23. Incidental findings on XON array: Our experience over the last two years

Abstract

Exon-level copy number variation (CNV) can be difficult to assess using whole-exome sequencing (WES) or whole-genome SNP microarray (CMA). The clinical implementation of the CytoScan XON array has allowed for the evaluation of exon-level CNVs that previously were either difficult to identify or missed entirely by preceding testing methods. Increasing the resolution of detection has not only aided in diagnosis of recessive disorders in which exome analysis identified a single variant within a candidate gene, but has also been useful in the diagnosis of dominant disorders in cases for which exome and/or CMA is negative. Furthermore, the increased resolution of detection in the assessment of exon-level CNVs has led to the discovery of significant incidental findings in a select few cases. In this report, we assess the prevalence and clinical significance of incidental findings detected by clinical XON array analysis over the last two years at the Greenwood Genetic Center. To illustrate our findings, four cases have been selected from approximately 300 to date with various clinical indications including: abnormal prenatal screening, hearing loss accompanied by developmental delay, and two cases with multiple congenital anomalies. For each case presented, previous testing was unremarkable and XON array analysis of phenotype-driven genes was negative. However, further analysis of the unmasked XON array data identified a potential causative aberration in each patient (e.g. exonic CNVs involving: CDH23, ARSA, PKD1 and ARID1A). This collection of cases not only demonstrates the utility and potential of the XON array in the context of complicated cases with unknown genetic etiology for which WES and CMA is negative, but provides further evidence for the importance of incidental findings in exon-level analysis.