Insights From Genetic Studies of Cerebral Palsy

Abstract

Cohort-based whole exome and whole genome sequencing and copy number variant (CNV) studies have identified genetic etiologies for a sizable proportion of patients with cerebral palsy (CP). These findings indicate that genetic mutations collectively comprise an important cause of CP. We review findings in CP genomics and propose criteria for CP-associated genes at the level of gene discovery, research study, and clinical application. We review the published literature and report 18 genes and 5 CNVs from genomics studies with strong evidence of for the pathophysiology of CP. CP-associated genes often disrupt early brain developmental programming or predispose individuals to known environmental risk factors. We discuss the overlap of CP-associated genes with other neurodevelopmental disorders and related movement disorders. We revisit diagnostic criteria for CP and discuss how identification of genetic etiologies does not preclude CP as an appropriate diagnosis. The identification of genetic etiologies improves our understanding of the neurobiology of CP, providing opportunities to study CP pathogenesis and develop mechanism-based interventions.

Yield of clinically reportable genetic variants in unselected cerebral palsy by whole genome sequencing

“…P/LP variants in genes typically associated with HSP were a frequent finding in this cohort (13.5% of diagnoses, SPAST (two cases), TUBB4A , KIDINS220 and ALDH3A2 ), confirming previous observations of the clinical overlap between early onset HSP and CP 12 , 37 , 38 and adding to the growing list of HSP genes contributing to the genetic landscape of CP 36 , 39 . These findings also underline the value of genetic testing in families where other family members may be at risk of a later onset disorder.…”

A Newly Identified Int22h1/Int22h2‐Mediated Xq28 Duplication Syndrome Case Misdiagnosed as Cerebral Palsy

“…A low threshold for a more indepth investigation of CP cases should occur when: (1) there is an absence of antenatal/perinatal insults, (2) there is a positive family history of CP, (3) a developmental regression is observed, (4) there are additional neurological signs not classically associated with CP (e.g., oculomotor abnormalities, involuntary movements, ataxia, muscle atrophy, sensory loss), (5) there is progression in severity or to pyramidal/extrapyramidal dysfunction, or (6) there is presence of otherwise atypical findings. 3,17 The diagnostic workup should include a brain and brainstem MRI as well as extended metabolic and biochemical studies, including cerebrospinal fluid analysis in the presence of symptoms with marked circadian fluctuations suggestive of a metabolic disease (e.g., monoamine neurotransmitter disorders or GLUT1 deficiency syndrome). 17 When performing genetic testing, both chromosomal microarrays and sequencing of gene panels have significantly benefited from technological advances over the past decade, but if conclusive diagnosis remains elusive, WES can further boost the diagnostic yield.…”

Genetic testing and the future of cerebral palsy malpractice cases

“…A number of risk factors have been associated with CP (TABLE 1, page 42), 3,6 which contribute to cell death in the brain or altered maturation of neurons and glia, resulting in abnormal white matter tracts and smaller central nervous system (CNS) volume or cerebellar hypoxia. 6 One very important aspect of assessment for CP is specific gene mutations, which may vary in part dependent upon the presence or absence of environmental factors (insults). 1 Mutations can lead to profound adverse effects with…”

“…Risk factors for cerebral palsy3,6 FAST TRACK may have been simply abandoned or dismissed are not reported. Furthermore, most settlements include confidentiality clauses, which may preclude the release of the financial value of the settlement.…”