Development of array based comparative genomic hybridization (CGH) as a diagnostic tool for cryptic chromosome aberrations in congenital disorders

人类基因组测序计划已经成功实施，99%的基因组测序准确率达到99.99%。在后测序时代，疾病相关基因组改变的检测与鉴定与多种先天性异常伴精神发育迟滞（MCA/MR）、自闭症和其他未知基因组疾病相关的基因直接相关。然而，我们没有任何工具来探索100 kb水平的隐性染色体畸变。为了克服这种情况，我们构建了如下高分辨率CGH阵列：（1）全基因组阵列（WGA）-4500，其包含贯穿整个基因组的4523个BAC，（2）癌症阵列-800，其包含不同癌症相关基因的800个BAC，（3）1 p36-contig阵列，其覆盖约20 Mb跨越1 p36区域，具有212个BAC，（4）染色体X-平铺阵列，其包含除了假常染色体区域之外的整个染色体X的1001个BAC，和（5）基因组病症（GD）-阵列，其用作已知基因组病症的诊断工具。使用这些内部BAC阵列，我们探讨了大量MCA/MR患者的隐性染色体畸变，并在其中一些患者中检测到与未知MCA/MR发病机制相关的从头亚显微畸变。

The human genome sequencing project had been conducted successfully, with 99% of the genome sequenced with 99.99% accuracy. In the post-sequence era, detection of disease-related genomic alterations is directly connected with identification of genes associated with multiple congenital anomalies with mental retardation (MCA/MR), autism, and other unknown genomic disorders. However, we had none of tools for exploring cryptic chromosome aberrations at 100kb-level. In order to overcome the situation, we have constructed high-resolution CGH-arrays as follows, (1) Whole Genome Array (WGA)-4500, which contains 4523 BACs throughout the whole genome, (2) Cancer Array-800, which harbors 800 BACs for different cancer-related genes, (3) 1p36-contig array, which covers about 20Mb spanning 1p36 region with 212 BACs, (4) Chromosome X-tiling array, which contains 1001 BACs throughout chromosome X except pseudo-autosomal region, and (5) Genome Disorder (GD)-array, which is employed as the diagnostic tool for known genomic disorders. Using those in-house BAC arrays, we explored cryptic chromosome aberrations in a large number of patients with MCA/MR, and detected de novo submicroscopic aberrations related to the pathogenesis of unknown MCA/MR in some of those patients.