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

Abstract

Cerebral palsy (CP) is the most common cause of childhood physical disability, with incidence between 1/500 and 1/700 births in the developed world. Despite increasing evidence for a major contribution of genetics to CP aetiology, genetic testing is currently not performed systematically. We assessed the diagnostic rate of genome sequencing (GS) in a clinically unselected cohort of 150 singleton CP patients, with CP confirmed at >4 years of age. Clinical grade GS was performed on the proband and variants were filtered, and classified according to American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines. Variants classified as pathogenic or likely pathogenic (P/LP) were further assessed for their contribution to CP. In total, 24.7% of individuals carried a P/LP variant(s) causing or increasing risk of CP, with 4.7% resolved by copy number variant analysis and 20% carrying single nucleotide or indel variants. A further 34.7% carried one or more rare, high impact variants of uncertain significance (VUS) in variation intolerant genes. Variants were identified in a heterogeneous group of genes, including genes associated with hereditary spastic paraplegia, clotting and thrombophilic disorders, small vessel disease, and other neurodevelopmental disorders. Approximately 1/2 of individuals were classified as likely to benefit from changed clinical management as a result of genetic findings. In addition, no significant association between genetic findings and clinical factors was detectable in this cohort, suggesting that systematic sequencing of CP will be required to avoid missed diagnoses.

Fig. 1. Summary of clinical characteristics of the study cohort.

Clinical descriptions for each individual in the cohort are in Supplementary Table 1. a Availability of parental samples. b Sex. c Motor type and Topography (n = 150): Cases were classified according to topography categories: hemiplegia, diplegia or triplegia/quadriplegia. For motor type, cases with any report of dyskinetic/dystonic motor type are reported as dystonic. d Neonatal data: Gestational age was confirmed by case note review (n = 137). Personalised birth weight centiles for this cohort were calculated using the Gestation Related Optimal Weight (GROW) software which accounts for individual physiological pregnancy variables (n = 118). e Comorbidities: Comorbidities were reported by parents and confirmed by clinical review where possible. Developmental delay reported in this cohort may include intellectual delays, as well as motor and other developmental delays. Data available: Autism n = 113, Developmental delay n = 130, Epilepsy n = 124, Visual impairment n = 116, Hearing impairment n = 110, Congenital abnormality n = 117.

Fig. 2. Percentage of cases with a clinically reportable variant by clinical characteristic.

For each clinical characteristic, only individuals for whom data were available are shown, with percentages calculated based on individuals having a variant interpreted as P/LP and causative or a risk factor for CP. Sample sizes: a Sex: Male, n = 93, Female, n = 57; b Neonatal data: Premature, n = 54; Term, n = 83; Intrauterine growth restriction (IUGR), n = 78; No growth restriction, n = 40; c Motor type and topography: Quadriplegia/triplegia, n = 44; Diplegia, n = 43; Hemiplegia, n = 62; Dystonic, n = 41; Ataxic, n = 1; Spastic, n = 142; d Comorbidities: Co-morbid, n = 88; No comorbidity, 49; Autism, n = 15, Developmental delay, n = 76, Epilepsy, n = 45.