Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Computer Science, Stanford University School of Engineering, Stanford, CA, USA.
Eur J Hum Genet. 2018 Dec;26(12):1810-1818. doi: 10.1038/s41431-018-0221-4. Epub 2018 Aug 7.
Approximately 2% of the human genome accounts for protein-coding genes, yet most known Mendelian disease-causing variants lie in exons or splice sites. Individuals who symptomatically present with monogenic disorders but do not possess function-altering variants in the protein-coding regions of causative genes may harbor variants in the surrounding gene regulatory domains. We present such a case: a male of Afghani descent was clinically diagnosed with Wilson Disease-a disorder of systemic copper buildup-but was found to have no function-altering coding variants in ATP7B (ENST00000242839.4), the typically causative gene. Our analysis revealed the homozygous variant chr13:g.52,586,149T>C (NC_000013.10, hg19) 676 bp into the ATP7B promoter, which disrupts a metal regulatory transcription factor 1 (MTF1) binding site and diminishes expression of ATP7B in response to copper intake, likely resulting in Wilson Disease. Our approach to identify the causative variant can be generalized to systematically discover function-altering non-coding variants underlying disease and motivates evaluation of gene regulatory variants.
人类基因组中约有 2%的部分编码蛋白质，但大多数已知的孟德尔疾病致病变体位于外显子或剪接位点。那些有明显单基因疾病症状但在致病基因的蛋白质编码区域没有功能改变变体的个体可能在周围的基因调控区域存在变体。我们提出了这样一个案例：一名阿富汗血统的男性被临床诊断为威尔逊病——一种全身性铜积累紊乱，但在 ATP7B（ENST00000242839.4），即通常的致病基因中没有发现功能改变的编码变体。我们的分析揭示了纯合变体 chr13:g.52,586,149T>C（NC_000013.10，hg19）676bp 进入 ATP7B 启动子，破坏了金属调节转录因子 1（MTF1）结合位点，并减少了对铜摄入的 ATP7B 表达，可能导致威尔逊病。我们识别致病变体的方法可以推广到系统地发现疾病潜在的功能改变的非编码变体，并促使对基因调控变体进行评估。
