The study, “Atypical cerebral palsy: genomics analysis enables precision medicine,” was published in the journal Genetics in Medicine.
Cerebral palsy (CP) comprises a group of neurological disorders that affect posture and restrict movement. These disorders are caused by brain lesions that occur in fetal development or infancy.
“The clinical presentation of CP is complicated by comorbidities including intellectual disability (ID), epilepsy, visual/hearing impairments, autism spectrum disorder, and movement disorders. These additional features contribute to the clinical heterogeneity of CP and make the diagnostic process challenging,” the investigators wrote.
“Exome (ES) and genome sequencing (GS) have accelerated discovery in the genetics of many diseases including neurodevelopmental disorders. These methods have [also] been successful in CP,” they added. Exome refers to the DNA sequence of all genes encoding for proteins; genome refers to all the genes present in our DNA.
In this study, a group of researchers from the University of British Columbia in Vancouver, Canada, and their collaborators set out to assess the genetic diagnostic capability of NGS in a group of patients with atypical cerebral palsy (ACP).
Next-generation sequencing is a type of DNA sequencing technology (accounting for a number of different platforms) that has revolutionized genomic research and allows an entire human genome to be sequenced within a single day.
Patients, which included children and adults, participating in the study were selected based on a series of eligibility criteria, including the presence of motor impairments at birth, or during the first year of life, and at least one of the following:
- severe intellectual disability, or other abnormalities found during neurological examination
- multiorgan disease
- congenital abnormalities outside the central nervous system (composed of the brain, brainstem, and cerebellum)
- family history of CP
- presence of neurological abnormalities not linked to CP
In addition, all selected patients must have undergone previous neurological and/or genetic assessments that failed to identify a specific cause for their condition.
In total, 50 patients from 49 different families were selected to participate in the study. Of these, NGS managed to establish a specific molecular diagnosis for 33 patients (65%). The genetic causes in the remaining 17 patients (35%) remained unknown.
“In 28/49 families, the ACP was attributed to a known disease gene(s) and in four cases we propose novel candidate genes that at present lack an associated OMIM disease designation (DGKZ, EPHA4, PALM, PLXNA2),” the researchers wrote. OMIM is a compendium of human genes that contains information on all known genetic disorders and more than 15,000 genes.
Half of the ACP genetic variants identified in the study had a dominant inheritance pattern, that is, only one copy of the mutated variant was enough to trigger the disease, and more than half (67%) were missense variants, which are single nucleotide — the building blocks of DNA — mutations that alter protein composition.
By the end of the study, targeted and personalized therapeutic interventions designed to assist patients in managing their condition were adopted in eight families (15%).
“For many families in this study, a molecular diagnosis assisted to end the diagnostic odyssey, improved genetic counseling, and directed access to services and resources in the community,” the scientists wrote.
“These [findings] emphasize the power of ES in diagnostics, but also underscore the critical role of the physician in detailed clinical phenotyping and the necessary communication and feedback that must exist between clinician and bioinformatics specialist for an accurate molecular diagnosis,” they concluded.