Department of Child Health, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr. Sardjito Hospital, Yogyakarta, Indonesia.
Department of Child Health, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Academic UGM Hospital, Yogyakarta, Indonesia.
PLoS One. 2023 Oct 25;18(10):e0293113. doi: 10.1371/journal.pone.0293113. eCollection 2023.
Neurogenetic disorders (NGDs) are complex Mendelian disorders that affect the neurological system. A molecular diagnosis will provide more information about pathophysiology, prognosis, and therapy, including future genetic therapy options. Whole-Exome Sequencing (WES) can rapidly discover the genetic basis in NGDs.
The purpose of this study was to assess the WES results and its value in diagnosing pediatric NGDs, especially those with unspecified clinical features.
A retrospective chart review was performed from May 2021- February 2023 in Dr. Sardjito General Hospital, a tertiary referral hospital in Yogyakarta, Indonesia. WES proband only was conducted on children aged 0 to 17 years old who met one or more of the following criteria: (1) epileptic encephalopathy and familial epilepsy; (2) complex neurodevelopmental phenotypes; (3) leukodystrophy; (4) movement disorders; and (5) neurocutaneous disorder. The WES was conducted in the certified laboratory, 3Billion, in Seoul, Korea.
The diagnosis yield of WES in our study was 45% (9/20). We identified nine positive results, including eight pathogenic single nucleotide variants (SNVs) in 8 genes (KCNQ2, ARSA, UBE3A, IRF2BPL, ATM, MECP2, TSC2, and NF1), and one variant with uncertain significance (VUS) in the ADK gene that has not been able to explain the observed clinical features. Of the nine patients with positive WES results, five had missense mutations, three frameshift mutations, and one nonsense mutation. Additionally, we identified two suggestive copy number variants (CNVs) in 15q11.2q13.1 and 1p31.3.
Whole-Exome Sequencing is an essential diagnostic tool for pediatric NGDs, especially those with unspecified clinical features. It ends multi-year diagnostic odysseys, provides personalized medicine therapy, and optimizes genetic counselling for these families.
神经遗传疾病（NGD）是影响神经系统的复杂孟德尔疾病。分子诊断将提供更多关于病理生理学、预后和治疗的信息，包括未来的基因治疗选择。全外显子组测序（WES）可以快速发现 NGD 的遗传基础。
本研究旨在评估 WES 结果及其在诊断儿科 NGD 中的价值，特别是那些具有未明临床特征的疾病。
对 2021 年 5 月至 2023 年 2 月在印度尼西亚日惹的三级转诊医院萨迪吉托综合医院进行的回顾性图表审查。WES 先证者仅在符合以下标准之一或多项的 0 至 17 岁儿童中进行：（1）癫痫性脑病和家族性癫痫；（2）复杂神经发育表型；（3）脑白质营养不良；（4）运动障碍；和（5）神经皮肤障碍。WES 在韩国首尔的 3Billion 认证实验室进行。
我们的研究中 WES 的诊断率为 45%（9/20）。我们确定了九个阳性结果，包括 8 个基因中的 8 个致病性单核苷酸变异（SNV）（KCNQ2、ARSA、UBE3A、IRF2BPL、ATM、MECP2、TSC2 和 NF1）和一个 ADK 基因中的意义不确定的变异（VUS），该变异无法解释观察到的临床特征。在 9 名 WES 阳性结果患者中，有 5 名存在错义突变，3 名存在移码突变，1 名存在无义突变。此外，我们在 15q11.2q13.1 和 1p31.3 中鉴定出两个提示性拷贝数变异（CNV）。
全外显子组测序是儿科 NGD 的重要诊断工具，特别是那些具有未明临床特征的疾病。它结束了多年的诊断探索，为这些家庭提供了个性化的药物治疗，并优化了遗传咨询。
