National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Genes (Basel). 2021 Oct 22;12(11):1669. doi: 10.3390/genes12111669.
(FMRP translational regulator 1) variants other than repeat expansion are known to cause disease phenotypes but can be overlooked if they are not accounted for in genetic testing strategies. We collected and reanalyzed the evidence for pathogenicity of coding, noncoding, and copy number variants published to date. There is a spectrum of disease-causing variation, with clinical and functional evidence supporting pathogenicity of five splicing, five missense, one in-frame deletion, one nonsense, and four frameshift variants. In addition, deletions occur in both mosaic full mutation patients and as constitutional pathogenic alleles. De novo deletions arise not only from full mutation alleles but also alleles with normal-sized CGG repeats in several patients, suggesting that the CGG repeat region may be prone to genomic instability even in the absence of repeat expansion. We conclude that clinical tests for potentially -related indications such as intellectual disability should include methods capable of detecting small coding, noncoding, and copy number variants.
（FMRP 翻译调节因子 1）除重复扩展以外的变体已知可引起疾病表型，但如果在遗传测试策略中未考虑这些变体，则可能会被忽略。我们收集并重新分析了迄今为止发表的编码、非编码和拷贝数变异的致病性证据。存在疾病引起的变异谱，具有临床和功能证据支持五种剪接、五种错义、一种框内缺失、一种无义和四种移码变异的致病性。此外，缺失发生在镶嵌型完全突变患者和作为构成性致病性等位基因中。从头缺失不仅来自完全突变等位基因，而且来自几个患者中具有正常大小 CGG 重复的等位基因，这表明即使没有重复扩展，CGG 重复区域也可能容易发生基因组不稳定性。我们得出结论，临床测试对于智力障碍等潜在相关指征，应包括能够检测小的编码、非编码和拷贝数变异的方法。
