Reduced Diagnostic Yield of Whole Exome Sequencing in Patients With Chromosomal Microarray Detected Copy Number Variants of Uncertain Significance

Abstract Chromosomal microarray is a first-line genetic test for many individuals with neurodevelopmental disorders and congenital anomalies. A common outcome is identification of a copy number variant of uncertain significance (CNV VUS), frequently prompting referral to a clinical genetics service. In the setting of a CNV VUS finding, clinical geneticists often proceed to whole exome sequencing (WES) to determine whether an alternative molecular diagnosis is present. The aim of this study was to determine whether the diagnostic yield of WES differs in individuals with a chromosomal microarray-detected CNV VUS compared with those without a reportable CNV, and to use this difference to estimate the proportion of CNV VUS that are likely to be disease-causing. Individuals who underwent WES at Genetic Health Western Australia (January-December 2022) were included. Phenotype and results were collected from retrospective medical record review. Results found that 32/177 (18%) individuals who underwent WES had an abnormal finding on microarray. WES identified causative variants in 27% overall, with a lower diagnostic yield in those with CNV VUS than those without (11% vs. 30%, p = .023). No diagnoses were made on WES for the 13 patients who had CNV VUS duplications ( p = .020), nor for the 16 individuals with CNV VUS 0.6Mb or larger ( p = .006). It was concluded that individuals with a CNV VUS had a significantly lower diagnostic yield from WES, suggesting that many reportable CNV VUS identified by chromosomal microarray are themselves responsible for the presenting phenotype. Based on the observed difference in diagnostic yield, approximately half of CNV VUS may represent the underlying molecular diagnosis.