NEW YORK – With the help of parent-child trio genome sequencing, a Canadian team has identified suspicious germline genetic variants in a subset of cerebral palsy cases, pointing to multifactorial processes that may contribute to the childhood movement disorder, which sometimes includes cognitive or behavioral symptoms.
"Our findings are a step forward in better understanding the complex genetic and environmental risk factors that may determine an individual's chance of developing this complex condition to help individualize future treatment approaches," Maryam Oskoui, one of the team leaders and director of the Montreal Children's Hospital neurology division, as well as a senior clinician scientist affiliated with the McGill University Health Centre, said in a statement.
As they reported in Nature Genetics on Friday, Oskoui and colleagues from the Hospital for Sick Children (SickKids), McGill University Health Centre, and the Holland Bloorview Kids Rehabilitation Hospital sequenced the genomes of 327 well-phenotyped children with cerebral palsy and, when possible, their parents.
They also included genome profiles from 292 more children in two pediatric/parent-child cohorts and three clinical cohorts comprising nearly 2,900 individuals in their analysis, which focused on potential genetic contributors to cerebral palsy, a childhood-onset condition marked by motor skill development problems.
While cerebral palsy has been linked to environmental factors ranging from injury or infection to lack of oxygen at or before birth, the team explained, the latest findings highlight the previously unappreciated role that germline genetic changes can have in the disease process.
"For 100 years, cerebral palsy was mostly thought to be the result of entirely environmental factors during birth," co-senior and corresponding author Stephen Scherer, chief of research with the SickKids' Genetics and Genome Biology program and director of SickKids' Centre for Applied Genomics, said in a statement. "Now that we have a better understanding into the complex relationship between cerebral palsy's genetic and environmental factors, we hope we can improve care for these children."
In particular, he and his colleagues uncovered pathogenic or likely pathogenic germline alterations — ranging from SNPs or small insertions or deletions to copy number variants, aneuploidies, or mitochondrial sequence changes — in 11.3 percent of the 327 cerebral palsy-affected children sequenced. Nearly 18 percent more carried variants of uncertain significance, suggesting there may be additional genetic contributors that have not yet been uncovered.
"Many of the children we see come through our doors have genetic variations that are associated with their cerebral palsy," co-first author Darcy Fehlings, a senior clinician scientist with the Holland Bloorview Kids Rehabilitation Hospital, said in a statement.
"This opportunity for precision medicine is of utmost importance to accurately diagnose etiology across all children with [cerebral palsy], improve family counseling, and choose interventions (medical and rehabilitation) best suited for the child," Fehlings added.
The pathogenic or likely pathogenic variants spanned 19 genes, the team explained, turning up most frequently in the collagen type IV alpha-subunit-coding gene COL4A1, which has been implicated in cerebral palsy and cerebrovascular diseases.
More than a dozen of the genes overlapped with genes affected by pathogenic or likely pathogenic variants in the clinical cohorts in the study, meanwhile, including genes linked to cerebral palsy or other neuromotor conditions.
When the researchers considered de novo variant burden and transmission disequilibrium patterns, they saw an overrepresentation of genes involved in autism spectrum disorder (ASD), schizophrenia, or other neurological or nervous system processes.
The team noted that pathogenic or likely pathogenic alterations turned up in a handful of candidate genes not linked to cerebral palsy in the past, including SMOC1, KDM5B, BCL11A, and CYP51A1.
Based on their findings, the authors suggested that a significant subset of children with cerebral palsy carry pathogenic or likely pathogenic variants that could be unearthed by diagnostic genome sequencing. Even so, nearly three-quarters of patients with pathogenic or likely pathogenic variants had perinatal or environmental risk factors, as well, consistent with "multifactorial causal pathways including genetic risk leading to [cerebral palsy]."
"Understanding the genetic underpinnings of [cerebral palsy] is of utmost importance to accurately diagnose etiology, improve family counseling, use targeted interventions where available, and avoid treatments that may be harmful," the authors wrote, noting that "[g]enetic testing will enable earlier identification of [cerebral palsy] 'mimics,' allowing earlier targeted treatment and appropriate counseling."
Genome sequencing data from the study will be available through an Ontario Brain Institute-managed analytics and informatics platform dubbed the Brain-CODE Neuroinformatics Platform.