Presymptomatic Diagnosis of Spinal Muscular Atrophy Through Newborn Screening

• Published in: The Journal of pediatrics 2017-11, Vol.190, p.124-129.e1
• Main Authors: Chien, Yin-Hsiu, Chiang, Shu-Chuan, Weng, Wen-Chin, Lee, Ni-Chung, Lin, Ching-Jie, Hsieh, Wu-Shiun, Lee, Wang-Tso, Jong, Yuh-Jyh, Ko, Tsang-Ming, Hwu, Wuh-Liang
• Format: Article
• Language: English
• Subjects: Early Diagnosis; Female; Humans; Infant; Infant, Newborn; Male; Muscular Atrophy, Spinal - diagnosis; Neonatal Screening - methods; newborn screening; Pilot Projects; real-time PCR; Real-Time Polymerase Chain Reaction - methods; recombination; SMN1; spinal muscular atrophy; Survival of Motor Neuron 1 Protein - genetics; Survival of Motor Neuron 2 Protein - genetics; Taiwan
• ISSN: 0022-3476; 1097-6833
• DOI: 10.1016/j.jpeds.2017.06.042

To demonstrate the feasibility of presymptomatic diagnosis of spinal muscular atrophy (SMA) through newborn screening (NBS). 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. 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. 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. ClinicalTrials.gov NCT02123186.