Chromosomal Microarray Analysis in Clinical Evaluation of Neurodevelopmental Disorders-Reporting a Novel Deletion of SETDB1 and Illustration of Counseling Challenge

BACKGROUND: The pathogenicity of copy number variations (CNV) in neurodevelopmental disorders is well supported by research literature. However, few studies have evaluated the utility and counseling challenges of CNV analysis in the clinic. METHODS: We analyzed the findings of CNV studies from a cohort referred for clinical genetics evaluation of autism spectrum disorders (ASD), developmental disability (DD), and intellectual disability (ID). RESULTS: Twenty-two CNV in 21 out of 115 probands are considered to be pathogenic (18.3%). Five CNV are likely pathogenic and 22 CNV are variants of unknown significance (VUS). We have found 7 cases with more than 2 CNV and 2 with a complex rearrangement of the 22q13.3 Phelan-McDermid syndrome region. We identified a new and de novo 1q21.3 deletion that encompasses SETDB1, a gene encoding methylates histone H3 on lysine-9 (H3K9) methyltransferase, in a case with typical ASD and ID. CONCLUSIONS: We provide evidence to support the value of CNV analysis in etiological evaluation of neurodevelopmental disorders. However, interpretation of the clinical significance and counseling families are still challenging because of the variable penetrance and pleotropic expressivity of CNVs. In addition, the identification of a 1q21.3 deletion encompassing SETDB1 provides further support for the role of chromatin modifiers in the etiology of ASD.