Diagnostic implications of pitfalls in causal variant identification based on 4577 molecularly characterized families

The central aim was to characterize challenges that prevent causal variant identification despite advanced sequencing technologies. The authors found that non-technical, interpretation-related factors account for the majority of diagnostic failures, contradicting the common belief that technical limitations are the primary barrier. Addressing these interpretation challenges alone could potentially boost diagnostic yield by approximately 71%. The study describes 357 novel gene-disease assertions and adds recessive forms to 23 genes previously linked only to dominant phenotypes. It also identifies 85 important founder variants in the local population. A key limitation is that the insights are derived from a specific, highly consanguineous population, which may limit direct generalizability to outbred populations. The findings underscore the critical need for investment in improved interpretation pipelines alongside new sequencing technologies to realize the full diagnostic potential of clinical genomics.