TY - JOUR T1 - ATR16 Syndrome: Mechanisms Linking Monosomy to Phenotype JF - bioRxiv DO - 10.1101/768895 SP - 768895 AU - Christian Babbs AU - Jill Brown AU - Sharon W. Horsley AU - Joanne Slater AU - Evie Maifoshie AU - Shiwangini Kumar AU - Paul Ooijevaar AU - Marjolein Kriek AU - Amanda Dixon-McIver AU - Cornelis L. Harteveld AU - Joanne Traeger-Synodinos AU - Douglas Higgs AU - Veronica Buckle Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/10/07/768895.abstract N2 - Background Sporadic deletions removing 100s-1000s kb of DNA, and variable numbers of poorly characterised genes, are often found in patients with a wide range of developmental abnormalities. In such cases, understanding the contribution of the deletion to an individual’s clinical phenotype is challenging.Methods Here, as an example of this common phenomenon, we analysed 34 patients with simple deletions of ∼177 to ∼2000 kb affecting one allele of the well characterised, gene dense, distal region of chromosome 16 (16p13.3), referred to as ATR-16 syndrome. We characterised precise deletion extent and screened for genetic background effects, telomere position effect and compensatory up regulation of hemizygous genes.Results We find the risk of developmental and neurological abnormalities arises from much smaller terminal chromosome 16 deletions (∼400 kb) than previously reported. Beyond this, the severity of ATR-16 syndrome increases with deletion size, but there is no evidence that critical regions determine the developmental abnormalities associated with this disorder. Surprisingly, we find no evidence of telomere position effect or compensatory upregulation of hemizygous genes, however, genetic background effects substantially modify phenotypic abnormalities.Conclusions Using ATR-16 as a general model of disorders caused by sporadic copy number variations, we show the degree to which individuals with contiguous gene syndromes are affected is not simply related to the number of genes deleted but also depends on their genetic background. We also show there is no critical region defining the degree of phenotypic abnormalities in ATR-16 syndrome and this has important implications for genetic counselling. ER -