Whole exome sequencing identified a significant prevalence of Mendelian disorders among individuals with cerebral palsy (CP). These findings were published in Annals of Clinical and Translational Neurology.
CP is a childhood-onset motor disability that is a descriptive term not dependent on etiology, can be caused by multiple factors, and result in differing symptom profiles. As such, much remains unknown about CP risk factors and 20% of CP cases have no clear explanation.
To explore the genetics of CP, patients with CP with established risk factors (non-cryptogenic CP; n=20), CP with no risk factors (cryptogenic CP; n=24), CP with progressive or regressive symptoms (CP masquerader; n=5), or unknown CP classification (n=1) were recruited at Boston Children’s Hospital. Study participants and their family members underwent whole exome sequencing, and the CP cohorts had a full clinical evaluation.
The study was comprised 30 boys or men and 20 girls or women aged mean 10.1±8.1 years and were classified as spastic diplegic (38%), spastic quadriplegic (32%), hypotonic-ataxic (16%), dyskinetic (10%), and spastic hemiplegic (4%). The hypotonia-ataxic subtype was only observed among patients in the cryptogenic group (P =.01) and communication impairment was more common among the non-cryptogenic cohort (P =.01).
A quarter of participants (26%) had pathogenic or likely pathogenic variants in 14 established disease genes and 23% had Mendelian disorders.
Most observed variants were de novo heterozygous or hemizygous variants in autosomal dominant (n=6) or X-linked (n=2) disorders.
A genetic cause for CP was identified in all but two participants. One patient had a variant and features consistent with laryngeal cleft, but it was unclear whether this was also related to their hemiplegia. The other patient with ambiguous genetic culpability was found to have a variant in a gene recently implicated with congenital kidney and urinary tract anomalies but did not present with such features.
Stratified by CP cohort, the presence of Mendelian disorders was highest among the CP masquerader group (60%), followed by cryptogenic CP (29%), and non-cryptogenic CP (15%).
Stratified by motor presentation, Mendelian disorders were most common among those with spastic hemiplegic (50%), followed by spastic quadriplegic (31%), hypotonic-ataxic (25%), spastic diplegic (21%), and dyskinetic (20%) subtypes.
The prevalence of Mendelian disorders differed significantly on the basis of magnetic resonance imaging findings, in which they were most common among patients with focal insult (100%), white matter and cortical injury (100%), deep gray matter injury (67%), and malformation (43%; P =.01).
This study was limited by not performing an analysis of copy number variants which can have a pathogenic role in CP.
This study identified a significant contribution of Mendelian disorders among patients with CP.
“On the basis of our findings, we propose basic guidelines for identifying patients who should be considered for genomic evaluation,” the researchers stated. “Establishing genetic diagnoses stands to improve patient, family, and provider understanding of etiology, and potentially management of thousands of individuals with CP.”
Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.
Chopra M, Gable DL, Love-Nichols J, et al. Mendelian etiologies identified with whole exome sequencing in cerebral palsy. Ann Clin Transl Neurol. Published online January 24, 2022. doi:10.1002/acn3.51506