Recurrent genomic rearrangements at 16p11.2 BP4-5 represent one of the most common causes of genomic disorders. Originally associated with increased risk for autism spectrum disorder, schizophrenia, and intellectual disability, as well as adiposity and head circumference, these CNVs have since been associated with a plethora of phenotypic alterations, albeit with high variability in expressivity and incomplete penetrance. Here, we comprehensively review the pleiotropy associated with 16p11.2 BP4-5 rearrangements to shine light on its full phenotypic spectrum. Illustrating this phenotypic heterogeneity, we expose many parallels between findings gathered from clinical versus population-based cohorts, which often point to the same physiological systems, and emphasize the role of the CNV beyond neuropsychiatric and anthropometric traits. Revealing the complex and variable clinical manifestations of this CNV is crucial for accurate diagnosis and personalized treatment strategies for carrier individuals. Furthermore, we discuss areas of research that will be key to identifying factors contributing to phenotypic heterogeneity and gaining mechanistic insights into the molecular pathways underlying observed associations, while demonstrating how diversity in affected individuals, cohorts, experimental models, and analytical approaches can catalyze discoveries.

中文翻译：

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近端 16p11.2 CNV 的多效性谱


16p11.2 BP4-5 位点的复发性基因组重排是基因组疾病的最常见原因之一。这些 CNV 最初与自闭症谱系障碍、精神分裂症和智力障碍以及肥胖和头围的风险增加有关，此后与大量表型改变有关，尽管表达性具有高度变异性和不完全外显率。在这里，我们全面回顾了与 16p11.2 BP4-5 重排相关的多效性，以阐明其完整的表型谱。为了说明这种表型异质性，我们揭示了从临床队列和基于人群的队列中收集的发现之间的许多相似之处，这些发现通常指向相同的生理系统，并强调 CNV 在神经精神病学和人体测量学特征之外的作用。揭示这种 CNV 复杂多变的临床表现对于携带者个体的准确诊断和个性化治疗策略至关重要。此外，我们讨论了研究领域，这些领域将是确定导致表型异质性的因素和获得对观察到的关联的分子途径的机制见解的关键，同时展示了受影响个体、队列、实验模型和分析方法的多样性如何催化发现。