Hong Sungkook, Hu Ping, Jang Jae Hee, Carrington Blake, Sood Raman, Berger Seth I, Roessler Erich, Muenke Maximilian
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park, Maryland, USA.
Hum Mutat. 2020 Dec;41(12):2155-2166. doi: 10.1002/humu.24119. Epub 2020 Oct 1.
Genetic variation in the highly conserved Sonic Hedgehog (SHH) gene is one of the most common genetic causes for the malformations of the brain and face in humans described as the holoprosencephaly clinical spectrum. However, only a minor fraction of known SHH variants have been experimentally proven to lead to abnormal function. Employing a phenotypic rescue assay with synthetic human messenger RNA variant constructs in shha knockout zebrafish, we evaluated 104 clinically reported in-frame and missense SHH variants. Our data helped us to classify them into loss of function variants (31), hypomorphic variants (33), and nonpathogenic variants (40). We discuss the strengths and weaknesses of currently accepted predictors of variant deleteriousness and the American College of Medical Genetics and Genomics guidelines for variant interpretation in the context of this functional model; furthermore, we demonstrate the robustness of model systems such as zebrafish as a rapid method to resolve variants of uncertain significance.
高度保守的音猬因子（SHH）基因的遗传变异是人类脑面部畸形（即全前脑临床谱系）最常见的遗传原因之一。然而，已知的SHH变异体中只有一小部分已通过实验证明会导致功能异常。我们在shha基因敲除斑马鱼中使用合成人类信使RNA变异体构建体进行表型拯救试验，评估了104个临床报告的框内和错义SHH变异体。我们的数据帮助我们将它们分为功能丧失变异体（31个）、亚效变异体（33个）和非致病变异体（40个）。我们讨论了当前公认的变异体有害性预测指标的优缺点，以及美国医学遗传学与基因组学学会在这种功能模型背景下的变异体解读指南；此外，我们证明了斑马鱼等模型系统作为解决意义不确定变异体的快速方法的稳健性。
