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 PARTICIPANTSA 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 MEASURESThe 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.

Genetic variants account for up to one-third of cases of cerebral palsy

“…In an article published recently in JAMA, Moreno-De-Luca and colleagues sought to determine the diagnostic yield of exome sequencing for CP. 3 This large cross-sectional study included results of exome sequencing performed in 2 settings. The first setting was a commercial laboratory in which samples were sent for analysis due to a diagnosis of CP, primarily in children (n = 1,345) with a median age of 8.8 years.…”

“…Although most of the identified genetic variants were de novo (that is, they arose in the affected individual and were not clearly inherited), some were inherited from carrier parents. 3 A number of other recent studies also have investigated genetic causes of CP and similarly have reported that a substantial number of cases are genetic. Several studies that performed chromosomal microarray analysis in individuals with CP found deleterious copy number variants in 10% to 31% of cases.…”

“…[4][5][6] Genomic variants detectable by exome sequencing have been reported in 15% to 20% of cases. 3 In a recent study in Nature Genetics, researchers performed exome sequencing on 250 parentchild "trios" in which the child had CP, and they found that 14% of cases had an associated genetic variant that was thought to be causative. 4 These studies all provide consistent evidence that a substantial proportion of CP cases are due to genetic causes.…”

“…12 In the recent study by Moreno-De-Luca and colleagues, some of the gene variants detected were previously associated with other forms of neurodevelopmental disability, such as epilepsy and autism spectrum disorder. 3 Many individuals in the study cohort were found to have multiple neurologic comorbidities, for example, CP as well as epilepsy, autism spectrum disorder, and/or intellectual disability. The presence of these additional comorbidities increased the likelihood of finding a genetic cause; the authors found that the diagnostic yield ranged from 11.2% with isolated CP to 32.9% with all 3 comorbidities.…”

Resistance to Neuromuscular Blockade by Rocuronium in Surgical Patients with Spastic Cerebral Palsy

“…A number of risk factors for CP have been identified, including prematurity, hypoxia-ischemia, placental insufficiency, chorio-amnionitis or other prenatal infection, perinatal inflammation, genetic causes, and combinations of these factors [ 6 , 7 , 8 , 9 ]. In particular, the presence of genetic variants have been investigated in some types of CP [ 10 , 11 ] with de novo copy number variants [ 12 , 13 , 14 , 15 , 16 , 17 ], single nucleotide variants [ 18 ], and de novo mutations [ 19 ] implicated in as many as 33% of the CP cases evaluated in those studies. Additional studies suggest that epigenetic alterations are associated with CP [ 20 , 21 , 22 , 23 ].…”