Molecular diagnosis of 405 individuals with autism spectrum disorder
Molecular diagnosis of 405 individuals with autism spectrum disorder
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DOI：
10.1038/s41431-023-01335-7
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发表时间：
2023-03-27
影响因子：
5.2
通讯作者：
Matsumoto，Naomichi
中科院分区：
文献类型：
--
作者：
Miyake，Noriko;Tsurusaki，Yoshinori;Matsumoto，Naomichi
自闭症谱系障碍（ASD）是由遗传和环境因素共同引起的。 ASD 的遗传率估计为 60-90%，遗传研究揭示了许多单基因因素。我们使用基于家族的外显子组测序分析了 405 名 ASD 患者，以检测引起疾病的单核苷酸变异 (SNV)、小插入和缺失 (indel) 以及拷贝数变异 (CNV)，以进行分子诊断。所有候选变体均通过桑格测序或定量聚合酶链反应进行验证，并使用美国医学遗传学和基因组学学院/分子病理学协会的分子诊断指南进行评估。我们在 53 名受影响个体中鉴定出 55 个致病 SNV/插入缺失，在 13 名受影响个体中鉴定出 13 个致病 CNV，从而对 405 名受影响个体中的 66 名 (16.3%) 实现了分子诊断。在 55 个致病 SNV/插入缺失中，51 个是从头发生的，2 个是复合杂合子（在一名患者中），2 个是从未患病母亲遗传的 X 连锁半合子变异。女性分子诊断率显着高于男性。我们分析了 24 个四胞胎和 2 个五胞胎的受影响兄弟姐妹病例，但只有一对兄弟姐妹具有相同的致病性变异。值得注意的是，单发病例的分子诊断率高于多发病例。我们的模拟表明诊断率每年增加 0.63%（范围 0-2.5%）。根据我们的简单模拟，诊断率随着时间的推移而提高。因此，应强烈鼓励未确诊的 ASD 患者定期重新评估 ES 数据。
Autism spectrum disorder (ASD) is caused by combined genetic and environmental factors. Genetic heritability in ASD is estimated as 60–90%, and genetic investigations have revealed many monogenic factors. We analyzed 405 patients with ASD using family-based exome sequencing to detect disease-causing single-nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variations (CNVs) for molecular diagnoses. All candidate variants were validated by Sanger sequencing or quantitative polymerase chain reaction and were evaluated using the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for molecular diagnosis. We identified 55 disease-causing SNVs/indels in 53 affected individuals and 13 disease-causing CNVs in 13 affected individuals, achieving a molecular diagnosis in 66 of 405 affected individuals (16.3%). Among the 55 disease-causing SNVs/indels, 51 occurred de novo, 2 were compound heterozygous (in one patient), and 2 were X-linked hemizygous variants inherited from unaffected mothers. The molecular diagnosis rate in females was significantly higher than that in males. We analyzed affected sibling cases of 24 quads and 2 quintets, but only one pair of siblings shared an identical pathogenic variant. Notably, there was a higher molecular diagnostic rate in simplex cases than in multiplex families. Our simulation indicated that the diagnostic yield is increasing by 0.63% (range 0–2.5%) per year. Based on our simple simulation, diagnostic yield is improving over time. Thus, periodical reevaluation of ES data should be strongly encouraged in undiagnosed ASD patients.