cohort study of patients with cerebral palsy that included a clinical laboratory referral cohort with data accrued between 2012 and 2018 and a health care-based cohort with data accrued between 2007 and 2017.

Exposures: Exome sequencing with copy number variant detection.

Main outcomes and measures: The primary outcome was the molecular diagnostic yield of exome sequencing.

Results: Among 1345 patients from the clinical laboratory referral cohort, the median age was 8.8 years (interquartile range, 4.4-14.7 years; range, 0.1-66 years) and 601 (45%) were female. Among 181 patients in the health care-based cohort, the median age was 41.9 years (interquartile range, 28.0-59.6 years; range, 4.8-89 years) and 96 (53%) were female. The molecular diagnostic yield of exome sequencing was 32.7% (95% CI, 30.2%-35.2%) in the clinical laboratory referral cohort and 10.5% (95% CI, 6.0%-15.0%) in the health care-based cohort. The molecular diagnostic yield ranged from 11.2% (95% CI, 6.4%-16.2%) for patients without intellectual disability, epilepsy, or autism spectrum disorder to 32.9% (95% CI, 25.7%-40.1%) for patients with all 3 comorbidities. Pathogenic and likely pathogenic variants were identified in 229 genes (29.5% of 1526 patients); 86 genes were mutated in 2 or more patients (20.1% of 1526 patients) and 10 genes with mutations were independently identified in both cohorts (2.9% of 1526 patients).

Conclusions and relevance: Among 2 cohorts of patients with cerebral palsy who underwent exome sequencing, the prevalence of pathogenic and likely pathogenic variants was 32.7% in a cohort that predominantly consisted of pediatric patients and 10.5% in a cohort that predominantly consisted of adult patients. Further research is needed to understand the clinical implications of these findings.

Figure 1.. Study Design and Flowchart

Each cohort predominantly consisted of pediatric or adult patients. ^aThe term trios refers to a patient with cerebral palsy plus both parents. ^bRefers to the DiscovEHR project, which is an ongoing collaboration between Geisinger and the Regeneron Genetics Center. ^cStandards and guidelines for the interpretation of sequence variants from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) recommend the use of a 5-tier terminology system (ie, pathogenic, likely pathogenic, uncertain significance, likely benign, and benign) to describe variants identified in genes associated with mendelian disorders and describes a process for classifying variants into these 5 categories using evidence-based criteria. ^dThe term pathogenic is used for variants with the strongest evidence of pathogenicity, whereas likely pathogenic is used to mean greater than 90% certainty of a variant causing a disease.

Figure 2.. Association of Neurodevelopmental Comorbidities With Likelihood of Detection of Pathogenic and Likely Pathogenic Variants in Patients With Cerebral Palsy

NA indicates not applicable. ^aMolecular diagnostic yield refers to the prevalence of pathogenic and likely pathogenic variants. ^bThe odds ratios were estimated from a logistic regression model that controlled for cohort and each individual neurodevelopmental comorbidity. The analysis assesses the likelihood of detection of pathogenic and likely pathogenic variants in patients with cerebral palsy and the neurodevelopmental comorbidity listed in the first column vs patients with cerebral palsy but without the comorbidity. When analyzing cohort-specific data, only the neurodevelopmental comorbidities were included in the model. ^cCalculated using a χ² test.