title: Copy number variation sequencing for comprehensive diagnosis of chromosome disease syndromes.
abstract: Detection of chromosome copy number variation (CNV) plays an important role in the diagnosis of patients with unexplained clinical symptoms and for the identification of chromosome disease syndromes in the established fetus. In current clinical practice, karyotyping, in conjunction with array-based methods, is the gold standard for detection of CNV. To increase accessibility and reduce patient costs for diagnostic CNV tests, we speculated that next-generation sequencing methods could provide a similar degree of sensitivity and specificity as commercial arrays. CNV in patient samples was assessed on a medium-density single nucleotide polymorphism array and by low-coverage massively parallel CNV sequencing (CNV-seq), with mate pair sequencing used to confirm selected CNV deletion breakpoints. A total of 10 ng of input DNA was sufficient for accurate CNV-seq diagnosis, although 50 ng was optimal. Validation studies of samples with small CNVs showed that CNV-seq was specific and reproducible, suggesting that CNV-seq may have a potential genome resolution of approximately 0.1 Mb. In a blinded study of 72 samples with known gross and submicroscopic CNVs originally detected by single nucleotide polymorphism array, there was high diagnostic concordance with CNV-seq. We conclude that CNV-seq is a viable alternative to arrays for the diagnosis of chromosome disease syndromes.
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Desheng
authors.initials: D
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Weigang
authors.initials: W
authors.lastname: Lv
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Linbei
authors.initials: L
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Yanghui
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Haoxian
authors.initials: H
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Pu
authors.initials: P
authors.lastname: Yang
authors.affiliation: Berry Genomics Co., Ltd., Beijing, China.
authors.forename: Jianguang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Berry Genomics Co., Ltd., Beijing, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Song
authors.affiliation: Berry Genomics Co., Ltd., Beijing, China.
authors.forename: Genming
authors.initials: G
authors.lastname: Xu
authors.affiliation: Berry Genomics Co., Ltd., Beijing, China. Electronic address: david.cram@berrygenomics.com.
authors.forename: David S
authors.initials: DS
authors.lastname: Cram
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China. Electronic address: wulingqian@sklmg.edu.cn.
authors.forename: Lingqian
authors.initials: L
authors.lastname: Wu
mesh_terms: D025063:Chromosome Disorders / Q000175:diagnosis* / Q000235:genetics*; D056915:DNA Copy Number Variations; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007621:Karyotyping; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D012303:Ring Chromosomes; D012680:Sensitivity and Specificity; D017384:Sequence Deletion; D013577:Syndrome