Bae Joon Seol, Koh InSong, Cheong Hyun Sub, Seo Jeong-Meen, Kim Dae-Yeon, Oh Jung-Tak, Kim Hyun-Young, Jung Kyuwhan, Sul Jae Hoon, Park Woong-Yang, Kim Jeong-Hyun, Shin Hyoung Doo
Laboratory of Translational Genomics, Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea.
Department of Physiology, College of Medicine, Hanyang University, Seoul, Republic of Korea.
Transl Res. 2016 Nov;177:31-40.e6. doi: 10.1016/j.trsl.2016.06.001. Epub 2016 Jun 14.
Hirschsprung disease (HSCR) is a neurocristopathy characterized by the absence of intramural ganglion cells along variable lengths of the gastrointestinal tract. Although the RET proto-oncogene is considered to be the main risk factor for HSCR, only about 30% of the HSCR cases can be explained by variations in previously known genes including RET. Recently, copy number variation (CNV) and loss of heterozygosity (LOH) have emerged as new ways to understand human genomic variation. The goal of this present study is to identify new HSCR genetic factors related to CNV in Korean patients. In the genome-wide genotyping, using Illumina's HumanOmni1-Quad BeadChip (1,140,419 markers), of 123 HSCR patients and 432 unaffected subjects (total n = 555), a total of 8,188 CNVs (1 kb ∼ 1 mb) were identified by CNVpartition. As a result, 16 CNV regions and 13 LOH regions were identified as associated with HSCR (minimum P = 0.0005). Two top CNV regions (deletions at chr6:32675155-32680480 and chr22:20733495-21607293) were successfully validated by additional real-time quantitative polymerase chain reaction analysis. In addition, 2 CNV regions (6p21.32 and 22q11.21) and 2 LOH regions (3p22.2 and 14q23.3) were discovered to be unique to the HSCR patients group. Regarding the large-scale chromosomal aberrations (>1 mb), 11 large aberrations in the HSCR patients group were identified, which suggests that they may be a risk factor for HSCR. Although further replication in a larger cohort is needed, our findings may contribute to the understanding of the etiology of HSCR.
先天性巨结肠症（HSCR）是一种神经嵴病，其特征是沿胃肠道不同长度的肠壁内神经节细胞缺失。尽管RET原癌基因被认为是HSCR的主要危险因素，但只有约30%的HSCR病例可由包括RET在内的先前已知基因的变异来解释。最近，拷贝数变异（CNV）和杂合性缺失（LOH）已成为理解人类基因组变异的新途径。本研究的目的是在韩国患者中鉴定与CNV相关的新的HSCR遗传因素。在对123例HSCR患者和432例未受影响的受试者（共555例）使用Illumina公司的HumanOmni1-Quad BeadChip（1,140,419个标记）进行全基因组基因分型时，通过CNVpartition共鉴定出8188个CNV（1 kb至1 mb）。结果，16个CNV区域和13个LOH区域被鉴定为与HSCR相关（最小P = 0.0005）。通过额外的实时定量聚合酶链反应分析成功验证了两个顶级CNV区域（6号染色体：32675155 - 32680480处的缺失和22号染色体：20733495 - 21607293处的缺失）。此外，发现2个CNV区域（6p21.32和22q11.21）和2个LOH区域（3p22.2和14q23.3）是HSCR患者组所特有的。关于大规模染色体畸变（>1 mb），在HSCR患者组中鉴定出11个大的畸变，这表明它们可能是HSCR的一个危险因素。尽管需要在更大的队列中进一步验证，但我们的发现可能有助于理解HSCR的病因。
