Exploring a genetic etiology
In considering the etiologies of CP, it is important to note that 21% to 40% of individuals with CP have an associated congenital anomaly, suggesting a genetic origin in at least some individuals. Moreover, a 40% heritability has been estimated in CP, which is comparable to the heritability rate for autism spectrum disorders.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. The yield was highest with CP and intellectual disability and CP with all 3 comorbidities. A few genes were particularly common, and some were reported previously in association with CP and/or other neurodevelopmental disorders. In some patients, variants were found in genes or gene regions associated with disorders that do not frequently include CP, such as Rett syndrome.3
Implications for ObGyns
The data from the study by Moreno-De-Luca and colleagues are interesting and relevant to pediatricians, neurologists, and geneticists, as well as obstetricians. Understanding the cause of any disease or disorder improves care, including counseling regarding the cause, the appropriate interventions or therapy, and in some families, the recurrence risk in another pregnancy. The treatment for CP has not changed significantly in many years. Increasingly, detection of an underlying genetic cause can guide precision treatments; thus, the detection of specific gene variants allows a targeted approach to therapy.
Identification of a genetic cause also can significantly impact recurrence risk counseling and prenatal diagnosis options in another pregnancy. In general, the empiric recurrence risk of CP is quoted as 1% to 2%,13 and with de novo variants this does not change. However, with inherited variants the recurrence risk in future children is substantially higher. While 72% of the genetic variants associated with CP in the Moreno-De-Luca study were de novo with a low recurrence risk, in the other 28% the mode of inheritance indicated a substantial risk of recurrence (25%–50%) in another pregnancy.3 Detecting such causative variant(s) allows not only accurate counseling about recurrence risk but also preimplantation genetic testing or prenatal diagnosis when recurrence risk is high.
In the field of obstetrics, the debate about the etiology of CP is important largely due to the medicolegal implications. Patient-oriented information on the internet often states that CP is caused by damage to the child’s brain just before, during, or soon after birth, supporting potential blame of those providing care during those times. Patient-oriented websites regarding CP do not list genetic disorders among the causes but rather include primarily environmental factors, such as prematurity, low birth weight, in utero infections, anoxia or other brain injury, or perinatal stroke. Even the Centers for Disease Control and Prevention website lists brain damage as the primary etiology of CP.14 Hopefully, these new data will increase a broader understanding of this condition.
Exome sequencing is now recommended as a first-tier test for individuals with many neurodevelopmental disorders, including epilepsy, intellectual disability, and autism spectrum disorder.15 However, comprehensive genetic testing is not typically recommended or performed in cases of CP. Based on recent data, including the report by Moreno-De-Luca and colleagues, it would seem that CP should be added to the list of disorders for which exome sequencing is ordered, given the similar prevalence and diagnostic yield. ●