Utility of Next Generation Sequencing in Paediatric Neurological Disorders: experience from South Africa

Abstract Next generation sequencing (NGS)-based tests have become routine first-line investigative modalities in paediatric neurology clinics in many high-income countries (HICs). Studies from these countries show that these tests are both cost-effective and reliable in diagnosing many complex childhood neurological diseases; however, NGS-based testing in low-and middle-income countries (LMICs) is limited due to cost. The primary objective of this study was to evaluate the diagnostic yield and impact of targeted gene panels in a selected paediatric cohort attending a tertiary paediatric neurology clinic in the Western Cape Province of South Africa. This retrospective study included 124 consecutive paediatric patients with neurological disease, referred for multi-gene panel testing over a 41-month period. Twenty-four different disease group-specific panels were utilized. A caregiver experience questionnaire was administered when a pathogenic variant was identified. The overall study diagnostic yield (DY) was 53% (66/124 patients). It was highest for neuromuscular disorders 64% (16/25), cerebral palsy spectrum disorders 54% (9/16) and early-onset epilepsies 44% (28/63). Testing proved inconclusive (variants of uncertain significance) in 38% (47/124). The majority of caregivers (97%) viewed NGS-based testing as a positive experience. The diagnostic yield in this study is similar to previously reported paediatric cohorts in HICs. The high yields for neuromuscular disorders and early epileptic encephalopathies suggest that NGS-based panels may be more cost-effective as first-line testing in well-defined phenotypes. The latter finding argues for early inclusion of all children with developmental epileptic encephalopathies (DEE), as early diagnosis leads to better treatment and avoidance of unnecessary investigations.