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. 2022 Mar 26;28(1):38.
doi: 10.1186/s10020-022-00464-x.

Diagnostic performance of automated, streamlined, daily updated exome analysis in patients with neurodevelopmental delay

Go Hun Seo  1 , Hane Lee  1 , Jungsul Lee  1 , Heonjong Han  1 , You Kyung Cho  1 , Minji Kim  2 , Yunha Choi  2 , Jeongmin Choi  3 , In Hee Choi  3 , Seonkyeong Rhie  4 , Kyu Young Chae  4 , Yoo-Mi Kim  5 , Chong Kun Cheon  6 , Su Jin Kim  7 , Jieun Lee  7 , Eungu Kang  8 , Jung Hye Byeon  8 , Hee Joon Yu  9 , Young-Lim Shin  10 , Arum Oh  11 , Woo Jin Kim  12 , Mi-Sun Yum #  13 , Beom Hee Lee #  14   15 , Baik-Lin Eun #  16
Affiliations

Diagnostic performance of automated, streamlined, daily updated exome analysis in patients with neurodevelopmental delay

Go Hun Seo et al. Mol Med. .

Abstract

Background: The diagnostic yield of whole-exome sequencing (WES) varies from 30%-50% among patients with mild to severe neurodevelopmental delay (NDD)/intellectual disability (ID). Routine retrospective reanalysis of undiagnosed patients has increased the total diagnostic yield by 10-15%. Here, we performed proband-only WES of 1065 patients with NDD/ID and applied a prospective, daily reanalysis automated pipeline to patients without clinically significant variants to facilitate diagnoses.

Methods: The study included 1065 consecutive patients from 1056 nonconsanguineous unrelated families from 10 multimedical centers in South Korea between April 2018 and August 2021. WES data were analyzed daily using automatically updated databases with variant classification and symptom similarity scoring systems.

Results: At the initial analysis, 402 patients from 1056 unrelated families (38.0%, 402/1,056 families) had a positive genetic diagnosis. Daily prospective, automated reanalysis resulted in the identification of 34 additional diagnostic variants in 31 patients (3%), which increased our molecular diagnostic yield to 41% (433/1056 families). Among these 31 patients, 26 were diagnosed with 23 different diseases that were newly discovered after 2019. The time interval between the first analysis and the molecular diagnosis by reanalysis was 1.2 ± 0.9 years, which was shorter in the patients enrolled during the latter part of the study period.

Conclusion: Daily updated databases and reanalysis systems enhance the diagnostic performance in patients with NDD/ID, contributing to the rapid diagnosis of undiagnosed patients by applying the latest molecular genetic information.

Keywords: Neurodevelopmental delay; Reanalysis; Whole exome sequencing.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
Comparison of the number of pathogenicityof identified variants between the initial and final results, including the reanalysis
Fig. 2
Fig. 2
The cumulative monthly number of undiagnosed patients (light blue), patients diagnosed by the initial analysis (green) and by reanalysis (red) from April 2018 to October 2021
Fig. 3
Fig. 3
Schematic diagram showing patients divided according to the three reported categories
Fig. 4
Fig. 4
The number of patients with newly reclassified variants (red line) and the number of newly reclassified variants (blue line) based on daily reanalysis data from April 2019 to October 2021
Fig. 5
Fig. 5
The time interval between the first analysis (blue dot) and the molecular diagnosis (red dot) of patients diagnosed by reanalysis. Number: Time interval converted to years
See this image and copyright information in PMC

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