Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Nat Genet. 2013 Mar;45(3):299-303. doi: 10.1038/ng.2543. Epub 2013 Feb 10.
Although genetic lesions responsible for some mendelian disorders can be rapidly discovered through massively parallel sequencing of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing and de novo assembly did we find that each of six families with MCKD1 harbors an equivalent but apparently independently arising mutation in sequence markedly under-represented in massively parallel sequencing data: the insertion of a single cytosine in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (∼1.5-5 kb), GC-rich (>80%) coding variable-number tandem repeat (VNTR) sequence in the MUC1 gene encoding mucin 1. These results provide a cautionary tale about the challenges in identifying the genes responsible for mendelian, let alone more complex, disorders through massively parallel sequencing.
虽然通过对全基因组或外显子组进行大规模平行测序，可以快速发现导致某些孟德尔疾病的遗传缺陷，但并非所有疾病都能轻易通过这种方法找到病因。我们描述了一个简单的孟德尔疾病——髓质囊性肾病 1 型（MCKD1）的案例，该疾病在十多年前被定位在 1 号染色体上的一个 2-Mb 区域。最终，我们通过克隆、毛细管测序和从头组装发现，每个 MCKD1 家族都携带一个相同但显然是独立出现的突变，该突变在大规模平行测序数据中明显缺失：在编码黏蛋白 1 的 MUC1 基因中，重复单元的一个拷贝（但在每个家族中是不同的拷贝）插入了一个单一的胞嘧啶。这些结果提供了一个警示故事，说明了通过大规模平行测序识别导致孟德尔疾病（更不用说更复杂的疾病）的基因所面临的挑战。
