46. Recurrent 16p13.11 Microduplications: A retrospective review of 16 cases identified at the University of North Carolina

      Recurrent 16p13.11 microduplications are mediated by segmental duplications within the 16p13.11-16p12.3 region [chr16:14781005-18793801 (GRCh37)], and have been associated with incomplete penetrance and variable expressivity involving a range of neurodevelopmental disorders including developmental delay (DD), intellectual disability (ID) and autism spectrum disorder (ASD). More rarely, congenital anomalies such as joint hypermobility, craniosynostosis, polydactyly and aortic disease have been reported. To further investigate the 16p13.11 microduplications, we reviewed 16 cases identified by chromosome microarray analysis at the University of North Carolina between May 2012 and October 2020. The microduplications ranged in size from 0.8 to 3.4 Mb, with each case encompassing the NDE1 and MYH11 genes that reside within the minimal region of overlap. Ten cases were analyzed and reported in-house and six were analyzed and reported by Integrated Genetics (LabCorp). Clinical information was obtained from each patient's electronic medical record. The clinical findings reported in our patient population correlate with what has previously been reported in the literature. The majority of our patients have been diagnosed with a neurodevelopmental disorder; one of these patients also has an aortic anomaly, which supports the need for cardiac evaluation in individuals with a 16p13.11 microduplication. Additionally, we observed the presence of other copy number variants (CNVs), apparent balanced translocations with concurrent karyotype analysis, and both inherited and de novo duplications. The 16p13.11 microduplication also serves as an interesting case study for variant classification as it has been reported in the literature as likely benign, a variant of uncertain significance (VUS), pathogenic with incomplete penetrance, and likely pathogenic in the context of DD/ID/ASD. Based on the 2020 ACMG and ClinGen technical standards for the interpretation and reporting of constitutional CNVs, we recommend that these 16p13.11 microduplications be classified and reported as VUS regardless of the patient's phenotype.
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