A Comprehensive Iterative Approach Is Highly Effective in Diagnosing Individuals Who Are Exome Negative

Genet Med. 2019 Jan;21(1):161-172. doi: 10.1038/s41436-018-0044-2. Epub 2018 Jun 15.

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.

Keywords: Exome sequencing; Genome sequencing; Phenotyping; Rare diseases; Undiagnosed diseases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Child
  • Developmental Disabilities / diagnosis*
  • Developmental Disabilities / epidemiology
  • Developmental Disabilities / genetics*
  • Exome / genetics*
  • Female
  • Genetic Predisposition to Disease*
  • Genomics
  • Humans
  • Male
  • Phenotype
  • Sequence Analysis, DNA
  • Whole Exome Sequencing / methods
  • Whole Genome Sequencing