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01-07-2020 | Primary Immunodeficiency | Original Article

Whole-Exome Sequencing-Based Approach for Germline Mutations in Patients with Inborn Errors of Immunity

Authors: Tsubasa Okano, Kohsuke Imai, Takuya Naruto, Satoshi Okada, Motoi Yamashita, Tzu-wen Yeh, Shintaro Ono, Keisuke Tanaka, Keisuke Okamoto, Kay Tanita, Kazuaki Matsumoto, Etsushi Toyofuku, Eri Kumaki-Matsumoto, Miko Okamura, Hiroo Ueno, Seishi Ogawa, Osamu Ohara, Masatoshi Takagi, Hirokazu Kanegane, Tomohiro Morio

Published in: Journal of Clinical Immunology | Issue 5/2020

Abstract

Purpose

Owing to recent technological advancements, using next-generation sequencing (NGS) and the accumulation of clinical experiences worldwide, more than 420 genes associated with inborn errors of immunity (IEI) have been identified, which exhibit large genotypic and phenotypic variations. Consequently, NGS-based comprehensive genetic analysis, including whole-exome sequencing (WES), have become more valuable in the clinical setting and have contributed to earlier diagnosis, improved treatment, and prognosis. However, these approaches have the following disadvantages that need to be considered: a relatively low diagnostic rate, high cost, difficulties in the interpretation of each variant, and the risk of incidental findings. Thus, the objective of this study is to review our WES results of a large number of patients with IEI and to elucidate patient characteristics, which are related to the positive WES result.

Methods

We performed WES for 136 IEI patients with negative conventional screening results for candidate genes and classified these variants depending on validity of their pathogenicity.

Results

We identified disease-causing pathogenic mutations in 36 (26.5%) of the patients which were found in known IEI-causing genes. Although the overall diagnostic rate was not high and was not apparently correlated with the clinical subcategories and severity, we revealed that earlier onset with longer duration of diseases were associated with positive WES results, especially in pediatric cases.

Conclusions

Most of the disease-causing germline mutations were located in the known IEI genes which could be predicted using patients’ clinical characteristics. These results may be useful when considering appropriate genetic approaches in the clinical setting.

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Title: Whole-Exome Sequencing-Based Approach for Germline Mutations in Patients with Inborn Errors of Immunity
Authors: Tsubasa Okano
Kohsuke Imai
Takuya Naruto
Satoshi Okada
Motoi Yamashita
Tzu-wen Yeh
Shintaro Ono
Keisuke Tanaka
Keisuke Okamoto
Kay Tanita
Kazuaki Matsumoto
Etsushi Toyofuku
Eri Kumaki-Matsumoto
Miko Okamura
Hiroo Ueno
Seishi Ogawa
Osamu Ohara
Masatoshi Takagi
Hirokazu Kanegane
Tomohiro Morio
Publication date: 01-07-2020
Publisher: Springer US
Keywords: Primary Immunodeficiency
Immunodeficiency
Published in: Journal of Clinical Immunology / Issue 5/2020
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-020-00798-3

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Purpose

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Conclusions

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