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. 2020 Dec;98(6):562-570.
doi: 10.1111/cge.13848. Epub 2020 Sep 17.

Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, EVIDENCE

Go Hun Seo  1 , Taeho Kim  2 , In Hee Choi  3 , Jung-Young Park  1 , Jungsul Lee  1 , Sehwan Kim  1 , Dhong-Gun Won  1 , Arum Oh  4 , Yena Lee  4 , Jeongmin Choi  2 , Hajeong Lee  5 , Hee Gyung Kang  6 , Hee Yeon Cho  7 , Min Hyun Cho  8 , Yoon Jeon Kim  9 , Young Hee Yoon  9 , Baik-Lin Eun  10 , Robert J Desnick  11 , Changwon Keum  1 , Beom Hee Lee  3   4
Affiliations

Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, EVIDENCE

Go Hun Seo et al. Clin Genet. 2020 Dec.

Abstract

EVIDENCE, an automated variant prioritization system, has been developed to facilitate whole exome sequencing analyses. This study investigated the diagnostic yield of EVIDENCE in patients with suspected genetic disorders. DNA from 330 probands (age range, 0-68 years) with suspected genetic disorders were subjected to whole exome sequencing. Candidate variants were identified by EVIDENCE and confirmed by testing family members and/or clinical reassessments. EVIDENCE reported a total 228 variants in 200 (60.6%) of the 330 probands. The average number of organs involved per patient was 4.5 ± 5.0. After clinical reassessment and/or family member testing, 167 variants were identified in 141 probands (42.7%), including 105 novel variants. These variants were confirmed as being responsible for 121 genetic disorders. A total of 103 (61.7%) of the 167 variants in 95 patients were classified as pathogenic or probably to be pathogenic before, and 161 (96.4%) variants in 137 patients (41.5%) after, clinical assessment and/or family member testing. Factor associated with a variant being regarded as causative includes similar symptom scores of a gene variant to the phenotype of the patient. This new, automated variant interpretation system facilitated the diagnosis of various genetic diseases with a 42.7% diagnostic yield.

Keywords: automated prioritization system; genetic diagnosis; variant; whole exome sequencing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic diagram showing the number of patients with and without variant identification and family member testing
FIGURE 2
FIGURE 2
Distribution of the probably pathogenicity of identified variants by EVIDENCE before family member testing, after addition of phenotypic specific rules (PP4), and after family member testing
FIGURE 3
FIGURE 3
Distribution of symptom similarity scores of patient phenotypes and genetic phenotypes suggested by the automated system. * P < .05
FIGURE 4
FIGURE 4
A, Distribution of patients in symptom space. B, Distribution of patients with identified variants in symptom and genetic variation space
See this image and copyright information in PMC

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