PhD Science Writer, New York, New York.
Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia.
Ann N Y Acad Sci. 2021 Dec;1506(1):5-17. doi: 10.1111/nyas.14658. Epub 2021 Aug 2.
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.
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因素，但潜在机制很难被破译。罕见的高风险变异可能为更清楚地描绘负责更常见特发性疾病的生物学机制提供机会。事实上，不同的罕见变异可以导致相同的行为表型，这表明遗传异质性，而相同的罕见变异可以导致不同的行为表型，这表明表现度可变。这些观察结果表明存在趋同的潜在生物学和神经学机制；识别这些机制最终可能揭示新的治疗靶点。在 2021 年 Keystone eSymposium“神经精神和神经发育障碍：利用罕见变异”上，该领域的专家小组描述了基因组发现和人类表型方面的重大进展，并提出了几个一致的问题，包括需要对罕见疾病进行详细的自然病史研究、队列招募的挑战，以及将表型视为受罕见变异影响的定量特征的重要性。
