Integrated omics analyses clarifies ATRXcopy number variant of uncertain significance

Partial duplications of genes can be challenging to detect and interpret and, therefore, likely represent an underreported cause of human disease. X-linked dominant variants in ATRXare associated with Alpha-thalassemia/impaired intellectual development syndrome, X-linked (ATR-X syndrome), a clinically heterogeneous disease generally presenting with intellectual disability, hypotonia, characteristic facies, genital anomalies, and alpha-thalassemia. We describe an affected male with a de novo hemizygous intragenic duplication of ~43.6 kb in ATRX, detected by research genome sequencing following non-diagnostic clinical testing. RNA sequencing and DNA methylation episignature analyses were central in variant interpretation, and this duplication was subsequently interpreted as disease-causing. This represents the smallest reported tandem duplication within ATRXassociated with disease. This case demonstrates the diagnostic utility of integrating multiple omics technologies, which can ultimately lead to a definitive diagnosis for rare disease patients.