▪ 染色体结构变化 ➢ More than 200 known disorders ➢ More than 1000 rare abnormalities
▪ 单基因病 (more than 8,000) ➢ Dominant ➢ Recessive
▪ 线粒体病 ▪ 多基因病
➢ Genes + Environments
肿瘤也是基因及基因组病
➢ 人类有60多种恶性肿瘤 ➢ 所有肿瘤都含有基因及基因组异常
Thompson & Thompson Genetics In Medicine. Eighth Edition
中国年出生1600万，出生陷发生率在5.6%, 每年新增出生缺陷数约90万例。 (婴儿在出生的一年内，体格上出现明显的结构异常和需要手术矫正的畸形）
CMA applications for clinical service
遗传病的基因及基因组检测
肿瘤的基因及基因组检测
❖ 受孕胚胎植入前的基因及基因组检测 ❖ 产前筛查及诊断 ❖ 新生儿筛查及诊断
❖ 遗传病病人（儿童及成人）诊断
❖ 健康人群隐性遗传病携带者检出 ❖ 健康及亚健康人群疾病易感基因检测
Validation-Agilent aCGH-244K
Yu, S. Bittel, DC. Kibiryeva, N. Zwick, D L. Cooley, LD. Validation of the Agilent 244K oligonucleotide array-based comparative genomic hybridization platform for clinical cytogenetic diagnosis. Am J Clin Pathol 2009;132(3):349-60.
基因芯片技术(microarray) 的临床应用
人类基因及基因组
➢ 23 对染色体--- 2 x 30 亿个碱基 ➢ 编码 21,000 个基因 ---编码序列占整个基因组 的1.5%
基因及基因组病 （遗传病）
▪ 染色体数量异常 ➢ Trisomy 21 （唐氏综合症） ➢ Trisomy 18 ➢ Trisomy 13 ➢ Sex chromosomal aneuploidies ➢ Mosaic trisomies of other chromosomes
Classification of Copy Number Variants identified by CMA based on their clinical significances
➢ Pathogenic ➢ Likely pathogenic ➢ Uncertain clinical significance ➢ Likely benign ➢ benign
➢ Future Trends of CMA for Clinical Service
aCGH techniques
Principles of CMAs
SNP microarray
1992 2003 2005
➢ Indicating the presence of uniparental disomy (UPD)
➢ Indicating the presence of consanguinity ➢ Indicating the presence of shared ancestry ➢ Identify recessive gene mutations ➢ Confirm CNV calls by checking SNP allele patterns ➢ Increase sensitivity for detection of mosaicism ➢ Identify triploidy for which aCGH fails to detect ➢ Determine parental origin of a de novo CNV ➢ Improves our understanding of genetic aberrations ➢ Enhances the quality control in the diagnostic laboratory workflow ➢ Identify genomic regions with LOH related to tumorigenesis
二代测序（NGS）
超高效 液相色谱
蛋白质及代 谢产物检测
酶学检测
电感耦合等 离子体质谱
高效液相色谱 -串联质谱
Chromosome Microarray Analysis (CMA)
➢ Principles of CMA
➢ Current Status of CMA Application for Clinical Service
Verification of aCGH findings
Yu S, Kielt, M, Stegner A, Bittel, DC. Cooley, LD. Application of Quantitative Real-Time PCR Methods for the Verification of Genomic Imbalances Detected by Microarray-based Comparative Genomic Hybridization. Genet Test Mol Biomarkers 2009;13(6):751-60.
➢智力低下 ➢迟发性疾病 ➢-------
遗传病的实验室诊断
原位荧光杂交 （FISH）
基因芯片 （Microarray）
一代测序 （Sanger Sequencing）
气相色谱-质谱
基因/基因组 检测
核型分析 （Karyotyping）
非测序分子生物学技术 （non-DNA techniques）
➢ 遗传性肿瘤携带者检出 ➢ 无症状早期筛查 ➢ 分子诊断 ➢ 靶向药物的选择 ➢ 预后判断 ➢ 治疗监控 ➢ 复发基因克隆检出
Validations of CMA platforms for Clinical Services
➢ Technical Validations ➢ Clinical Validations