P188: Clinical and personal utility of population screening for neurodevelopmental psychiatric copy number variants and sex chromosome aneuploidies in 580 adults

elevated LDL-C, (ii) the first prescription of statin, and (iii) a phenotype score developed by fitting a logistic regression model based on 264 phenotypes with known relevance to atherosclerotic disease.Positive controls were individuals with the established APOB pathogenic variants (p.Arg3527Gln and p.Arg3527Trp) as well as those with pathogenic variants in LDLR.Results: Ninety-three participants (0.07%) had a truncating variant in APOB, and 127 had one of the two APOB p.Arg3527 pathogenic variants.Participants with a truncating variant in APOB had fewer and later onset documented elevations in LDL-C compared to those without a variant (Hazard Ratio (HR) = 0.09 (0.01-0.6)), or to those with pathogenic variants.The same result was observed for the date of first statin prescription (HR = 0.14 (0.05-0.4).Aligning with these clinical observations, we find that truncating variants are associated with lower than average LDL-C levels, up through the last exon of the APOB gene by using the Power Window method (an optimized sliding window approach to identify key regions of a gene associated with a phenotype).Conclusion: This population study provides strong evidence that truncating variants in APOB do not cause Familial Hypercholesterolemia.For variant interpretation, these variants should not be returned as VUS, and we suggest to automatically call them as benign in the context of Familial Hypercholesterolemia. A similar approach can be used for all genes where haploinsufficiency is not the mechanism of disease.Clear evidence that pLOF variants are not pathogenic in these scenarios will reduce the burden of variant interpretation without decreasing the accuracy of the screening.