Clinical exome sequencing: results from 2819 samples reflecting 1000 families

TLDR

The study recommends using WES as a first‑line diagnostic test for patients lacking a clear differential diagnosis to improve personalized care. Clinical data were coded into HPO terms and WES was performed under standardized protocols. Across 1000 WES cases from 2819 samples worldwide, pathogenic variants were found in 30.7% of families, variants of unknown significance in 25.3%, and WES demonstrated higher diagnostic yield in consanguineous, severe, syndromic, and multi‑symptom patients, confirming its clinical utility.

Abstract

We report our results of 1000 diagnostic WES cases based on 2819 sequenced samples from 54 countries with a wide phenotypic spectrum. Clinical information given by the requesting physicians was translated to HPO terms. WES processes were performed according to standardized settings. We identified the underlying pathogenic or likely pathogenic variants in 307 families (30.7%). In further 253 families (25.3%) a variant of unknown significance, possibly explaining the clinical symptoms of the index patient was identified. WES enabled timely diagnosing of genetic diseases, validation of causality of specific genetic disorders of PTPN23, KCTD3, SCN3A, PPOX, FRMPD4, and SCN1B, and setting dual diagnoses by detecting two causative variants in distinct genes in the same patient. We observed a better diagnostic yield in consanguineous families, in severe and in syndromic phenotypes. Our results suggest that WES has a better yield in patients that present with several symptoms, rather than an isolated abnormality. We also validate the clinical benefit of WES as an effective diagnostic tool, particularly in nonspecific or heterogeneous phenotypes. We recommend WES as a first-line diagnostic in all cases without a clear differential diagnosis, to facilitate personal medical care.