Abstract
BACKGROUND: Exome sequencing (ES) is now widely accepted as an appropriate first-tier diagnostic test for developmental disorders (DD). International guidelines recommend that in diagnostic settings, ES findings be validated with an orthogonal method, such as Sanger sequencing, before reporting. However, more recent guidance recognizes that confirmatory testing for variants meeting strict quality criteria is redundant. Weighing up the cost to benefit ratio of this practice is crucial in settings where ES is not routinely implemented. The Deciphering Developmental Disorders in Africa (DDD-Africa) study aims to enable equitable implementation of genomic medicine in low-resourced settings, focusing on using ES in resolving DD in Africa. METHODS: We performed confirmatory Sanger sequencing for the first 64 probands (70 variants) that underwent ES in which a variant of interest was identified. Strict quality parameters were key to diminishing the observation of false-positive variants. RESULTS: All high confidence variants identified by ES (n = 38) were confirmed using Sanger sequencing and low confidence variants (n = 32) were confirmed as false-positive. CONCLUSION: Confirming ES results with an orthogonal approach like Sanger sequencing is unnecessary in a resource-limited setting when robust, context-informed quality thresholds are applied. This recommendation removes significant barriers to the implementation of genomic medicine and allows for accelerated genomic access globally.