Congenital genetic disorders affecting limb morphology in humans and other mammals are particularly well described, due to both their rather high frequencies of occurrence and the ease of their detection when expressed as severe forms. In most cases, their molecular and cellular etiology remained unknown long after their initial description, often for several decades, and sometimes close to a century. Over the past 20 yr, however, experimental and conceptual advances in our understanding of gene regulation, in particular over large genomic distances, have allowed these cold cases to be reopened and, eventually, for some of them to be solved. These investigations led not only to the isolation of the culprit genes and mechanisms, but also to the understanding of the often complex regulatory processes that are disturbed in such mutant genetic configurations. Here, we present several cases in which dormant regulatory mutations have been retrieved from the archives, starting from a historical perspective up to their molecular explanations. While some cases remain open, waiting for new tools and/or concepts to bring their investigations to an end, the solutions to others have contributed to our understanding of particular features often found in the regulation of developmental genes and hence can be used as benchmarks to address the impact of noncoding variants in the future.

中文翻译：

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遗传性感冒病例：解决复杂先天性肢体疾病的经验教训

影响人类和其他哺乳动物肢体形态的先天性遗传疾病得到了特别详尽的描述，因为它们的发生频率相当高，而且当以严重形式表达时易于检测。在大多数情况下，它们的分子和细胞病因在最初描述后很长一段时间内仍然未知，通常持续数十年，有时甚至接近一个世纪。然而，在过去的 20 年里，我们对基因调控的理解在实验和概念上取得了进展，特别是在基因组距离较大的情况下，这使得这些悬而未决的案例得以重新审理，并最终解决了其中一些问题。这些调查不仅导致了罪魁祸首基因和机制的分离，而且还有助于了解在此类突变基因配置中受到干扰的通常很复杂的调节过程。在这里，我们展示了几个从档案中检索到休眠调节突变的案例，从历史的角度到它们的分子解释。虽然一些案例仍然开放，等待新的工具和/或概念来结束他们的调查，但其他案例的解决方案有助于我们理解发育基因调控中经常发现的特定特征，因此可以用作基准解决未来非编码变体的影响。