Regular ArticleGenomics in Cerebral Palsy phenotype across the lifespan: Comparison of diagnostic yield between children and adult population
Introduction
A common definition for Cerebral Palsy (CP) is “a group of permanent disorders of the development of movement and posture, causing activity limitations, that are attributed to non-progressive disturbances that occurred in the developing fetal or infant brain”. However, it is now accepted that CP is an umbrella term for a group of clinically defined conditions [1] which include different motor presentations, with heterogeneity as relates to the etiology, type, severity and associated features. In recent years it has been suggested to use the term “cerebral palsy spectrum disorder”, considering that the term CP cannot cover this wide spectrum of heterogeneous disease [2]. In the etiology of CP there are multiple metabolic and genetic conditions [[3], [4], [5]] adding to the diagnostic complexity. Moreover, signs and symptoms may further change over time and present differently in children in comparison to adult patients.
With a prevalence of CP of approximately 2–3 in 1000 live births, intellectual disability (ID) in 2–3% in general population [6], and Neurodevelopmental disorders (NDD) affecting >3% of children [7], CP can be more commonly diagnosed across the lifespan.
Research on differential yield of genetic testing for adults with ID [8], as well literature on individuals: children and adults with epilepsy and comorbid ID [9], advocate for improving access for genetic testing for adults and compare the utility between these two populations.
Currently, the majority of genetic testing is conducted in the pediatric patient population and the yield of investigation for diagnostic and management purposes in adults with CP phenotype is not well described in general, and specifically as compared to pediatric patients.
We present the data of NGS in a pediatric and adult patient group in two Canadian tertiary care centres, between the years 2015–2020 (adult cohort) and 2017–2020 (pediatric cohort) respectively.
Section snippets
Ethics
The study was approved by the Vancouver General Hospital, University of British Columbia Ethics Board (#H19–02511). Retrospective chart review of patients fulfilling eligibility criteria was performed in the Adult Metabolic Diseases Clinic.
The pediatric study was approved by the University of Alberta Ethics Board (HREB B Pro00056682 REN 2,3). Retrospective chart review of patients fulfilling eligibility criteria was performed in the pediatric neurometabolic clinic.
Patients
In the Adult Metabolic
Results
A total of 37 patients were eligible for the adult study. Out of these, 28 patients had a genetic diagnosis and 9 patients had either negative WES results, or were variants that cause autosomal recessive conditions and no other variant was found in the gene (Table 1). The yield for positive diagnosis was 75.6%. One patient who had a negative WES was later diagnosed with Juvenile Huntington disease (79 CAG repeats in HTT). Out of the total number of patients with positive diagnosis, 15 were
Discussion
The utility of Next Generation Sequencing for molecular diagnosis of patients with Cerebral Palsy has been previously studied. The overall diagnostic yield for pediatric patients presenting with CP is quite variable, the largest case series investigating 250 children reporting only a 14% diagnostic yield [10], but can be also higher, such as 65% as shown in our previous report [11], or 53 and 55% [12,13]. There have been no case series reported for adult patients presenting with clinical
Conclusions
There is growing evidence that genetic mutations can be responsible for a proportion of CP cases. In the era of genomic investigations there is a high likelihood that children will be screened for these, as it is demonstrated by the establishment in 2018 of the Cerebral Palsy Genomics Consortium [16]. As genetic investigations continue, more and more genes will be added to the list of genetic causes of CP, advancing our understanding of the genotype-phenotype correlation.
Establishing a genetic
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Cited by (0)
- 1
Present address: Department of Pediatrics, Ministry of the National Guard-Health Affairs, Jeddah, Saudi Arabia.
- 2
Present address: King Abdullah International Medical Research Center, Jeddah, Saudi Arabia.
- 3
These two authors have contributed equally to the manuscript.