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Presymptomatic Diagnosis of Spinal Muscular Atrophy Through Newborn Screening.
J Pediatr 2017; 190:124-129.e1JPed

Abstract

OBJECTIVE

To demonstrate the feasibility of presymptomatic diagnosis of spinal muscular atrophy (SMA) through newborn screening (NBS).

STUDY DESIGN

We performed a screening trial to assess all newborns who underwent routine newborn metabolic screening at the National Taiwan University Hospital newborn screening center between November 2014 and September 2016. A real-time polymerase chain reaction (RT-PCR) genotyping assay for the SMN1/SMN2 intron 7 c.888+100A/G polymorphism was performed to detect homozygous SMN1 deletion using dried blood spot (DBS) samples. Then the exon 7 c.840C>T mutation and SMN2 copy number were determined by both droplet digital PCR (ddPCR) using the original screening DBS and multiplex ligation-dependent probe amplification (MLPA) using a whole blood sample.

RESULTS

Of the 120 267 newborns, 15 tested positive according to the RT-PCR assay. The DBS ddPCR assay excluded 8 false-positives, and the other 7 patients were confirmed by the MLPA assay. Inclusion of the second-tier DBS ddPCR screening assay resulted in a positive prediction value of 100%. The incidence of SMA was 1 in 17 181 (95% CI, 1 in 8323 to 1 in 35 468). Two of the 3 patients with 2 copies of SMN2 and all 4 patients with 3 or 4 copies of SMN2 were asymptomatic at the time of diagnosis. Five of the 8 false-positives were caused by intragenic recombination between SMN1 and SMN2.

CONCLUSION

Newborn screening can detect patients affected by SMA before symptom onset and enable early therapeutic intervention. A combination of a RT-PCR and a second-tier ddPCR can accurately diagnose SMA from DBS samples with no false-positives.

TRIAL REGISTRATION

ClinicalTrials.gov NCT02123186.

Authors+Show Affiliations

Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan; Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan; Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Pediatrics and Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.Genephile Bioscience Laboratory, Ko's Obstetrics and Gynecology, Taipei, Taiwan.Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan; Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: hwuwlntu@ntu.edu.tw.

Pub Type(s)

Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28711173

Citation

Chien, Yin-Hsiu, et al. "Presymptomatic Diagnosis of Spinal Muscular Atrophy Through Newborn Screening." The Journal of Pediatrics, vol. 190, 2017, pp. 124-129.e1.
Chien YH, Chiang SC, Weng WC, et al. Presymptomatic Diagnosis of Spinal Muscular Atrophy Through Newborn Screening. J Pediatr. 2017;190:124-129.e1.
Chien, Y. H., Chiang, S. C., Weng, W. C., Lee, N. C., Lin, C. J., Hsieh, W. S., ... Hwu, W. L. (2017). Presymptomatic Diagnosis of Spinal Muscular Atrophy Through Newborn Screening. The Journal of Pediatrics, 190, pp. 124-129.e1. doi:10.1016/j.jpeds.2017.06.042.
Chien YH, et al. Presymptomatic Diagnosis of Spinal Muscular Atrophy Through Newborn Screening. J Pediatr. 2017;190:124-129.e1. PubMed PMID: 28711173.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Presymptomatic Diagnosis of Spinal Muscular Atrophy Through Newborn Screening. AU - Chien,Yin-Hsiu, AU - Chiang,Shu-Chuan, AU - Weng,Wen-Chin, AU - Lee,Ni-Chung, AU - Lin,Ching-Jie, AU - Hsieh,Wu-Shiun, AU - Lee,Wang-Tso, AU - Jong,Yuh-Jyh, AU - Ko,Tsang-Ming, AU - Hwu,Wuh-Liang, Y1 - 2017/07/12/ PY - 2017/02/03/received PY - 2017/05/15/revised PY - 2017/06/16/accepted PY - 2017/7/18/pubmed PY - 2017/11/29/medline PY - 2017/7/17/entrez KW - SMN1 KW - newborn screening KW - real-time PCR KW - recombination KW - spinal muscular atrophy SP - 124 EP - 129.e1 JF - The Journal of pediatrics JO - J. Pediatr. VL - 190 N2 - OBJECTIVE: To demonstrate the feasibility of presymptomatic diagnosis of spinal muscular atrophy (SMA) through newborn screening (NBS). STUDY DESIGN: We performed a screening trial to assess all newborns who underwent routine newborn metabolic screening at the National Taiwan University Hospital newborn screening center between November 2014 and September 2016. A real-time polymerase chain reaction (RT-PCR) genotyping assay for the SMN1/SMN2 intron 7 c.888+100A/G polymorphism was performed to detect homozygous SMN1 deletion using dried blood spot (DBS) samples. Then the exon 7 c.840C>T mutation and SMN2 copy number were determined by both droplet digital PCR (ddPCR) using the original screening DBS and multiplex ligation-dependent probe amplification (MLPA) using a whole blood sample. RESULTS: Of the 120 267 newborns, 15 tested positive according to the RT-PCR assay. The DBS ddPCR assay excluded 8 false-positives, and the other 7 patients were confirmed by the MLPA assay. Inclusion of the second-tier DBS ddPCR screening assay resulted in a positive prediction value of 100%. The incidence of SMA was 1 in 17 181 (95% CI, 1 in 8323 to 1 in 35 468). Two of the 3 patients with 2 copies of SMN2 and all 4 patients with 3 or 4 copies of SMN2 were asymptomatic at the time of diagnosis. Five of the 8 false-positives were caused by intragenic recombination between SMN1 and SMN2. CONCLUSION: Newborn screening can detect patients affected by SMA before symptom onset and enable early therapeutic intervention. A combination of a RT-PCR and a second-tier ddPCR can accurately diagnose SMA from DBS samples with no false-positives. TRIAL REGISTRATION: ClinicalTrials.gov NCT02123186. SN - 1097-6833 UR - https://www.unboundmedicine.com/medline/citation/28711173/Presymptomatic_Diagnosis_of_Spinal_Muscular_Atrophy_Through_Newborn_Screening_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-3476(17)30892-2 DB - PRIME DP - Unbound Medicine ER -