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Clinical and Molecular Characterization of 2p16.1-p15 Microduplications: A Genotype-Phenotype Analysis

Creative Commons 'BY' version 4.0 license

Advances in genetic testing technology, specifically the development of chromosomal microarray analysis, made it possible to accurately identify submicroscopic duplicated or deleted regions across the genome. Microarray testing is now a first-tier diagnostic test for individuals with unexplained intellectual disability, developmental delay, or congenital anomalies, due to the ability to detect chromosomal alterations much smaller than classic cytogenetic techniques such as karyotype. The widespread use of microarray testing has led to the rapid discovery of novel microduplications and microdeletions, including 2p16.1-p15 Microdeletion Syndrome. While both deletions and duplications within this region are rare, enough patients with 2p16.1p15 microdeletions and a characteristic set of phenotypic features have been reported for the condition to be classified as a distinct syndrome. Individuals with 2p16.1-p15 Microdeletion Syndrome share clinical manifestations including moderate to severe intellectual disability, developmental delay, structural brain abnormalities, and a distinct pattern of dysmorphic craniofacial features. Reports of patients with microduplications within this same region, however, are much more limited and associated clinical manifestations are still being discovered and characterized. This study surveyed the treating clinicians of patients with 2p16.1-p15 microduplications, in order to investigate whether a similar syndromic association exists for duplications of this region. Detailed clinical and molecular genetic characteristics of 9 patients with duplications either within or including the 2p16.1-p15 chromosomal region were collected and are presented here. The most common clinical characteristics reported included neurodevelopmental abnormalities (89% cases), structural or signaling brain abnormalities (67% cases), cardiovascular abnormalities (67% cases), and dysmorphic facial features involving the ears (78% cases), periorbital region (67% cases), lips, mouth, or oral region (67% cases), and nose (44%). These findings are consistent with the clinical features reported in previously published cases of 2p16.1p15 microduplications, and interestingly, some of the features reported in patients with 2p16.1p15 microdeletions, suggesting that disruption of genes within this region may have syndromic consequences due to haploinsufficiency or triplosensitivity. Additionally, specific abnormalities appeared to segregate with duplications containing more distal or proximal breakpoints, suggesting that triplosensitivity of specific gene(s) located at either end of the region of interest may be responsible for certain features; however, more research is necessary to confirm this hypothesis. The standardized compilation of detailed phenotype data included in this report provides clinicians with additional information on the features associated with this rare condition, that can be used to better guide medical management, screening, and genetic counseling, ultimately benefiting patients and their families.

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