Eur J Hum Genet . 2022 Jun;30(6):712-720. doi: 10.1038/s41431-022-01094-x.

Highly identical segmental duplications (SDs) account for over 5% of the human genome and are enriched in the short arm of the chromosome 16. These SDs are susceptibility factors for recurrent chromosomal rearrangements mediated by non-allelic homologous recombination (NAHR). Chromosomal microarray analysis (CMA) has been widely used as the first-tier test for individuals with developmental disabilities and/or congenital anomalies and several genomic disorders involving the 16p-arm have been identified with this technique. However, the resolution of CMA and the limitations of short-reads whole genome sequencing (WGS) technology do not allow the full characterization of the most complex chromosomal rearrangements. Herein, we report on two unrelated patients with a de novo 16p13.11p11.2 triplication associated with a 16p11.2 duplication, detected by CMA. These patients share a similar phenotype including hypotonia, severe neurodevelopmental delay with profound speech impairment, hyperkinetic behavior, conductive hearing loss, and distinctive facial features. Short-reads WGS could not map precisely any of the rearrangement's breakpoints that lie within SDs. We used optical genome mapping (OGM) to determine the relative orientation of the triplicated and duplicated segments as well as the genomic positions of the breakpoints, allowing us to propose a mechanism involving recombination between allelic SDs and a NAHR event. In conclusion, we report a new clinically recognizable genomic disorder. In addition, the mechanism of these complex chromosomal rearrangements involving SDs could be unraveled by OGM.