P697: MYH11 triplosensitivity in TAAD and 16p13.11 microduplication syndrome: A supportive case series

variant(s) that were consistent with the phenotype reported in the proband and were consistent with the inheritance pattern of the associated disease.Cases were considered potentially positive if two or more variants with unknown phase were found in a gene with an autosomal recessive inheritance pattern if the disease association of that gene was consistent with the patient phenotype and at least one of the variants was classified as P/LP.Results: GS resulted in a positive or potentially positive finding in 29.8% (31/104) of all patients.In total, there were 43 variants reported in positive and potentially positive cases including nonsense (n=11), missense (n=10), frameshift (n=7), copy number variants (n=6), intronic (n=3), Alu insertion (n=2), canonical splice (n=1), in-frame indel (n=1), noncoding (n=1), and synonymous (n=1) variants.Mode of inheritance was autosomal dominant in 35.5% of cases, compound heterozygous in 29.0% of cases, homozygous in 25.8% of cases, hemizygous in 3.2% of cases, and two variants in the same gene, phase unknown in the two (6.5%) potentially positive cases.Fourteen of the 31 cases solved by GS had previously uninformative diagnostic testing including 5 cases with previous panel only testing, 7 cases with previous exome sequencing, and 2 cases with previous panel and exome testing.In total, 45.2% of positive cases (14/31) including 25.4% (14/55) of all cases with previous testing, received a positive result with GS.This suggests an incremental yield of approximately 25% for GS compared to other testing modalities in our cohort.Of the cases solved by GS with previously non-informative genetic testing, the most common variant types reported in GS positive cases with previous negative testing were copy number variants (n=4) and intronic variants outside of the +/-10bp splice region (n=3). Conclusion:The results of this study do indicate that GS leads to an incremental diagnostic yield in individuals with IRD compared to other commonly utilized testing modalities.This supports GS as a first-tier molecular test for individuals with IRDs.