| 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. |
| Publication Type | Journal Article |
| Year of Publication | 2017 |
| Authors | Feng, Y, Ge, X, Meng, L, Scull, J, Li, J, Tian, X, Zhang, T, Jin, W, Cheng, H, Wang, X, Tokita, M, Liu, P, Mei, H, Wang, Y, Li, F, Schmitt, ES, Zhang, WV, Muzny, DM, Wen, S, Chen, Z, Yang, Y, Beaudet, AL, Liu, X, Eng, CM, Xia, F, Wong, L-J, Zhang, J |
| Journal | Genet Med |
| Volume | 19 |
| Issue | 8 |
| Pagination | 936-944 |
| Date Published | 2017 Aug |
| ISSN | 1530-0366 |
| Keywords | Gene Dosage, Genetic Carrier Screening, High-Throughput Nucleotide Sequencing, Humans, Muscular Atrophy, Spinal, Polymorphism, Single Nucleotide, Reproducibility of Results, Sensitivity and Specificity, Survival of Motor Neuron 1 Protein, Survival of Motor Neuron 2 Protein |
| Abstract | PURPOSE: 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).METHODS: 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.RESULTS: 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.CONCLUSION: 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.
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| DOI | 10.1038/gim.2016.215 |
| Alternate Journal | Genet Med |
| PubMed ID | 28125085 |