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A comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative.

  • Author(s): Shashi, Vandana
  • Schoch, Kelly
  • Spillmann, Rebecca
  • Cope, Heidi
  • Tan, Queenie K-G
  • Walley, Nicole
  • Pena, Loren
  • McConkie-Rosell, Allyn
  • Jiang, Yong-Hui
  • Stong, Nicholas
  • Need, Anna C
  • Goldstein, David B
  • Undiagnosed Diseases Network
  • et al.
Abstract

PURPOSE:Sixty to seventy-five percent of individuals with rare and undiagnosed phenotypes remain undiagnosed after exome sequencing (ES). With standard ES reanalysis resolving 10-15% of the ES negatives, further approaches are necessary to maximize diagnoses in these individuals. METHODS:In 38 ES negative patients an individualized genomic-phenotypic approach was employed utilizing (1) phenotyping; (2) reanalyses of FASTQ files, with innovative bioinformatics; (3) targeted molecular testing; (4) genome sequencing (GS); and (5) conferring of clinical diagnoses when pathognomonic clinical findings occurred. RESULTS:Certain and highly likely diagnoses were made in 18/38 (47%) individuals, including identifying two new developmental disorders. The majority of diagnoses (>70%) were due to our bioinformatics, phenotyping, and targeted testing identifying variants that were undetected or not prioritized on prior ES. GS diagnosed 3/18 individuals with structural variants not amenable to ES. Additionally, tentative diagnoses were made in 3 (8%), and in 5 individuals (13%) candidate genes were identified. Overall, diagnoses/potential leads were identified in 26/38 (68%). CONCLUSIONS:Our comprehensive approach to ES negatives maximizes the ES and clinical data for both diagnoses and candidate gene identification, without GS in the majority. This iterative approach is cost-effective and is pertinent to the current conundrum of ES negatives.

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