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Abstract：
Human imprinting disorders cause a range of dysmorphic and neurocognitive phenotypes, and they may elude traditional molecular diagnosis such exome sequencing. The discovery of novel disorders related to imprinted genes has lagged behind traditional Mendelian disorders because current diagnostic technology, especially unbiased testing, has limited utility in their discovery. To identify novel imprinting disorders, we reviewed data for every human gene hypothesized to be imprinted, identified each mouse ortholog, determined its imprinting status in the mouse, and analyzed its function in humans and mice. We identified 17 human genes that are imprinted in both humans and mice, and have functional data in mice or humans to suggest that dysregulated expression would lead to an abnormal phenotype in humans. These 17 genes, along with known imprinted genes, were preferentially flagged 538 clinical exome sequencing tests. The identified genes were: DIRAS3 [1p31.3], TP73 [1p36.32], SLC22A3 [6q25.3], GRB10 [7p12.1], DDC [7p12.2], MAGI2 [7q21.11], PEG10 [7q21.3], PPP1R9A [7q21.3], CALCR [7q21.3], DLGAP2 [8p23.3], GLIS3 [9p24.2], INPP5F [10q26.11], ANO1 [11q13.3], SLC38A4 [12q13.11], GATM [15q21.1], PEG3 [19q13.43], and NLRP2 [19q13.42]. In the 538 clinical cases, eight cases (1.7%) reported variants in a causative known imprinted gene. There were 367/758 variants (48.4%) in imprinted genes that were not known to cause disease, but none of those variants met the criteria for clinical reporting. Imprinted disorders play a significant role in human disease, and additional human imprinted disorders remain to be discovered. Therefore, evolutionary conservation is a potential tool to identify novel genes involved in human imprinting disorders and to identify them in clinical testing.
摘要：
人类印记障碍引起一系列畸形和神经认知表型，它们可能会避开传统的分子诊断，如外显子组测序。与印迹基因相关的新型疾病的发现落后于传统的孟德尔障碍，因为目前的诊断技术，尤其是无偏见的测试，在他们的发现中具有有限的效用。为了识别新的印记障碍，我们回顾了每个假设被印记的人类基因的数据，确定每个小鼠的直系同源，确定了它在鼠标中的印记状态，并分析了其在人类和小鼠中的功能。我们确定了17个基因在人类和小鼠中都有印记，并且在小鼠或人类中的功能数据表明表达失调会导致人类的异常表型。这17个基因,连同已知的印记基因，优先标记538个临床外显子组测序测试。鉴定的基因是：DIRAS3[1p31.3]，TP73[1p36.32],SLC22A3[6q25.3]，GRB10[7p12.1],DDC[7p12.2],MAGI2[7q21.11],PEG10[7q21.3]，PPP1R9A[7q21.3],CALCR[7q21.3]，DLGAP2[8p23.3]，GLIS3[9p24.2]，INPP5F[10q26.11],ANO1[11q13.3]，SLC38A4[12q13.11],GATM[15q21.1]，PEG3[19q13.43]，和NLRP2[19q13.42]。在538例临床病例中，8例(1.7%)报告了已知印记基因的变异。印迹基因中有367/758个变异（48.4％）不知道会引起疾病，但这些变异均不符合临床报告标准.印记障碍在人类疾病中起着重要作用，和其他人类印记疾病仍有待发现。因此,进化保守是一个潜在的工具，用于鉴定与人类印记障碍有关的新基因，并在临床试验中进行鉴定。
