Cerebral palsy and related neuromotor disorders: Overview of genetic and genomic studies

Cerebral palsy (CP) is a debilitating condition characterized by abnormal movement or posture, beginning early in development. Early family and twin studies and more recent genomic investigations clearly demonstrate that genetic factors of major effect contribute to the etiology of CP. Most copy number variants and small alterations of nucleotide sequence that cause CP arise as a result of de novo mutations, so studies that estimate heritability on basis of recurrence frequency within families substantially underestimate genetic contributions to the etiology. At least 4% of patients with typical CP have disease-causing CNVs, and at least 14% have disease-causing single nucleotide variants or indels. The rate of pathogenic genomic lesions is probably more than twice as high among patients who have atypical CP, i.e., neuromotor dysfunction with additional neurodevelopmental abnormalities or malformations, or with MRI findings and medical history that are not characteristic of a perinatal insult. Mutations of many different genetic loci can produce a CP-like phenotype. The importance of genetic variants of minor effect and of epigenetic modifications in producing a multifactorial predisposition to CP is less clear. Recognizing the specific cause of CP in an affected individual is essential to providing optimal clinical management. An etiological diagnosis provides families an "enhanced compass" that improves overall well-being, facilitates access to educational and social services, permits accurate genetic counseling, and, for a subset of patients such as those with underlying inherited metabolic disorders, may make precision therapy that targets the pathophysiology available. Trio exome sequencing with assessment of copy number or trio genome sequencing with bioinformatics analysis for single nucleotide variants, indels, and copy number variants is clinically indicated in the initial workup of CP patients, especially those with additional malformations or neurodevelopmental abnormalities.