Clinical Exome Sequencing at UCLA: diagnosis rate, variant spectrum and novel gene discoveries. H. Lee1, J. L. Deignan1, N. Dorrani3, S. Strom1, N. Ghahramani1, S. Kantarci1, F. Quintero-Rivera1, K. Das1, M. Fox3, W. W. Grody1,2,3, E. Vilain2,3, S. F. Nelson1,2 1) Pathology and Laboratory Medicine, UCLA, Los Angeles, CA; 2) Human Genetics, UCLA, Los Angeles, CA; 3) Pediatrics, UCLA, Los Angeles, CA.

   The CLIA-certified/CAP-accredited UCLA Clinical Genomics Center launched Clinical Exome Sequencing (CES) in 2012 to improve the genetic diagnosis of rare Mendelian disorders. CES has substantial clinical utility with a higher diagnostic yield than most other single-gene or panel-based molecular diagnostics. Here, we report on the first sequential 500 cases performed at UCLA to explore broad-based usage of CES and outcomes. The most frequent clinical indication for CES was developmental delay (DD) presenting as part of a complex syndrome including co-morbid diagnosis of seizures, hypotonia or dysmorphic features. Most causative genes were observed as mutated in only one pedigree. However, mutations in KMT2A, ZEB2, DYRK1A and SCN2A were determined to be causative in multiple independent cases, suggesting these genes are more commonly altered in individuals with syndromic DD. Pathogenic variants were identified and reported in 25% of all cases. Of these 126 diagnoses, 62 were based on heterozygous variants revealing an autosomal dominant disease (35 de novo, 3 inherited from an affected parent, 24 in proband-only cases), 22 were based on homozygosity of a recessive allele, 35 were based on compound heterozygosity, and 10 were based on X-linked recessive inheritance. The conclusive diagnosis rate was higher when CES was performed on a trio (30%, vs 21% for proband-only cases, p=0.046). New case reports with clear causal variants are serving to expand and clarify the full spectrum of phenotypes for some disease genes such as KMT2A (identified as the disease gene for Wiedemann-Steiner Syndrome only two years ago by whole exome sequencing). Gene discovery in rare Mendelian disorders is continuing at a fast pace and CES is well-suited to convert these new findings into meaningful diagnostic tests for patients. For instance, we observed two independent de novo variants in TUBB2A, recently demonstrated to be pathogenic for brain malformations, permitting specific molecular diagnosis in both cases. In 19 patients, 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 case. These genes are now being investigated as novel disease genes. As more patients are having CES performed as the first-line diagnostic tool, we expect the diagnostic yield to increase, the phenotype spectrum of the known genes to expand, and the novel gene discoveries to continue.

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