Neurodevelopmental neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, have strong genetic risk components, but the underlying mechanisms have proven difficult to decipher. Rare, high-risk variants may offer an opportunity to delineate the biological mechanisms responsible more clearly for more common idiopathic diseases. Indeed, different rare variants can cause the same behavioral phenotype, demonstrating genetic heterogeneity, while the same rare variant can cause different behavioral phenotypes, demonstrating variable expressivity. These observations suggest convergent underlying biological and neurological mechanisms; identification of these mechanisms may ultimately reveal new therapeutic targets. At the 2021 Keystone eSymposium “Neuropsychiatric and Neurodevelopmental Disorders: Harnessing Rare Variants” a panel of experts in the field described significant progress in genomic discovery and human phenotyping and raised several consistent issues, including the need for detailed natural history studies of rare disorders, the challenges in cohort recruitment, and the importance of viewing phenotypes as quantitative traits that are impacted by rare variants.

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利用神经精神和神经发育障碍中的罕见变异——Keystone 研讨会报告

神经发育神经精神疾病，如自闭症谱系障碍和精神分裂症，具有很强的遗传风险成分，但事实证明其潜在机制难以破译。罕见的高风险变异可能提供了一个机会，可以更清楚地描述更常见的特发性疾病的生物学机制。事实上，不同的罕见变异可以导致相同的行为表型，表明遗传异质性，而相同的罕见变异可以导致不同的行为表型，表明可变的表现力。这些观察表明趋同的潜在生物学和神经学机制；识别这些机制可能最终会揭示新的治疗靶点。在 2021 年 Keystone 电子研讨会“神经精神和神经发育障碍：