First year experience of Clinical Exome Sequencing for rare disease diagnosis at UCLA. H. Lee1, J. L. Deignan1, N. Dorrani3, F. Quintero-Rivera1, S. Kantarci1, K. Das1, T. Toy2, S. Strom1, R. Baxter2, T. Hambuch9, Y. Xue8, L. Li7, C. Louie6, D. Cherukuri1, E. Lin1, B. Harry2, M. Yourshaw2, M. Fox3, C. Palmer2,5, D. Wong3, B. L. Fogel4, W. W. Grody1,2,3, E. Vilain2,3, S. F. Nelson1,2 1) Dept Pathology and Laboratory Medicine, Univ California, Los Angeles, Los Angeles, CA; 2) Dept Human Genetics, Univ California, Los Angeles, Los Angeles, CA; 3) Dept Pediatrics, Univ California, Los Angeles, Los Angeles, CA; 4) Dept of Neurology, Univ California, Los Angeles, Los Angeles, CA; 5) Dept of Psychiatry and Biobehavioral Sciences, Univ California, Los Angeles, Los Angeles, CA; 6) Clinical Molecular Diagnostics Laboratory, City of Hope National Medical Center, Duarte, CA; 7) Department of Pathology & Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA; 8) Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA; 9) Illumina Clinical Services Laboratory, Illumina, San Diego, CA.

   The CLIA/CAP-accredited UCLA Clinical Genomics Center launched Clinical Exome Sequencing (CES) in 2012 to improve genetic diagnosis of rare Mendelian disorders. Validated as a single test from DNA extraction to Genomic Data Board interpretation, we have found CES to offer high clinical utility with a higher diagnostic yield than most of the other single-gene or panel-based clinical molecular tests. Here, we report on the first sequential 252 cases within the first year of testing. CES is offered as a Trio CES, where both parents also have CES and as a Proband CES, where only the patient is sequenced. Overall, a conclusive molecular diagnosis (causative mutation(s) identified in a clinically relevant gene) was provided for 80 of the 252 total cases (32%). 105 of the 252 cases were Trio CES, and 42 (40%) of those 105 were provided with a conclusive molecular diagnosis. De novo and phased compound heterozygous (CH) variants are the two major categories not possible to deduce without sequencing the unaffected parents. Among these 42 trios with a conclusive result, 43% had a de novo variant, 17% had a homozygous variant, 29% had CH variants in trans, 5% had an inherited variant from a similarly affected parent, and 7% had an X-linked hemizygous variant. Of the 134 Proband CES, we established a conclusive molecular diagnosis in 34 cases (25%). Thus, Trio CES provided a significantly higher diagnostic yield than Proband CES (p=0.01), and it is therefore the recommended approach. For genetically heterogeneous disorders such as developmental delay, the improved diagnostic rate and more straightforward interpretation with Trio CES are critical. We have also observed diagnostic reclassification in 15% of the cases post-CES, largely due to the phenotypic heterogeneity of many Mendelian disorders. In 12 of the cases (5%) novel variants were identified in genes that are not yet associated with any human disorder but have animal models available with significant phenotypic overlap with the patients condition. Most of these variants (7/12) were highlighted because they were de novo, and these genes are now being investigated as novel disease genes. We note that many cases referred for CES have been performed as a last resort after exhausting most other diagnostic options. However, more recently we have observed a shift, where physicians order CES as the first line genetic diagnostic tool, and as a result, we expect the diagnosis rate to increase further.

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