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Detecting Low-Variant Allele Frequency Mosaic Pathogenic Variants of NF1, TSC2, and AKT3 Genes from Blood in Patients with Neurodevelopmental Disorders

 Se Hee Kim  ;  Soon Sung Kwon  ;  Mi Ri Park  ;  Hyeon Ah Lee  ;  Ji Hun Kim  ;  JiHoon Cha  ;  Sangwoo Kim  ;  Seung Tae Baek  ;  Se Hoon Kim  ;  Joon Soo Lee  ;  Heung Dong Kim  ;  Jong Rak Choi  ;  Seung-Tae Lee  ;  Hoon-Chul Kang 
 JOURNAL OF MOLECULAR DIAGNOSTICS, Vol.25(8) : 583-591, 2023-08 
Journal Title
Issue Date
Brain Diseases* ; Gene Frequency ; High-Throughput Nucleotide Sequencing / methods ; Humans ; Mosaicism ; Mutation ; Neurocutaneous Syndromes* ; Neurodevelopmental Disorders* ; Proto-Oncogene Proteins c-akt / genetics
Growing evidence indicates that early and late postzygotic mosaicism can cause neurodevelopmental disorders (NDDs), but detection of low variant allele frequency (VAF) mosaic variants from blood remains a challenge. Data of 2162 patients with NDDs who underwent conventional genetic tests were reviewed and a deep sequencing was performed using a specifically designed mosaic next-generation sequencing (NGS) panel in the patients with negative genetic test results. Forty-four patents with neurocutaneous syndrome, malformation of cortical development, or nonlesional epileptic encephalopathies were included. In total, mosaic variants were detected from blood in 1.2% (25/2162) of the patients. Using conventional NGS panels, 22 mosaic variants (VAF, 8.8% to 29.8%) were identified in 18 different genes. Using a specifically designed mosaicism NGS panel, three mosaic variants of the NF1, TSC2, and AKT3 genes were identified (VAF, 2.0% to 11.2%). Mosaic variants were found frequently in the patients who had neurocutaneous syndrome (2/7, 28.6%), whereas only one or no mosaic variant was detected for patients who had malformations of cortical development (1/20, 5%) or nonlesional epileptic encephalopathies (0%, 0/17). In summary, mosaic variants that contribute to the spectrum of NDDs can be detected from blood via conventional NGS and specifically designed mosaicism NGS panels, and detection of mosaic variants using blood will increase diagnostic yield.

Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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1. College of Medicine (의과대학) > Dept. of Biomedical Systems Informatics (의생명시스템정보학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Hoon Chul(강훈철) ORCID logo https://orcid.org/0000-0002-3659-8847
Kwon, Sun Sung(권순성)
Kim, Sangwoo(김상우) ORCID logo https://orcid.org/0000-0001-5356-0827
Kim, Se Hoon(김세훈) ORCID logo https://orcid.org/0000-0001-7516-7372
Kim, Se Hee(김세희) ORCID logo https://orcid.org/0000-0001-7773-1942
Kim, Heung Dong(김흥동) ORCID logo https://orcid.org/0000-0002-8031-7336
Lee, Seung-Tae(이승태) ORCID logo https://orcid.org/0000-0003-1047-1415
Lee, Joon Soo(이준수) ORCID logo https://orcid.org/0000-0001-9036-9343
Choi, Jong Rak(최종락) ORCID logo https://orcid.org/0000-0002-0608-2989
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