8. A partial deletion of the EP300 gene detected by microarray in an individual with mild autism

      Current chromosomal microarray (CMA) methods identify deletions and duplications as small as ∼25 kilobases, thereby providing a useful test for clinically relevant copy number variants (CNVs). When a pathogenic CNV is identified by CMA, it is most often several hundred kilobases in size, encompassing multiple disease-associated genes. Here, we report a de novo 37 kilobase deletion of the terminal exons of the EP300 gene, detected by CMA in an individual with autism. The patient was a female diagnosed with mild autism as an adolescent; additional clinical indications included developmental delay, obesity, and congenital heart anomaly. Loss-of-function variants in the EP300 gene are reported to cause Rubinstein-Taybi syndrome, a condition characterized by short stature and intellectual disability, with variable features including obesity, respiratory problems, and/or cardiac anomalies. While a partial deletion of EP300 provided a likely cause of disease in our patient, we had to exercise caution due to the indefinite boundaries of CNVs as detected by CMA due to sparse probe coverage. Notably, while the deletion appeared to encompass the final four exons of the EP300 gene, it was possible that only the last 1-2 exons were deleted, thereby allowing the EP300 transcript to escape nonsense-mediated decay. Parental follow-up CMA testing did not detect the same partial EP300 deletion in either unaffected parent, confirming that the deletion occurred de novo and supporting a likely pathogenic role for this submicroscopic deletion. This is the first report of a deletion encompassing the terminal exons of the EP300 gene in an individual diagnosed with autism. In addition, our work highlights the importance of evaluating CNVs near the limit of detection of CMA when analyzing autistic patients.
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