Revisiting the genetics of cerebral palsy

CP. Over the last few years, a range of high-impact publications have revolutionized our understanding of the genetics of cerebral palsy (CP). While CP is traditionally thought of as an exclusively acquired disorder, massive parallel sequencing studies have suggested causative genetic etiologies in up to 30% of individuals. Here is an overview of the emerging genetics of CP through the lens of neurodevelopmental disorders, questioning some of the assumptions that are typically made when comparing both disease groups.

Figure 1. A comparison of frequencies of causative genetic etiologies in two large genetics studies on cerebral palsy and neurodevelopmental disorders. The above figure compares frequency in the meta-analysis by Gonzalez-Mantilla in 2023 on 2612 individuals with cerebral palsy with the frequencies of de novo variants in 31,000 individuals with neurodevelopmental disorders as reported by Kaplanis and collaborators in 2020.

Cerebral palsy. In 2020, the first major publication on the genetics of cerebral palsy was published in Nature Genetics by Jin and collaborators. The authors introduced their study by taking a large historical sweep, invoking the history of CP as initially described by Little, Osler and Freud. Yes, the founder of psychoanalysis had been involved in thinking about pediatric neurology prior to writing the Interpretation of Dreams. The National Institute for Neurological Disorders and Stroke (NINDS) defines CP as a group of neurological disorders that appear in infancy or early childhood and permanently affect body movement and muscle coordination. CP is caused by damage to or abnormalities inside the developing brain that disrupt the brain’s ability to control movement and maintain posture and balance. In child neurology, CP is typically considered the result of a static lesion in early childhood and is typically caused by an acquired brain lesion, such as an hypoxic-ischemic brain injury.

Mimickers. In a significant subset of individuals, the degree of brain injury does not seem to align with the degree of neurological deficits. It is this group of individuals where the identification of genetic etiologies may both provide an explanation for an individual’s disease and provide new avenues for treatment. For example, individuals with DOPA-responsive dystonia due to disease-causing variants in GCH1 may present with clinical features similar to a static brain injury, but are significantly improved with L-DOPA. However, thinking about the genetics of cerebral palsy more broadly sometimes feels like moving into unknown territory, a feeling that we recently experienced in our weekly ENGIN teaching session. From the perspective of a team involved in epilepsy genetics and neurogenetics, thinking about genes for cerebral palsy raises the issue whether we are looking at an overlapping spectrum or whether the genetic etiology of CP is somewhat unique. In brief, the answer is: both.

CP genes. In the initial study by Jin and collaborators, the authors suggested that genetic etiologies involved in CP are related to neuritogenesis in addition to identifying an overlap of candidate genes for cerebral palsy risk genes with genes for neurodevelopmental disorder. Analyzing 250 patient-parent trios, the authors identified eight genes with multiple de novo mutations, including TUBA1A and CTNNB1 achieving genome-wide significance. Two novel monogenic etiologies emerged from the study by Jin and collaborators, namely FBXO31 and RHOB. In a meta-analysis by Gonzalez-Mantilla and collaborators in 2023, the authors identified the following genes as the genetic etiologies with the highest frequency of disease-causing variants in cerebral palsy: CTNNB1, SPAST, GNAO1, ATL1, CACNA1A, TUBB4A, COL4A1, KCNQ2, TUBA1A, KIF1A, MECP2, FOXG1, SCN1A. Looking from a neurogenetic angle, this list of genes requires some context. In Figure 1, we have compared the frequency of these 10 genes in cerebral palsy to the frequency of de novo variants in neurodevelopmental disorders, using the data generated by Kaplanis and collaborators in 2020. Here are the patterns that emerge from this data.

Gene groups. Comparing overall frequencies in CP compared to neurodevelopmental disorders, the following five categories of genetic etiologies stand out, including (1) genes implicated in hereditary spastic paraplegia such as SPAST1 and ATL1, (2) genes implicated in tubulinopathies such as TUBA1A or TUBB4A, (3) genes for hyperkinetic movement disorders such as GNAO1, and (4) genes implicated in prenatal or neonatal intracerebral hemorrhage, resulting in porencephaly and periventricular leukomalacia including COL4A1. Distinct genetic etiologies with a clinical CP presentation such as CTNNB1 represent the fifth subgroup. In brief, de novo variants in CTNNB1 have been found to result in a relatively homogeneous phenotype of truncal hypotonia with nonprogressive peripheral spasticity or hypertonia. The presence of these five groups suggests that genetic CP is not a homogeneous condition, but a group of neurogenetic disorders that present more frequently with CP-related symptoms due to at least five different disease mechanisms. This heterogeneity of mechanisms underlines the need for genomic testing in individuals with CP as the various genetic etiologies may require different treatment strategies. For examples, individuals with disease-causing variants in GNAO1 may benefit from deep-brain stimulation, while individuals with COL4A1 may require surveillance for vasculopathies.

What you need to know. The genetics of cerebral palsy is a relatively new field of research, changing paradigms on how the diagnostic work-up in individuals with cerebral palsy is performed. With a diagnostic yield of up to 30% in some studies, better insight into the underlying genetic etiologies may hold the key for better treatments, helping the field of cerebral palsy research to take part in the genomic revolution and development of precision medicines.

Ingo Helbig is a child neurologist and epilepsy genetics researcher working at the Children’s Hospital of Philadelphia (CHOP), USA.