A rare triplication of 16p11.2: Unravelling the genomic complexity and review of the literature

16p11.2 triplication is a rare chromosomal disorder associated with developmental delay, behavioral abnormalities, and various dysmorphic features. Here, we present a case study of a four-year-old girl with 16p11.2 triplication, whose healthy father has a smaller 16p11.2 duplication that partially overlaps with that of the daughter. She has a global developmental delay, autism spectrum disorder, anxiety, and sensory processing issues, alongside dysmorphic features. Genetic analysis revealed triplication within the 16p11.2 duplication region. We used different technical approaches to pinpoint the exact genetic architecture of the triplication and to gain further functional insights. Using array-CGH and Fluorescence In Situ Hybridization (FISH), we detected the location of the triplication. We later sought to confirm this with Oxford Nanopore Technologies (ONT); however, detecting duplications and triplications proved to be challenging. Finally, RNA sequencing showed overexpression of genes within the triplication region, including INO80E, PAGR1, SPN, KIF22, HIRIP3, TAOK2, and TMEM219, some of which had been associated with neurodevelopmental disorders and/or increased body mass index by GWAS (1). Our findings contribute to the understanding of the phenotypic spectrum and molecular mechanisms of 16p11.2 triplication. Moreover, the challenges in detecting triplications using current sequencing methods highlight the need for improved diagnostic techniques.