Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing
Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing
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DOI：
10.1038/ng.2543
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发表时间：
2013-03-01
期刊：
影响因子：
30.8
通讯作者：
Daly, Mark J.
中科院分区：
文献类型：
--
作者：
Kirby, Andrew;Gnirke, Andreas;Daly, Mark J.
虽然通过对整个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病变，但并非所有疾病都容易屈服于这种努力。我们描述了说明性的情况下，简单的孟德尔氏疾病髓样囊性肾病1型（MCKD 1），映射到一个2 Mb的1号染色体上的区域在十多年前。最终，只有通过克隆，毛细管测序和从头组装，我们才发现六个MCKD 1家族中的每一个家族都携带了一个等效的，但显然独立出现的序列突变，在大规模平行测序数据中显着不足：在一个拷贝中插入一个胞嘧啶（但在每个家族中有不同的拷贝）的重复单元，所述重复单元包含极长的（类似于1.5-5 kb），编码粘蛋白1的MUC 1基因中富含GC（>80%）的编码可变数目串联重复（VNTR）序列。这些结果为通过大规模平行测序确定孟德尔遗传疾病（更不用说更复杂的疾病）的基因提供了一个警示。
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 (similar to 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.