Genetics and Molecular Biology Graduate Program, Federal University of Goiás, Goiânia, Goiás, Brazil.
Replicon Research Group, Master Program in Genetics, School of Medical and Life Science, Pontifical Catholic University of Goiás, Goiânia, Goiás, Brazil.
PLoS One. 2022 Apr 7;17(4):e0266493. doi: 10.1371/journal.pone.0266493. eCollection 2022.
Intellectual Disability (ID) is a neurodevelopmental disorder that affects approximately 3% of children and adolescents worldwide. It is a heterogeneous and multifactorial clinical condition. Several methodologies have been used to identify the genetic causes of ID and in recent years new generation sequencing techniques, such as exome sequencing, have enabled an increase in the detection of new pathogenic variants and new genes associated with ID. The aim of this study was to evaluate exome sequencing with analysis of the ID gene panel as a tool to increase the diagnostic yield of patients with ID/GDD/MCA in Central Brazil, together with karyotype and CMA tests. A retrospective cohort study was carried out with 369 patients encompassing both sexes. Karyotype analysis was performed for all patients. CMA was performed for patients who did not present structural and or numerical alterations in the karyotype. Cases that were not diagnosed after performing karyotyping and CMA were referred for exome sequencing using a gene panel for ID that included 1,252 genes. The karyotype identified chromosomal alterations in 34.7% (128/369). CMA was performed in 83 patients who had normal karyotype results resulting in a diagnostic yield of 21.7% (18/83). Exome sequencing with analysis of the ID gene panel was performed in 19 trios of families that had negative results with previous methodologies. With the ID gene panel analysis, we identified mutations in 63.1% (12/19) of the cases of which 75% (9/12) were pathogenic variants,8.3% (1/12) likely pathogenic and in 16.7% (2/12) it concerned a Variant of Uncertain Significance. With the three methodologies applied, it was possible to identify the genetic cause of ID in 42.3% (156/369) of the patients. In conclusion, our studies show the different methodologies that can be useful in diagnosing ID/GDD/MCA and that whole exome sequencing followed by gene panel analysis, when combined with clinical and laboratory screening, is an efficient diagnostic strategy.
智力障碍（ID）是一种影响全球约 3%儿童和青少年的神经发育障碍。它是一种异质性和多因素的临床病症。已经使用了几种方法来确定 ID 的遗传原因，近年来，新一代测序技术，如外显子组测序，已经能够增加新的致病性变体和与 ID 相关的新基因的检测。本研究的目的是评估外显子组测序结合 ID 基因panel 分析作为一种工具，以增加巴西中部 ID/GDD/MCA 患者的诊断率，同时结合核型和 CMA 检测。进行了一项回顾性队列研究，共纳入 369 例男女患者。对所有患者进行核型分析。对于核型无结构和/或数量改变的患者进行 CMA。在进行核型和 CMA 后仍未诊断的病例，使用包含 1252 个基因的 ID 基因 panel 进行外显子组测序。核型鉴定出 34.7%（128/369）的染色体改变。对核型正常的 83 例患者进行 CMA，诊断率为 21.7%（18/83）。对先前方法学检测结果为阴性的 19 个家系的 trio 进行了外显子组测序和 ID 基因 panel 分析。通过 ID 基因 panel 分析，我们在 63.1%（12/19）的病例中发现了突变，其中 75%（9/12）为致病性变体，8.3%（1/12）为可能致病性变体，16.7%（2/12）为意义不明的变体。通过应用这三种方法，能够确定 369 例患者中的 42.3%（156/369）的遗传原因。总之，我们的研究表明，不同的方法可用于诊断 ID/GDD/MCA，全外显子组测序结合基因 panel 分析，与临床和实验室筛查相结合，是一种有效的诊断策略。
