title: The next generation of population-based spinal muscular atrophy carrier screening: comprehensive pan-ethnic SMN1 copy-number and sequence variant analysis by massively parallel sequencing.
abstract: To investigate pan-ethnic SMN1 copy-number and sequence variation by hybridization-based target enrichment coupled with massively parallel sequencing or next-generation sequencing (NGS).
  
  
  
  NGS reads aligned to SMN1 and SMN2 exon 7 were quantified to determine the total combined copy number of SMN1 and SMN2. The ratio of SMN1 to SMN2 was calculated based on a single-nucleotide difference that distinguishes the two genes. SMN1 copy-number results were compared between the NGS and quantitative polymerase chain reaction and/or multiplex ligation-dependent probe amplification. The NGS data set was also queried for the g.27134T>G single-nucleotide polymorphism (SNP) and other SMN1 sequence pathogenic variants.
  
  
  
  The sensitivity of the test to detect spinal muscular atrophy (SMA) carriers with one copy of SMN1 was 100% (95% confidence interval (CI): 95.9-100%; n = 90) and specificity was 99.6% (95% CI: 99.4-99.7%; n = 6,648). Detection of the g.27134T>G SNP by NGS was 100% concordant with an restriction fragment-length polymorphism method (n = 493). Ten single-nucleotide variants in SMN1 were detectable by NGS and confirmed by gene-specific amplicon-based sequencing. This comprehensive approach yielded SMA carrier detection rates of 90.3-95.0% in five ethnic groups studied.
  
  
  
  We have developed a novel, comprehensive SMN1 copy-number and sequence variant analysis method by NGS that demonstrated improved SMA carrier detection rates across the entire population examined.Genet Med advance online publication 19 January 2017.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Baylor Genetics Laboratories, Houston, Texas, USA.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Ge
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Linyan
authors.initials: L
authors.lastname: Meng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Jennifer
authors.identifier: 0000-0002-3953-1744
authors.initials: J
authors.lastname: Scull
authors.affiliation: Baylor Genetics Laboratories, Houston, Texas, USA.
authors.forename: Jianli
authors.identifier: 0000-0002-9856-0895
authors.initials: J
authors.lastname: Li
authors.affiliation: Baylor Genetics Laboratories, Houston, Texas, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Tian
authors.affiliation: Baylor Genetics Laboratories, Houston, Texas, USA.
authors.forename: Tao
authors.identifier: 0000-0003-4889-1044
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Baylor Genetics Laboratories, Houston, Texas, USA.
authors.forename: Weihong
authors.initials: W
authors.lastname: Jin
authors.affiliation: Baylor Genetics Laboratories, Houston, Texas, USA.
authors.forename: Hanyin
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Xia
authors.identifier: 0000-0002-7750-1167
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Tokita
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Mei
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yue
authors.identifier: 0000-0002-9197-9810
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Fangyuan
authors.identifier: 0000-0001-7516-3195
authors.initials: F
authors.lastname: Li
authors.affiliation: Baylor Genetics Laboratories, Houston, Texas, USA.
authors.forename: Eric S
authors.identifier: 0000-0002-4098-1275
authors.initials: ES
authors.lastname: Schmitt
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Wei V
authors.initials: WV
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Muzny
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Wen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yaping
authors.identifier: 0000-0001-5608-8628
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Arthur L
authors.identifier: 0000-0001-8285-5528
authors.initials: AL
authors.lastname: Beaudet
authors.affiliation: Current affiliation: AmCare Genomics Lab, Guangzhou, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Baylor Genetics Laboratories, Houston, Texas, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Lee-Jun
authors.initials: LJ
authors.lastname: Wong
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Jinglan
authors.identifier: 0000-0002-4600-7123
authors.initials: J
authors.lastname: Zhang
mesh_terms: D018628:Gene Dosage; D006580:Genetic Carrier Screening; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D009134:Muscular Atrophy, Spinal / Q000208:ethnology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics
chemical_list: C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein