J Hum Genet. 2026 May 29. doi: 10.1038/s10038-026-01482-x. Online ahead of print.
ABSTRACT
Given the increasing number of diseases for which causative genes have been identified, we are facing the need for implementing comprehensive genome sequence analysis as a molecular diagnostic system for patients with hereditary diseases in daily clinical practice. We established a laboratory-developed test (LDT) with the implementation of whole-exome sequence analysis (WES) as the clinical sequencing system at an academic institution. WES was conducted on 81 patients with suspected hereditary disorders referred from clinical departments in our hospital from 2021 to 2024. Target genes were selected on the basis of the clinical presentations of the patients and expanded when necessary. Additional analyses, including copy number and zygosity analyses, further improved the diagnostic accuracy. The overall diagnostic yield was 42.0%, excluding four patients with transthyretin cardiac amyloidosis confirmed as wild-type ATTR Amyloidosis (ATTRwt). High diagnostic yields were associated with the presence of family histories. Secondary findings were searched in 73 patients, and pathogenic or likely pathogenic variants were disclosed to three patients, leading to their subsequent clinical follow-up. Internal and external quality controls ensured analytical reliability. This study demonstrates that the implementation of LDT-based comprehensive genome analysis is highly useful in daily clinical practice, achieving a high diagnostic yield comparable to those in previous large-scale studies; furthermore, the clinical sequencing seamlessly harmonizes the research-level investigations, providing highly valuable results. Broader insurance coverage will be essential for expanding equitable access to the genetic tests based on comprehensive genome sequence analysis.
PMID:42215795 | DOI:10.1038/s10038-026-01482-x